Abstract
The human genome is ‘pervasively transcribed’ leading to a complex array of non-coding RNAs (ncRNAs) that far outnumber coding mRNAs. ncRNAs have regulatory roles in transcription and post-transcriptional processes as well numerous cellular functions that remain to be fully described. Best characterized of the ‘expanding universe’ of ncRNAs are the ~22 nucleotide microRNAs (miRNAs) that base-pair to target mRNA’s 3′ untranslated region within the RNA-induced silencing complex (RISC) and block translation and may stimulate mRNA transcript degradation. Long non-coding RNAs (lncRNAs) are classified as >200 nucleotides in length, but range up to several kb and are heterogeneous in genomic origin and function. lncRNAs fold into structures that interact with DNA, RNA and proteins to regulate chromatin dynamics, protein complex assembly, transcription, telomere biology and splicing. Some lncRNAs act as sponges for miRNAs and decoys for proteins. Nuclear-encoded lncRNAs can be taken up by mitochondria and lncRNAs are transcribed from mtDNA. Both miRNAs and lncRNAs are dysregulated in endocrine cancers. This review provides an overview on the current understanding of the regulation and function of selected lncRNAs and miRNAs, and their interaction, in endocrine-related cancers: breast, prostate, endometrial and thyroid.
Introduction
Cancer is a disease of the genome in which tumors have a constellation of genomic and epigenetic alterations that drive their clinical behavior and patient prognosis (Macconaill & Garraway 2010). The Central Dogma proposed by Francis Crick in 1958 envisioned that information flowed from DNA to mRNA, which is translated into functional proteins with the assistance of tRNA and rRNA (reviewed in Morris & Mattick 2014, Jarroux et al. 2017). With time, additional classes of RNA that have important regulatory roles in cellular biology were discovered: short nuclear and small nucleolar RNAs (snRNAs and snoRNAs), followed by microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). The Encyclopedia of DNA Elements (ENCODE) Consortium was started in 2003 as an international collaboration funded by the National Human Genome Institute (NHGRI). Analysis of the human genome revealed that while ~85% is transcribed, only ~1% is protein-coding mRNA (ENCODE Project Consortium 2012, Djebali et al. 2012, Dykes & Emanueli 2017). The GENCODE consortium (https://www.gencodegenes.org/) is a subproject of ENCODE that produces high-quality reference gene annotation and experimental validation. The current GENECODE, version 27 of the human genome includes 58,288 genes; 200,401 total transcripts; 19,826 protein-coding genes; 15,778 lncRNAs; 14,694 pseudogenes; 7569 small non-coding RNA (ncRNA) genes and 1881 miRNAs. Most (85%) small ncRNAs are snRNAs, snoRNAs, miRNAs and tRNAs (Djebali et al. 2012). In addition to GENECODE, the FANTOM (Functional Annotation of Mammalian Genomes) project is creating a comprehensive catalog of transcripts encoded in human, mouse, rat, dog, Rhesus monkey and chicken genomes (http://fantom.gsc.riken.jp) (Kawaji et al. 2017). Analysis of data from FANTOM5 identified 27,919 human lncRNA genes with high-confidence 5′ ends and provided evidence that 69% (19,175) are functional (Hon et al. 2017). The history of the discovery of regulatory RNAs, notably the ncRNAs, has been reviewed (Morris & Mattick 2014).
The advent of next-generation sequencing (NGS) by RNA sequencing (RNA-seq), also called ‘whole transcriptome shotgun sequencing’ and ‘deep RNA-seq’, has allowed characterization of the cellular transcriptomes, i.e., the entire spectrum of RNAs produced in a cell type (Wolf 2013), resulting in a glut of data that can be mined by investigators. One database of transcriptomes of potential interest for readers of this review is the NURSA website (www.nursa.org). The transcriptome includes mRNA, rRNA and tRNA; and the ncRNAs: miRNAs, enhancer RNAs (eRNAs), endogenous small-interfering RNAs (siRNAs), Piwi-interacting RNAs (piRNAs), circular RNAs (circRNAs) and lncRNAs (Marrone et al. 2014). Table 1 highlights features of these ncRNAs and their roles in cellular processes. The function of piRNAs and snoRNAs in endocrine-related cancers was reviewed (Venkatesh et al. 2015). miRNAs are best characterized for their gene silencing of target mRNA by complementary base-paring with the 3′UTR within the RNA-induced silencing complex (RISC) to repress translation and/or cause mRNA degradation (Muluhngwi & Klinge 2015). Like miRNAs, siRNAs and piRNAs bind argonaute (AGO) family members and base-pair with target RNA to cause RNA degradation and/or translation repression (Watanabe & Lin 2014). Studies have shown that RNA polymerase (pol) II-mediated transcriptional activity at gene enhancers is ‘pervasive’ and bidirectional, generally producing transcripts in both directions including short eRNAs that play roles in enhancer–promoter interactions (reviewed in Lam et al. 2014). Enhancers are relatively insensitive to position and distance of their target genes and about half are intragenic, which can result in inhibition or attenuation of nascent transcript elongation (Cinghu et al. 2017). circRNAs are usually formed by noncannonical splice reactions and reside in the cytoplasm where one circRNA, CDR1AS, regulates miR-7 stability and transport in neurons (Piwecka et al. 2017).
Summary of ncRNAs in humans, excluding rRNA and tRNA, with their size, cellular location, aspects of biogenesis, function, citations for reviews for roles in various endocrine-related cancers and websites.
| ncRNA | Description, size, location, function and example of findings in endocrine cancers | Websites |
|---|---|---|
| miRNA | ~21 nt ssRNA
| miRBase http://www.mirbase.org miRTarBase: experimentally validated miRNA-target Interactions http://miRTarBase.mbc.nctu.edu.tw miRAD: intragenic miRNA database http://bmi.ana.med.uni-muenchen.de/miriad/ MAGIA http://gencomp.bio.unipd.it/magia/start/ TargetScanHuman search for predicated miRNA targets http://www.targetscan.org/vert_71/ IsomiRage http://cru.genomics.iit.it/Isomirage/ |
| circRNAs | Circular RNAs: 4 types: exonic circRNAs (ecircRNA), circular RNAs from introns, exon–intron circRNAs (EIciRNA) and intergenic circRNAs (Meng et al. 2017)
| CIRCexplorer (Yang et al. 2017c) https://omictools.com/circexplorer-tool CIRI https://omictools.com/ciri-tool CircRNA_finder https://omictools.com/circrna-finder-tool MapSplice 2 for mapping RNA-seq data to ref genome for splice junction discovery http://www.netlab.uky.edu/p/bioinfo/MapSplice2 CirclncRNAnet (RRIC:SCR_015794) https://dknet.org/scicrunch/Resources/record/nlx_144509-1/2d26f6b1-5909-5066-a261-a05ca13e12d9/search?mc_cid=23e8e71213&mc_eid=ed4995675c |
| eRNAs | Enhancer RNAs are produced from enhancers (Lam et al. 2014)
| |
| piRNA | PIWI-interacting RNAs
| |
| Endo-siRNA | Endogenous small-interfering RNAs
| |
| lncRNAs | Long non-coding RNAs
| HUGO Gene Nomenclature Committee lncRNAs https://www.genenames.org/cgi-bin/genefamilies/set/788 NONCODE v. 5.0 ncRNA http://www.noncode.org/ lncRNASNP2 is a database of functional SNPs and mutations in human and mouse lncRNAs http://bioinfo.life.hust.edu.cn/lncRNASNP2 Websites reviewed in (Fritah et al. 2014) LNCipedia 4.1 https://lncipedia.org/ (146,742 human annotated lncRNAs) DIANA-LncBase v.2 includes miRNA:lncRNA interactions (Paraskevopoulou et al. 2016) NONCODE v5.0 http://www.noncode.org/index.php |
| Predicting miRNA/target duplex (Rehmsmeier et al. 2004) has been used to examine miRNA/lncRNA interaction (Zhou et al. 2017) | http://bibiserv.techfak.uni-bielefeld.de/rnahybrid/ |
Both miRNAs and lncRNAs are epigenetic regulators of human cancers (Liz & Esteller 2016). Moreover, these RNAs are chemically modified, e.g., by post-transcriptional methylation on N6 of adenosine (m6A), which alters their activities, providing an additional layer of regulation termed ‘epitranscriptomics’ (Li et al. 2016c). Many more papers have been published on miRNAs than lncRNAs in endocrine cancers (Fig. 1). This review provides a brief overview of the identity, regulation and roles of miRNAs and lncRNAs in selected endocrine-related cancers. Because of the scope of published literature on these topics, this review is not a comprehensive analysis of lncRNAs and miRNAs in breast, prostate, endometrial and thyroid cancers. The reader is provided with citations to recent reviews and primary literature for further information.
PubMed referenced papers on miRNAs and lncRNAs for endocrine cancers. Values were determined on November 28, 2017.
Citation: Endocrine-Related Cancer 25, 4; 10.1530/ERC-17-0548
PubMed referenced papers on miRNAs and lncRNAs for endocrine cancers. Values were determined on November 28, 2017.
Citation: Endocrine-Related Cancer 25, 4; 10.1530/ERC-17-0548
PubMed referenced papers on miRNAs and lncRNAs for endocrine cancers. Values were determined on November 28, 2017.
Citation: Endocrine-Related Cancer 25, 4; 10.1530/ERC-17-0548
lncRNAs: classification and functional activities
lncRNAs are defined as ncRNAs of >200 nucleotides that are transcribed by RNA pol II from regulatory regions including promoter upstream elements and technically include eRNAs (Andersson et al. 2014). However, eRNAs differ from lncRNAs by being shorter (<2 kbp), without being spliced and are not polyadenylated (Kim et al. 2015). By total cellular RNA mass, lncRNA constitutes only 0.03–0.2% while mRNA constitute 3–7% (Dykes & Emanueli 2017). lncRNAs are classified based on their genomic organization: (1) intergenic lncRNAs (lincRNAs) are transcribed between two protein-coding genes; (2) intronic lncRNAs are transcribed from introns of protein-coding genes; (3) overlapping lncRNAs, as the name implies, constitute transcripts that overlap known protein-coding genes; and (4) antisense (as) lncRNAs are transcribed in a direction opposite that of the protein-coding gene (Peng et al. 2017b) (Fig. 2). Pseudogenes that arise from DNA duplication of coding genes followed by inactivating mutations that render the pseudogene non-coding are transcribed as lncRNAs and sequester some of the miRNAs that interact with conserved miRNA response elements (MREs) in the functional gene (Dykes & Emanueli 2017). However, given the low levels of lncRNA, the functional role of lncRNAs as ‘miRNA sponges’ by base-pairing and thus blocking miRNA-MRE binding to target mRNA-3′UTRs, is debated. It seems likely that more highly expressed lncRNAs (with higher FKPM (Fragments Per Kilobase Million reads in RNA-seq)) would be more likely to act as competing endogenous RNA (ceRNA) to sequester miRNAs (Dykes & Emanueli 2017). Additional classifications of lncRNAs are by (1) length, e.g. very long lincRNA (vlincRNA); (2) being encoded within specific DNA regulator elements and loci, e.g., in telomeres (TERRA), centromeres, rDNA loci (PAPAS) or 3′UTR-associated RNAs (uaRNA); (3) biogenesis pathway; (4) subcellular localization or origin, e.g., nuclear, cytoplasmic or mitochondrial; (5) function, e.g., scaffold lncRNA (HOTAIR) and (6) association with specific biological processes (Jarroux et al. 2017).
Classification of lncRNAs based on their location and transcription in relation to protein-coding genes. Gene structure is diagramed 5′–3′, left to right, for RNA pol II transcription.
Citation: Endocrine-Related Cancer 25, 4; 10.1530/ERC-17-0548
Classification of lncRNAs based on their location and transcription in relation to protein-coding genes. Gene structure is diagramed 5′–3′, left to right, for RNA pol II transcription.
Citation: Endocrine-Related Cancer 25, 4; 10.1530/ERC-17-0548
Classification of lncRNAs based on their location and transcription in relation to protein-coding genes. Gene structure is diagramed 5′–3′, left to right, for RNA pol II transcription.
Citation: Endocrine-Related Cancer 25, 4; 10.1530/ERC-17-0548
lncRNAs show chromatin marks that are typical of transcribed coding genes: H3K4me3 for transcription initiation and H3K36me3 for elongation (Rinn & Chang 2012) and are regulated by transcription factors binding to their promoters. lncRNAs are alternatively spliced, thus generating isoforms. lncRNAs associated with enhancer regions can act in cis, leading to increased transcription of neighboring genes, including other lncRNAs (Ørom Ulf & Shiekhattar 2013). Some lncRNAs directly bind target mRNAs which can either target the mRNA for degradation or stabilize the transcript. A class of lncRNAs called ‘activating ncRNA-as’ specifically activate neighboring coding genes by binding to specific DNA sequences while associating with the Mediator-cohesin complex to loop enhancer/promoter regions (Dykes & Emanueli 2017). Despite their length, which can be several kb, lncRNAs do not have a functional protein-encoding capacity, i.e., those that contain small open reading frames (ORFs) do not form a template for translation (Hu et al. 2012).
As indicated in the Introduction, the number of human lncRNAs varies between databases. For example, the NONCODE v5 database includes 96,308 lncRNA genes (Xiyuan et al. 2017) compared with 15,778 in GENECODE and 27,919 in FANTOM (Hon et al. 2017). lncRNAs are expressed in a tissue-specific manner and are usually 5′-end capped and some are 3′-end polyadenylated (Li et al. 2016a). Some lncRNAs, e.g., MALAT1 and NEAT1, have a triple-helical structure at the 3′end that protects them from degradation. The landscape of isoforms of lncRNAs adds to the complexity of understanding lncRNA function (Ziegler & Kretz 2017). In addition, the presence of lncRNA modifications and lncRNA editing has been reported and associated with structural and functional changes, which further increases the variety of lncRNAs (reviewed in Ziegler & Kretz 2017). For example, m6A modification is required for XIST1-mediated gene silencing (Patil et al. 2016). Accumulating evidence implicates roles for dysregulated lncRNAs in cancer (Huarte 2015), autoimmune and inflammatory diseases (Chen et al. 2017), including type 1 (Mirza et al. 2017) and type 2 diabetes (Motterle et al. 2016, Leti & DiStefano 2017) and other diseases.
lncRNA function depends on cellular location (Fig. 3). lncRNAs fold in various conformations that allows interaction with RNA, DNA and proteins to regulate nuclear, cytoplasmic (Delas & Hannon 2017) and mitochondrial function (De Paepe et al. 2017). lncRNAs regulate processes including gene transcription, chromatin dynamics, chromatin looping, histone modifications, telomere biology, protein complex assembly, RNA splicing and translation (Mercer & Mattick 2013). Within the nucleus, specific lncRNAs, including AIRN, ANRIL, HOTAIR and XIST interact with specific transcription factors, enzymes involved in DNA methylation (DNMT1), chromatin modification (HDAC1, EZH2 (a lysine N-methyltransferase)) and polycomb repressive complex 2 (PRC2) (Nakagawa & Kageyama 2014). lncRNAs are involved in assembly of active e.g., NEAT1, or repressed, e.g., XIST, nuclear chromatin domains in a cell-dependent manner (Rinn & Guttman 2014). NEAT1 is an architectural RNA that interacts with >60 RNA-binding proteins and transcription factors in paraspeckles (Yamazaki & Hirose 2015). NEAT1 is also acts as a ‘sponge’ for miR-214 and mIR-101, thus upregulating targets of these miRNAs, i.e., HMGA1 and EZH2, respectively (Qian et al. 2017, Wang et al. 2017a,c). Thus, many biological processes are regulated by lncRNAs including cell differentiation, proliferation and survival.
Examples of interactions of lncRNAs and miRNAs in endocrine-related cancers. Not all these interactions may be expected in one cell type. lncRNAs can act in cis on an adjacent gene to regulate its transcription and translation. An example is HOTAIR’s interaction with AR (Zhang et al. 2015a). Nuclear miRNAs can be transported into mitochondria through unknown mechanisms and miRNAs are produced from the mtDNA genome (ds DNA plasmids shown), both are called ‘mitomiRs’. lncRNAs are transcribed from mtRNA and are called mitolncRNAs. Pri-miRNAs are process to pre-miRNAs by the Drosha microprocessor complex and exported by Exportin/RAN GTPase to the cytoplasm where they are cleaved into mature miRNAs by DICER which interacts with the lncRNA SRA1 (Redfern et al. 2013). LINbib1139 acts as a scaffold for PIP3, BRK, LRK2 and GPNMB, which leads to HIF-1α phosphorylation (Lin et al. 2017). MALAT1 acts as a ceRNA and ‘sponges’ miRNAs including miR-101, miR-125b and mIR-217 (Table 2 and Supplementary Table 1).
Citation: Endocrine-Related Cancer 25, 4; 10.1530/ERC-17-0548
Examples of interactions of lncRNAs and miRNAs in endocrine-related cancers. Not all these interactions may be expected in one cell type. lncRNAs can act in cis on an adjacent gene to regulate its transcription and translation. An example is HOTAIR’s interaction with AR (Zhang et al. 2015a). Nuclear miRNAs can be transported into mitochondria through unknown mechanisms and miRNAs are produced from the mtDNA genome (ds DNA plasmids shown), both are called ‘mitomiRs’. lncRNAs are transcribed from mtRNA and are called mitolncRNAs. Pri-miRNAs are process to pre-miRNAs by the Drosha microprocessor complex and exported by Exportin/RAN GTPase to the cytoplasm where they are cleaved into mature miRNAs by DICER which interacts with the lncRNA SRA1 (Redfern et al. 2013). LINbib1139 acts as a scaffold for PIP3, BRK, LRK2 and GPNMB, which leads to HIF-1α phosphorylation (Lin et al. 2017). MALAT1 acts as a ceRNA and ‘sponges’ miRNAs including miR-101, miR-125b and mIR-217 (Table 2 and Supplementary Table 1).
Citation: Endocrine-Related Cancer 25, 4; 10.1530/ERC-17-0548
Examples of interactions of lncRNAs and miRNAs in endocrine-related cancers. Not all these interactions may be expected in one cell type. lncRNAs can act in cis on an adjacent gene to regulate its transcription and translation. An example is HOTAIR’s interaction with AR (Zhang et al. 2015a). Nuclear miRNAs can be transported into mitochondria through unknown mechanisms and miRNAs are produced from the mtDNA genome (ds DNA plasmids shown), both are called ‘mitomiRs’. lncRNAs are transcribed from mtRNA and are called mitolncRNAs. Pri-miRNAs are process to pre-miRNAs by the Drosha microprocessor complex and exported by Exportin/RAN GTPase to the cytoplasm where they are cleaved into mature miRNAs by DICER which interacts with the lncRNA SRA1 (Redfern et al. 2013). LINbib1139 acts as a scaffold for PIP3, BRK, LRK2 and GPNMB, which leads to HIF-1α phosphorylation (Lin et al. 2017). MALAT1 acts as a ceRNA and ‘sponges’ miRNAs including miR-101, miR-125b and mIR-217 (Table 2 and Supplementary Table 1).
Citation: Endocrine-Related Cancer 25, 4; 10.1530/ERC-17-0548
Functional roles of lncRNAs in the cytoplasm including acting as a scaffold. For example, the RNA stem-loop structure of LINbib1139 (also called LINK-A) provides a scaffold for HBEGF (heparin-binding epidermal growth factor (EGF)-like growth factor)-triggered, EGF receptor (EGFR):GPNMB (glycoprotein NMB) heterodimer-mediated recruitment of PTK6 (protein tyrosine kinase 6, also called BRK) and LRRK2 (leucine-rich repeat kinase-2) for phosphorylation and stabilization of HIF-1α in MDA-MB-231 triple-negative breast cancer (TNBC) cells (Lin et al. 2016). LINbib1139 also binds phosphatidylinositol-3,4,5-trisphosphate (PIP3) and promotes AKT recruitment and phosphorylation (Lin et al. 2017). Several lncRNAs modulate mRNA stability (reviewed in Rashid et al. 2016). lncRNAs also associate with ribonucleoprotein complexes to regulate translation. For example, ZFAS1 associates with the 40S ribosome in the cytoplasm of MDA-MB-468 breast cancer (BCa) cells and is downregulated in breast tumors compared with normal breast tissue (Hansji et al. 2016).
Examples of lncRNAs dysregulated in endocrine-related cancers
Although many lncRNAs have been identified using bioinformatic approaches, relatively few have been functionally characterized and little is known about the mechanism(s) of action of even the best characterized lncRNAs. This review is not comprehensive with respect to lncRNAs in endocrine-related cancers, but summarizes representative lncRNAs that are best characterized (Table 2 and described below). Examples of recent reviews of lncRNAs include roles in: female reproductive cancers (Ong et al. 2017), BCa (Malih et al. 2015, Venkatesh et al. 2015, Miano et al. 2016, Niknafs et al. 2016, Warburton & Boone 2017), prostate cancer (PCa) (Alahari et al. 2016, Zhang et al. 2016a,c, Yang et al. 2017b) and thyroid cancer (Murugan et al. 2017).
Examples of the roles of selected lncRNAs identified in endocrine-related cancers. Name, size, and genome location information is summarized from the sources for lncRNAs in Table 1. Other information is from the references cited.
| lncRNA gene | Name, size, location | Interactions | Regulation | Endocrine cancer |
|---|---|---|---|---|
| PCA3 | Prostate cancer-associated 323,134 nt9q21.2Antisense lincRNA within PRUNE2 | PCA3 and PRUNE2 pre-mRNA are co-expressed and form a double-stranded RNA that recruits adenosine deaminase acting on RNA (ADAR) proteins to form a complex (Zhang et al. 2016a,c) | Increased by androgens in prostate cancer cells (Salameh et al. 2015)Suppressed by ERβ (Zhang et al. 2016a,c) | PCa-specific urine biomarker (Laxman et al. 2008); levels inversely correlate with the tumor suppressor PRUNE2 in human PCa specimens (Salameh et al. 2015) |
| GAS5 | Growth arrest specific 51q25.1The GAS5 gene has 12 exons that are alternatively spliced into 2 mature lncRNAs and GAS5 introns encode 10 snoRNAs (reviewed in Pickard & Williams 2014)Tumor suppressor | Forms hairpin structures and interacts with the DNA binding domain of GR to inhibit GR-GRE binding and GR-induced gene transcription (Kino et al. 2010)Represses onco-miR-21 (Zhang et al. 2013)Inhibited miR-103 in EC cells (Guo et al. 2015)Inhibited activation of the AKT/mTOR pathway in PC3 PCa cells (Xue et al. 2016a) | Low expression correlated with poor prognosis in thyroid cancer tissues (Guo et al. 2017); low expression in breast tumors from trastuzumab-treated patient (Li et al. 2016b)Lower in PCa tissues than normal prostate (Xue et al. 2016a) | |
| MEG3 | Maternally expressed 314q32.281,622 ntTumor suppressor | Binds miR-421 (Zhang et al. 2017c,e)Co-immunoprecipitates with PI3K in HEC-1B EC cells (Sun et al. 2017a) | Downregulated in breast (Zhang et al. 2016a,c, 2017c,e), prostate (Zhang et al. 2016a,c), endometrial (Guo et al. 2016b, Sun et al. 2017a), and PTC (Murugan et al. 2017) tumors |
One of the first characterized lncRNAs, HOTAIR (HOX Transcript Antisense RNA) is a 2.2 kb lncRNA found only in mammals and its structure is conserved, despite changed sequences, especially in its protein-binding segments, implying evolutionary importance (Jarroux et al. 2017). HOTAIR is transcribed from the HOXC locus from a position intergenic and antisense to the flanking HOXC11 and HOXC12 genes. HOTAIR facilitates the HOXD gene cluster for transcriptional repression by recruiting PRC2 (Rinn et al. 2007). Analysis of data in the Cancer Genome Atlas (TCGA) revealed that increased HOTAIR expression correlates with metastasis and poor prognosis in breast and prostate cancers (Weidle et al. 2017). HOTAIR is both nuclear and cytoplasmic and considered an onco-lncRNA because of its ability to promote papillary thyroid cancer (PTC) cell proliferation and silencing its expression inhibited cell growth (Zhu et al. 2016). HOTAIR is a scaffold for the PRC2 and LSD1 complexes affecting H3K27 methylation and H3K4 demethylation for epigenetic gene silencing promoting cancer metastasis (Wu et al. 2014). HOTAIR decreases oxidative phosphorylation (OXPHOS) complex III subunit VII (UQCRQ) protein expression, thus reducing OXPHOS efficiency and suggesting that HOTAIR is important for mitochondrial function in HeLa cells (Zheng et al. 2015).
According to Gene Cards (www.genecards.org), HOTAIR has binding sites for 70 proteins involved in transcriptional regulation including AGO1, SIN3A, REST, SUZ12, RELA, ROSL1, MAX, MAZ, NR2C2 (orphan NR TR4), TBP, EGR2, ELK4 and SP2. HOTAIR is upregulated by HIF-1α, histone methylase MLL1 and coactivator p300 (Bhan et al. 2017). HOTAIR was reported to be induced by E2 in MCF-7 BCa cells (Bhan et al. 2013), but others reported that E2-ERα directly that repressed HOTAIR in MCF-7 cells by binding to a genomic site 14.5 kb upstream of HOTAIR (Xue et al. 2016b). HOTAIR is downregulated by miR-141 (Chiyomaru et al. 2014) and is directly targeted by miR-34a in PCa cells (Chiyomaru et al. 2013). The 3′ domain of HOTAIR binds lysine-specific demethylase 1 (LSD1)-CoREST and PRC2 interacts with a 5′ domain. HOTAIR–PRC2 interaction represses targets, e.g., HOXD10, PTEN, miR-7 and WIF1, which leads to the activation of the Wnt/β-catenin signaling pathway (Hajjari & Salavaty 2015). HOTAIR binds androgen receptor (AR), blocking MDM2 interaction, and preventing AR ubiquitination and protein degradation, thus contributing to castration-resistant prostate cancer (CRPCa) progression (Zhang et al. 2015). HOTAIR is upregulated in endocrine-resistant BCa cells and its overexpression activates ERα transcriptional activity independent of ligand (Xue et al. 2016a). ERα interacts directly of HOTAIR in RNA pulldown assays using nuclear extracts from MCF-7 BCa cells (Xue et al. 2017). Overexpression of HOTAIR in MCF-7 cells grown under hormone-free (serum-starved) medium conditions increases the number of DNA sites to which ERα binds in chromatin immunoprecipitation assays (ChIP) and increases mRNA expression of some ERα target genes, e.g., GREB1, TFF1, PGR and CTSD (Xue et al. 2016b). The authors concluded that HOTAIR increases ligand-independent ERα transcription. This observation is concordant with a report of increased HOTAIR immunostaining in tamoxifen-resistant human breast tumors (Xue et al. 2016b).
In contrast, HOTAIR was not among the 20 lncRNAs identified as upregulated and 9 downregulated by ‘apo-ERα’ (non-ligand-occupied ERα) in a bioinformatic analysis of BCa cell lines and tumor tissues with experimental follow-up in MCF-7 cells (Miano et al. 2016). That study identified DSCAM-AS1 as the most apo-ERα-upregulated lncRNA and its expression was higher in luminal A and B breast tumors compared to normal breast, HER2+ or basal-like tumors. Knockdown of DSCAM-AS1 stimulated an increase in epithelial-to-mesenchymal (EMT) markers in MCF-7 cells. DSCAM-AS1 was also upregulated in prostate and lung tumors (Miano et al. 2016). A bioinformatics interrogation of 947 breast tumor RNA-seq libraries identified gene sets positively correlated with DSCAM-AS1 expression as significantly associated with clinical signatures of cancer aggression, tamoxifen resistance, higher grade, stage and metastasis (Niknafs et al. 2016).
HOTAIR interacts with ERβ in a complex with eNOS on gene promoters to stimulate transcription in LNCaP PCa cells and a primary prostate tumor-derived cell line (called C27IM) and with ERα/eNOS in MCF-7 cells (Aiello et al. 2016). A potential concern with regard to the conclusion of the ChIPping of ERβ is the notorious lack of specificity of ERβ antibodies (Andersson et al. 2017, Nelson et al. 2017). HOTAIR is upregulated in endometrial cancer (EC) (Smolle et al. 2015) and contributes to cisplatin resistance by inhibiting autophagy (Sun et al. 2017b). HOTAIR is highly expressed in ovarian cancer (Luo et al. 2017); endometrial, ovarian and cervical cancers (Li et al. 2017a) and thyroid cancers (Zhang et al. 2017c,e), including PTC (Zhu et al. 2016).
MALAT1 (metastasis-associated lung adenocarcinoma transcript 1, 8755 nt) is another well-studied lncRNAs with roles in endocrine-related cancers (reviewed in Zhang et al. 2017d). MALAT1 is expressed in almost all human tissues and is conserved across 33 mammalian species (Jarroux et al. 2017). MALAT1 lacks a poly A tail, but has a genomically encoded poly A tract and is processed into a 6.7 kb nuclear form and a smaller MALAT1-associated small cytoplasmic RNA (mascRNA) (Zhang et al. 2017d). MALAT1 is m6A modified on 4 of 7 sites located in hairpins of MALAT1 within HeLa, HEK-293T and MDA-MB-231 cells (Liu et al. 2013). Others reported that m6A on position 2577 of MALAT1 alter its secondary structure, enhancing its interaction with the m6A reader heterogeneous nuclear ribonucleoprotein C (HNRNPC) (Zhou et al. 2016). The DROSHA-DGCR8 microprocessor associates with the 5′ end of MALAT1. MALAT1 acts as a sponge for nuclear miR-9 and cytoplasmic miR-133, miR-200s and miR-205, although the exact mechanisms of how MALAT1 gets to the cytoplasm are unclear (Zhang et al. 2017d). In turn, MALAT1 is post-transcriptionally downregulated by miR-101, miR-125b and miR-217. The crystal structure of MALAT1 revealed it to be a triple helix RNA that is stable in cells, e.g., t 1/2 of 7 h in HeLa cells (Brown et al. 2014). Functionally, nuclear speckle-associated MALAT1 is involved in alternative splicing by acting as a scaffold (Tripathi et al. 2010). MALAT1 is considered oncogenic and it upregulates the Wnt/β-catenin pathway (Ong et al. 2017). Capture hybridization analysis of RNA targets (CHART) identified MALAT1 genomic-binding sites to be at actively transcribed loci (reviewed in Zhang et al. 2017d). However, Malat1-knockout (ko) mice showed no obvious phenotype, were viable and fertile and showed correct localization of nuclear speckles (Nakagawa et al. 2012). Expression of the lncRNA Neat1, which is located 30 kb upstream (5′) to Malat1, was lower in Malat1 ko mice, suggesting a role for Malat1 as a cis-regulator of Neat1. RNA-seq studies in adult Malat1 ko mice revealed upregulation of a small number of adjacent genes, also suggesting cis regulation (Zhang et al. 2012). One explanation for the lack of concordance between cellular and whole mouse studies is that Malat1 may only function under stress conditions (reviewed in Zhang et al. 2017d). Increased MALAT1 is found in many cancers including breast tumors (Ellis et al. 2012), castration-resistant prostate (Ren et al. 2013, Wang et al. 2014, Sowalsky et al. 2015), EEC (Zhao et al. 2014), recurrent ovarian cancer (Yang et al. 2017b) and thyroid tumors (Zhang et al. 2017a,b). Studies suggest that increased MALAT1 plays a role in metastasis (reviewed in Zhang et al. 2017d). MALAT1 mutations are frequent in breast tumors (Arun et al. 2016, Nik-Zainal et al. 2016). MALAT1 expression was higher in thyroid cancer tissues and in thyroid cancer cells than normal thyroid (Huang et al. 2016a). Likewise, NEAT1 is upregulated in breast (Qian et al. 2017), endometrial (Wang et al. 2017a,c), ovarian (Chen et al. 2016) and thyroid tumors (Li et al. 2017b) and is the highest lncRNA in prostate cancer and strongly associated with metastasis (Chakravarty et al. 2014).
lincRNA-p21 (gene name TP53COR1) is a transcript of ~3 kb that is increased by p53 in response to DNA damage and serves as a transcriptional repressor in the p53 pathway by directly interacting with HNRNPK (hnRNP-K), increasing p21 transcription and inhibiting the transcription of pro-survival genes, thus triggering apoptosis (Barsotti & Prives 2010, Dimitrova et al. 2014). lincRNA-p21 is increased by hypoxia via HIF-1α and interacts with and stabilizes HIF-1α, resulting in increased glycolysis in HeLa cells (Yang et al. 2014). lincRNA-p21 is degraded by let-7 (Yoon et al. 2014). lincRNA-p21 is transcribed into two isoforms with Alu inverted repeat elements and colocalizes with the lncRNA NEAT1 in the nucleus of U2OS, HCT-116 and MCF-7 cells (Chillón & Pyle 2016). lincRNA-p21 represses the translation of specific target genes, including CTNNB1 (β-catenin), through RISC complex activation. Knockdown of heat-shock factor 1 (HSF1) in MDA-MB-231 cells increased lincRNA-p21 expression and the authors identified miR-320a, b and c as dependent on HSF1 that may target lincRNA-p21 through its 5′ sequence, although this was not demonstrated (Chou et al. 2015). lincRNA-21 is downregulated in PCa and acts as a tumor suppressor in PCa cells (Wang et al. 2017a,c). Overexpression of lincRNA-p21 in DU145 and LNCaP PCa cells decreased pyruvate kinase M2 (PKM2) expression in a PTEN/AKT/mTOR cascade-dependent manner and transfection with shlincRNAP21 reduced glucose consumption (Wang et al. 2017b,d). There are no reports on lncRNA-21/TP53COR1 in either endometrial or thyroid cancer.
lncRNAs in breast tumors
A recent review of the function of selected lncRNAs upregulated (19) and downregulated (5) in BCa noted that while thousands of dysregulated lncRNAs have been identified, about most relatively little is known (Warburton & Boone 2017). Bioinformatic reanalysis of RNA-seq data from 658 invasive ductal carcinomas from TCGA and sorted by PAM50 assay transcriptomic data identified 1623 lncRNAs expressed at FPKM (fragments per kilobase of non-overlapped exon per million fragments mapped) >1 in 10% of the tumors that the authors postulated are relevant in BCa (Su et al. 2014). lncRNA-based unsupervised hierarchical consensus clustering revealed four subgroups that correlated with mRNA transcriptome PAM50 classification: basal-like, HER2-enriched and luminal A and B. Clustering suggested that HOTAIR was higher in HER2-enriched breast tumors. Abib5152.3, RP11-84E24.2 and HOTAIRM1 were higher in basal-like breast tumors, whereas RP11-53019.2 and RP11-473L15.3 were higher in luminal-type tumors. Su and coworkers correlated increases in lncRNAs with increased adjacent gene expression: HOTAIR with HOXC11; HOTAIRM1 with HOXAI; RP11-53O19.2 and RP11-473L15.3 with MRPS30 and Abib5152.3 and RP11-84E24.2 with SOX9 (Su et al. 2014). HOTAIRM1 SOX9 is a stem cell factor involved in tamoxifen-resistant BCa (Jeselsohn et al. 2017). HOTAIR and BCL2 expression were correlated in breast tumors and HOTAIR was shown to act as a ceRNA by base-pairing with miR-206, thus relieving mIR-206’s repression of BCL2 expression (Ding et al. 2017). HOTAIRM1 expression increased in recurrent ovarian cancer (Yang et al. 2017b), but acts as a tumor suppressor in colorectal cancer (Wan et al. 2016).
Another group performed a similar analysis on RNA-seq data in the TCGA using ~1000 breast tumors, an independent RNA-seq dataset of 50 pairs of matched tumors and adjacent normal tissues from BCa patients, and 23 normal breast tissues from healthy women (Zhang et al. 2016b,d). They identified 2171 lincRNAs expressed in at least one sample, often at low levels, and ultimately identified 83 differentially expressed lincRNAs of which 60 were downregulated in breast tumor samples. Among the upregulated lincRNAs, GATA-AS1 was associated with higher expression of its adjacent protein-coding gene GATA3 and both were associated with ERα+ breast cancer. GATA3 regulates the transcription of genes involved in maintaining luminal mammary gland differentiation (Kouros-Mehr et al. 2006) and acts as a licensing factor for ERα-chromatin binding (Theodorou et al. 2013). GATA-AS1 may be unique in BCa since no reports were found for the other endocrine cancers discussed in this review. One upregulated lincRNA RP5-1198O20 was associated with lower survival rates in BCa patients (Zhang et al. 2016b,d). How RP5-1198O20 contributes to BCa mortality is currently unknown.
ANRIL was identified as the lncRNA with the highest expression in SK-BR3 HER2+ BCa cells vs MCF-10A cells in a lncRNA array qPCR study (Lee et al. 2017). ANRIL expression was also higher in MCF-7 and T47D cells compared with MCF-10A cells. Some lncRNAs are associated with specific metastasis, e.g., lnc-BM (OR5BM1P) for BCa brain metastasis by interacting with JAK2 to activate a STAT3-ICAM1 axis that increases cell adhesion to brain capillaries and extravasation (Wang et al. 2017b,d).
XIST is best known for X chromosome inactivation (da Rocha & Heard 2017). However, XIST interacts on a genome-wide scale with a variety of proteins, including the scaffold attachment factor A (SAF-A), in the non-chromatin nuclear scaffold/matrix (Creamer & Lawrence 2017). XIST is downregulated in breast tumors, but its molecular mechanisms as a tumor suppressor are unclear (Huang et al. 2016b). One idea is that loss of XIST induces reactivation of X-linked genes that contribute to BCa progression (Chaligne et al. 2015). However, XIST’s role as a tumor suppressor may depend on the type of breast tumor. Patients with high XIST mRNA and low protein expression of 53BP1 in BRCA1-like breast tumors showed no benefit from high-dose alkylating chemotherapy and lower disease-free and overall survival (Schouten et al. 2016). XIST expression was also decreased in uterine papillary serous carcinoma accompanied by widespread X chromosome demethylation (Zhang et al. 2014). There are no apparent functional studies of XIST in EC cells.
New lncRNAs continue to be discovered. A recent example is ESRP2-AS that was first identified in a methylated lncRNA screen in a transgenic mouse model of human BCa (C3(1) SV40Tag) and shown to be higher in human breast tumors compared to normal breast tissue (Heilmann et al. 2017). Additional lncRNAs identified in BCa are included in Table 2.
lncRNAs in prostate tumors
Most lncRNAs identified in PCa are upregulated, thus acting as oncogenes (reviewed in Zhang et al. 2016a,c). Upregulated lncRNAs include HOTAIR, PCGEM1, PRNCR1, ANRIL, PCAT1, MALAT1 and specific for PCa PCA3. Downregulated lncRNAs in PCa include GAS5, PTENP1 and MEG3. Refer Table 2 for details on PCA3, GAS5 and MEG3. MEG3 modulates the activity of TGF-β genes by binding to distal regulatory elements forming an RNA–DNA triplex and interacts with the PRC2 complex (Mondal et al. 2015). PCAT1 is the most highly upregulated lncRNA in PCa (Alahari et al. 2016). Mechanistically PCAT1 post-transcriptionally represses tumor suppressor gene BRCA2, thus impairing homologous recombination DNA repair. Overexpression of PCAT1 in DU145 PCa cells increased proliferation, migration, and invasion and post-transcriptionally upregulated MYC by interacting with miR-3667-3p (Prensner et al. 2014). Another study showed interaction between PCAT1 and miR-145-5p that resulted in upregulation of FSCN1, an actin-binding protein involved in invasion and migration (Xu et al. 2017). Overall, PCAT1 has an oncogenic role in PCa (Alahari et al. 2016). Interestingly, a PCa risk SNP (rs7463708) promotes transformation via upregulation of PCAT1 lncRNA (Guo et al. 2016a). PCAT1 is also upregulated in hepatocellular carcinoma (HCC) (Zhang et al. 2017a,b). Additional lncRNAs in PCa are included in Table 2.
lncRNAs in EC
The death rate for cancer of the uterine corpus, which is associated with obesity, is increasing in the U.S. (Siegel et al. 2017). EC is classified as type I or II with most patients having well-differentiated endometrioid endometrial carcinomas (EEC, type I) (Takenaka et al. 2016). The identity and characteristics of lncRNAs dysregulated in EEC, including MALAT1, HOTAIR, SRA, H19, OVAAL, RP11395G12.3, LA16313D11.11, CASC2, ASLNbib4080 and ENSbib50294 were reviewed (Takenaka et al. 2016). The roles and functions of selected lncRNAs, i.e., MALAT1, HOTAIR, H19, MEG2, CCA2, ANRIL, OCAL, BC2200 and CUDR in cancers of the female reproductive system including endometrial, ovarian and cervical cancers were recently reviewed (Hosseini et al. 2017). H19 is a well-studied imprinted, maternally expressed lncRNA that encodes miR-675 and is overexpressed in breast, HCC, prostate, colorectal, esophageal, bladder and many other cancers but is downregulated in adrenocortical neoplasms (reviewed in Huarte 2015).
lncRNAs in thyroid cancer
The role of lncRNAs in the pathogenesis of thyroid cancer was recently reviewed (Murugan et al. 2017). PTC is the most common thyroid malignancy (Siegel et al. 2017). A microarray analysis of lncRNAs in 62 PTC tumors identified 3499 lncRNAs (1192 upregulated, 2307 downregulated) that were differentially expressed compared with paired noncancerous tissue (Lan et al. 2015). qPCR confirmed the ‘direction’ of lncRNA expression in PTC: TCONS_l2_00010365, n386477, n340790, lnc-LLPH-2:1 and NR_003225.2 were upregulated and lnc-PSD4-1:14, n335550, lnc-KCMF1-2:1, lnc-PLA2R1-1:1 and ENSbib422494.1 were downregulated (Lan et al. 2015). As indicated in Table 2, MALAT1 is upregulated in thyroid tumors (Zhang et al. 2017a,b). MALAT1 is also upregulated in SW1736, KAT18 and FTC133 thyroid cancer cells and knockdown of MALAT1 inhibited cell proliferation and invasion by upregulating the expression of the scaffolding protein IQGAP1 (Huang et al. 2016a).
Mitochondrial-encoded lncRNAs and lncRNA imported into mitochondria
The human mitochondrial DNA (mtDNA) genome is transcribed as a polycistronic precursor and encodes 13 proteins that function in mt OXPHOS, two rRNAs that are components of the mt ribosome and 22 tRNA (Kim et al. 2017b). Seven lncRNAs have been identified to be derived from mtDNA (De Paepe et al. 2017). These are referred to as mitolncRNAs (Vendramin et al. 2017). Several are chimeric lncRNAs containing nucleotides of mtDNA: LIPCAR, SncmtRNA, ASncmtRNA-1 and ASncmtRNA-2. LIPCAR is cardiac specific and levels are elevated in circulation of patients with chronic heart failure (Kumarswamy et al. 2014). ASncmtRNA-1 and ASncmtRNA-2 are present in mitochondria and nuclei, suggesting a possible role in retrograde signaling (De Paepe et al. 2017). ASncmtRNA-1 and ASncmtRNA-2 are downregulated in breast and prostate tumors (Burzio et al. 2009), suggesting tumor suppressor activity. However, complete knockdown of ASncmtRNA-1 and ASncmtRNA-2 stimulated apoptotic cell death by downregulating the translation of survivin, an anti-apoptotic protein, only in cancer cells through an undefined mechanism, although these lncRNAs were shown to interact with DICER (Vidaurre et al. 2014). To date, the mechanism of ASncmtRNA-1 and ASncmtRNA-2 remains unknown (De Paepe et al. 2017, Dong et al. 2017). Three lncRNAs: ncND5, lncND6 and lncCyt b were identified as antisense transcripts of the mtND5, mtND6 and mtCYTB mRNAs but little is known about their function (Rackham et al. 2011). There is speculation that these three lncRNAs are transported to the nucleus by unknown RNA-binding proteins (Dong et al. 2017). Recently, two novel lncRNAs MDL1 and MDL1AS encoded in the D-loop of human mitochondrial DNA were discovered and identical transcripts were identified in mouse and rat genomes (Gao et al. 2017).
RMRP (RNA Component Of Mitochondrial RNA-Processing Endoribonuclease) is a nuclear DNA-encoded lncRNA that binds RNA-binding proteins HUR, PNPASE and GRSF1 for transport into mitochondria where RMRP is the RNA component of the mitochondrial RNA-processing endoribonuclease (RNase MRP) for mtDNA replication and RNA processing (Dong et al. 2017). RMRP acts as a sponge for miR-206 an oncogene in lung cancer (Meng et al. 2016). Deep sequencing of 360 primary breast tumors identified mutations in the promoters of lncRNAs RMRP and NEAT1 that increased their expression and noted increased expression of these lncRNAs in breast tumors (Rheinbay et al. 2017). However, RMRP’s role in BCa remains to be fully elucidated, and no publications were found with respect to RMRP in prostate, endometrial, ovarian or thyroid cancer.
SRA1, steroid receptor RNA activator, was first identified as an RNA transcript acting as an RNA coactivator in a complex with SRC-1 (NCOA1) to increase progesterone, glucocorticoid, androgen, estrogen, thyroid hormone, retinoic acid and peroxisome proliferator-activated receptor (PR, GR, AR, ERα, TRβ, RARγ, RXRγ and PPARγ) transcriptional activity (Lanz et al. 1999). Knockout of Sra1 in mice showed that the Sra−/− mice were resistant to high-fat diet-induced obesity and had lower fat mass (Liu et al. 2014). In humans, inactivating SRA1 mutations were identified in three families with a proband with idiopathic hypogonadotropic hypogonadism (Kotan et al. 2016). The SRA1 gene also encodes a protein steroid receptor coactivator protein (SRAP) (reviewed in Leygue 2007) that interacts with AR and is involved in PCa (Kawashima et al. 2003). Notably, SRA1 and SRAP do not interact (McKay et al. 2014). SRA1’s identity as a lncRNA was revealed in 2012 (Novikova et al. 2012). Additional protein-binding partners of SRA1 were recently reviewed (Liu et al. 2016). SRA1 interacts with DICER (Redfern et al. 2013). By its interaction with SLIRP (SRA stem-loop interacting RNA-binding protein), SRA1 has a repressive function by recruiting corepressors (reviewed in Liu et al. 2016). SLIRP represses NR transactivation in an SRA1-dependent manner (Hatchell et al. 2006). Interestingly, Slirp-knockout mice are sub-fertile, and males have defects in sperm motility and mitochondrial morphology (Colley et al. 2013). SRA1 and SLIRP were identified as a BCL2-interacting RNA and proteins, respectively in mitochondria of H1299 lung adenocarcinoma cells (Trisciuoglio et al. 2016). The SMRT/HDAC1 corepressor complex interacts with SRA1 (Dong et al. 2017). SRA1 is upregulated in steroid hormone-responsive tumors including breast, endometrial and ovarian (reviewed in Liu et al. 2016).
lncRNAs in circulation
Circulating nucleic acids, including miRNAs and lncRNAs, are found in cell-free serum, plasma and other bodily fluids and differ between cancer patients, including those with prostate and breast tumors and non-cancer/normal individuals (reviewed in Qi et al. 2016). In addition, virtually all cells release membrane-enclosed extracellular vesicles (EV): exosomes (0.04–0.15 µm diameter) and microvesicles (0.2–1 µm diameter); further, apoptotic cells release apoptotic bodies (0.5–2 µm diameter) that do not contain miRNAs and lncRNAs (Kim et al. 2017a). Exosomes, which arise from the endosomal pathway, and microvesicles have been reported to transport mRNAs, ncRNAs, including miRNAs, lncRNAs and circRNAs, as a mechanism of intercellular communication (Kim et al. 2017a). Cancer exosomes modulate the immune response and the tumor environment locally and at a distance, i.e., metastasis to secondary sites, by horizontal cargo transfer to recipient cells (Ruivo et al. 2017). In a recent study, isolated exosomes from tamoxifen-resistant LCC2 BCa cells were shown to contain ~25-fold higher lncRNA UCA1 compared to parental MCF-7 cells and incubation of MCF-7 cells with exosomes from LCC2 cells resulted in decreased growth inhibition by tamoxifen (Xu et al. 2016), although no uptake of UCA1 or other lncRNAs or miRNAs was examined. There is great interest in EVs as biomarkers and as tools to deliver therapeutic genetic materials and drugs. Interestingly, a recent study reported that EVs isolated from BCa patients with metastatic disease and whose initial tumor had been ERα+/PR+/HER2-contained mtRNA from cancer-associated fibroblasts (CAFs) (Sansone et al. 2017). Xenograft transplantation studies in immunocompromised mice demonstrated that transfer of mtDNA from CAFs contributed to resistance to fulvestrant in vivo. Whether accompanying miRNAs and lncRNAs play a role in these findings was not evaluated.
lncRNA therapeutics
Antisense oligonucleotides (ASO), liposome-delivered RNAi, vector-expressed shRNAs and decoy RNAs or small molecules that compete for domain–domain interactions between lncRNA and proteins or within the lncRNA are of interest in targeting overexpressed lncRNAs in cancer (Weidle et al. 2017). Targeting of lncRNAs using lncRNAs and nanoparticle-coated siRNAs has been successful in preclinical mouse models of BCa (Liu et al. 2015, Wang et al. 2017b,d). Approximately 25 RNAi-based therapeutics are under clinical investigation (Weidle et al. 2017).
Overview of miRNA biosynthesis in endocrine-related cancers
miRNAs are small (22 nucleotides), evolutionarily conserved, single-stranded, ncRNAs that regulate mRNA translation or stability by base-pairing with miRNA response elements (MREs) in the 3′UTR of the target transcript within the RNA-induced silencing complex (RISC). The chronology of miRNA discovery was recently reviewed (Drusco & Croce 2017). Comparative genomics analysis indicated that >60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs with >45,000 miRNA-binding sites within 3′UTRs conserved (Friedman et al. 2009). The human genome includes 2,588 mature miRNAs (mirBase release 21) http://www.mirbase.org/ (Kozomara & Griffiths-Jones 2014).
The biogenesis of miRNAs has been reviewed (Ha & Kim 2014, Klinge 2015). In brief, in the canonical pathway of miRNA biogenesis, miRNAs are transcribed as primary-micro-RNAs (pri-miRNAs) by RNA pol II either as independent transcription units or are cotranscribed within introns of pre-mRNAs (~50% of miRNAs) (Saini et al. 2007). Most pri-miRNAs are >1 kb, thus meeting the definition of a lncRNA (Dykes & Emanueli 2017). About half of all miRNAs are produced from non-coding transcripts, i.e., host lncRNAs. One example is DLEU2 that encodes the miR-15a/16.1 cluster and MIR155HG that encodes miR-155 (reviewed in Dykes & Emanueli 2017). Pri-miRs are capped and polyadenylated (Cai et al. 2004). The microprocessor complex of DROSHA (an RNAse III endonuclease) and DGCR8, plus additional proteins, cleaves hairpin-loop-containing pri-miR into 60–70 nucleotide (nt) precursor (pre)-miRNAs. The efficiency of pri-miRNA processing depends on stem length (36 ± 3 nt) and the appearance of bulges in the structure (Roden et al. 2017). DGCR8 acts as an oncogene in prostate cancer whereas DROSHA has oncogenic or tumor suppressor activity depending on the cancer type (reviewed in Hata & Kashima 2016). Alternative pathways of miRNA biogenesis include miRtrons, which are processed by spliceosomes in a DROSHA/DGCR8-independent/DICER-dependent manner and DROSHA/DGCR8-dependent/DICER-independent yielding miR-451 (reviewed in Daugaard & Hansen 2017). The widespread reduction of miRNAs in human tumors has been attributed to dysregulation of the DROSHA/DGCR8 microprocessor complex as a result of the many pathways that regulate microprocessor components, e.g., p72 is sequestered by YAP in the Hippo pathway in a cell-density-dependent manner (Mori et al. 2014). RNA-binding proteins also regulate pri-miRNA accessibility (Fernandez et al. 2017).
Pre-miRNAs are exported from the nucleus by Exportin and Ran-GTP or CRM1 to the cytoplasm where they are cleaved by DICER (DICER1, an RNAse III enzyme) forming ~21–23 nt transiently double-stranded miRNA duplexes (Kurzynska-Kokorniak et al. 2015). DICER, in association with cofactors TRBP and PACT, transfer the mature miRNA to RISC, which contains the catalytic argonaute proteins (AGO1, AGO2, AGO3 and AGO4) (Hock & Meister 2008)) that unwind the mIRNA duplexes to form single-stranded miRNAs. The lncRNA SRA1 binds DICER complex components PACT, TRBP and PKR in various cell lines and also binds NRs, including ERα (Redfern et al. 2013). DICER also plays a role in the DNA damage response in which DNA damage results in phosphorylation and binding to double-strand breaks and recruits DNA repair factor MDC1 and 53BP1 (Burger et al. 2017). DICER acts as an oncogene in PCa but as a tumor suppressor in breast, endometrial and ovarian cancer (reviewed in Hata & Kashima 2016). DICER is regulated transcriptionally, post-transcriptionally, including by alternative splicing, and by post-translational modifications, e.g. phosphorylation, glycosylation and SUMOylation (Kurzynska-Kokorniak et al. 2015). Germline DICER1 mutations, DICER1 syndrome, were identified as causative in differentiated thyroid cancer and multinodular goiter (de Kock et al. 2014, Rutter et al. 2016, Khan et al. 2017).
In cancer tissues, overexpressed miRNAs that act as oncogenes are referred to as oncomiRs while downregulated miRNAs are called tumor suppressor miRs with their targets, tumor suppressors and oncogenes, respectively dysregulated. However, as we learn more about miRNAs, it is clear that generalization about a particular miRNA being oncogenic or a tumor suppressor depends on cellular context. miRNAs are involved in the post-transcriptional regulation of genes involved in EMT, stemness, cell signaling pathways and regulation of the tumor microenvironment, including the conversion of normal fibroblasts into cancer-associated fibroblasts (CAFs) by transfer of exosomal miRNAs from tumor cells (reviewed in Yang et al. 2017a). An issue in the field is the lack of congruence of miRNAs identified for a particular cancer type, e.g., thyroid cancer, even within a subtype, in different studies. This may be attributed to the number of tumor samples examined, tumor heterogeneity, whole tumor RNA isolation vs laser-capture microdissected tumor cells, the technique used to identify the miRNA (microarray, quantitate real-time PCR (qPCR), or NGS/RNA-seq.), the gene normalizer and statistical approaches used. Databases of putative and experimentally verified targets of miRNAs are listed in Table 1.
Despite the large datasets available on miRNAs in endocrine cancer, functional studies are needed for each miRNA and its targets. Functional analysis of overexpression and silencing of individual miRNAs is used to validate the role of deregulated miRNAs in cancer cells in vitro and animal tumor models, including human tumor cell xenografts and patient-derived xenograft (PDX) in vivo. An essential step to validate the identify of an mRNA target of a miRNA is to clone the 3′-UTR of the mRNA target downstream of a luciferase reporter and then transfect that reporter into a cell line, with an appropriate loading control either in the same plasmid or another cotransfected reporter, with overexpression and knockdown of the putative miRNA regulator. The investigator should detect reduced luciferase reporter activity and mutation of the MRE in the 3′UTR is required confirm direct miRNA-mRNA target regulation, i.e., validating that the mRNA is a bona fide target of that miRNA. Further validation steps include Western blot to demonstrate decrease target protein expression. Target validation in clinical samples is used to demonstrate disease relevance of the miRNA and its target.
Supplementary Table 1 (see section on supplementary data given at the end of this article) summarizes examples of miRNA dysregulated in BCa, PCa, EC and thyroid cancer with examples of their bona fide, validated, mRNA targets. Cellular functions associated with the miRNA are listed in Supplementary Table 1. In addition, I have added lncRNAs that either downregulate a miRNA or act as ceRNAs, i.e., endogenous sponge for binding a miRNA. It will be clear to the reader that many of the miRNA:lncRNA interactions listed are from non-endocrine cancers and are single reports requiring further validation.
miRNAs in BCa
In the 12 years since miRNAs were identified to be dysregulated in BCa (Iorio et al. 2005), about 3600 papers have been published in miRNAs in BCa (Fig. 1). There are many recent reviews of the identity, regulation and targets of miRNAs in BCa, e.g., (Egeland et al. 2015, Klinge 2015, Muluhngwi & Klinge 2015, van Schooneveld et al. 2015, Yahya & Elsayed 2015, Li et al. 2017c, O’Bryan et al. 2017, Smith et al. 2017). miRNAs regulate key pathways dysregulated in BCa including apoptosis, cell cycle, cellular energetics, invasion, metabolism and metastasis.
The majority (70%) of primary breast tumors express ERα, and these patients are treated with endocrine therapies including tamoxifen (TAM); the selective estrogen downregulator (SERD), e.g., fulvestrant and aromatase inhibitors (AI), e.g., anastrozole and letrozole (Ring & Dowsett 2004, Clarke et al. 2015). Hence, many miRNA studies have examined the correlation of miRNAs with diagnostic markers related to ERα in BCa, estrogen-regulated miRNAs and the potential role of miRNAs in endocrine resistance (Klinge 2015, Muluhngwi & Klinge 2015). ERα is the target of miRNAs including miR-221, miR-222, miR-873, let-7b and let-7i (reviewed in Muluhngwi & Klinge 2015).
Computational approaches are used to identify putative mRNA and lncRNA targets of miRNAs (Table 2). In addition, specific algorithms to identify possible targets of dysregulated miRNAs in breast tumors and BCa cell lines have been reported (O’Day & Lal 2010, Cava et al. 2014, Ru et al. 2015, Liang et al. 2016, Zhang et al. 2016b,d). More recently, various strategies to directly identify miRNA:RNA targets and RNA modifications by protein:RNA immunoprecipitation and high-throughput RNA-seq have been used to examine protein:RNA interactions in human biology, e.g., HITS-CLIP (high-throughput RNA-seq isolated by crosslinking immunoprecipitation) (Darnell 2010); PAR-CLIP (photoactivatable ribonucleoside-enhanced CLIP) (Farazi et al. 2014), iCLIP (crosslinking and immunoprecipitation) (Hong et al. 2015), eCLIP (enhanced CLIP) (Van Nostrand et al. 2016) and dCLIP (denaturing CLIP) (Rosenberg et al. 2017). A downside is that CLIP techniques are technically challenging.
Dysregulation of miRNAs in PCa
Dysregulation of miRNA expression is correlated with aggressive PCa phenotypes including tumor stage, Gleason grade and disease recurrence (Ren et al. 2014, Cha et al. 2016). Altered miRNA expression is associated with physiological changes in tumorigenesis and disease progression in PCa (reviewed in Chun-Jiao et al. 2017, Vanacore et al. 2017). Changes in miRNA expression contribute to altered expression of genes involved in pathogenesis of metastatic PCa (Kojima et al. 2017). Changes in miRNA expression in PCa have been reviewed and described below.
miRNAs upregulated by AR in PCa include miR-21, miR-27a, miR-32, miR-125b, miR-135a, miR-141 and AR overexpression in PCa downregulates miR-99a (Massillo et al. 2017). miR-125b is the most overexpressed miRNA in PCa and downregulates apoptotic genes including BAK1. A recent review of 104 studies of miRNAs in PCa tissues identified six miRNA consistently upregulated: miR-34a, miR-106b, miR-183, miR-200a/b and miR-301a; and sixteen miRNAs downregulated: miR-1, miR-23b, miR-27b, miR-34b/c, miR-99b, miR-125b, miR-152, miR-187, miR-199a, miR-204, miR-205, miR-224, miR-452, miR-454 and miR-505 (Chun-Jiao et al. 2017). Other oncomiRs overexpressed in PCa are miR-21, miR-32, miR-221, miR-222, miR-181, miR-18a and miR-429 (reviewed in Kanwal et al. 2017). ‘Andro-miRs’: let-7c, miR-31, miR-124, miR-185, miR-205 and miR-488 downregulate AR expression (Massillo et al. 2017). Notably, the top four downregulated miRNAs in PCa tissues are miR-187, miR-205, miR-222 and miR-31 (Fuse et al. 2012). Additional tumor suppressor miRNAs in PCa and their targets include miR-331-3p that downregulates ERBB2 and AR and is associated with castration-resistant PCa (reviewed in Kanwal et al. 2017). miRNAs associated with metastasis include downregulation of miR-1, miR-15, miR-16, miR-23a, miR-29b, miR-126, miR-130, miR-132, miR-141, miR-195, miR-200b, miR-200c, miR-203, miR-205, miR-218, miR-375, miR-377, miR-466, miR-573, miR-675, and miR-802 and upregulation of miR-21, miR-22, miR-25, miR-93, miR-106b, miR-154-3p, miR-379, miR-543 and miR-590-3p (reviewed in Massillo et al. 2017). miRNAs upregulated or downregulated in serum, plasma and urine with potential prognostic value in separating men with potentially lethal PCa vs indolent disease were recently reviewed (Massillo et al. 2017).
Dysregulation of miRNAs in EC
EC is the most frequently diagnosed gynecological cancer (Siegel et al. 2017). Among the miRNAs differentially expressed in EC vs normal endometrial tissue are the increased expression of miR-10b, miR-21, miR-31, miR-182, miR-183, miR-205, miR-222, miR-223, miR-410, miR-429, miR-449a, miR-994, and miR-1228; and downregulation of let-7, miR-34b-5p, miR-34c-3p, miR-34c-5p, miR-99b, miR-101, miR-130a, miR-143, miR-145, miR-184, miR-193b, miR-204, miR-340, miR-372, miR-429, miR-449a, miR-490 and miR-495 (reviewed in Srivastava et al. 2017). In serum samples from women with EC, increased levels of miR-186, miR-222 and miR-223 were identified compared with controls (Montagnana et al. 2017). Targets of upregulated miRs in EC include the tumor suppressor PTEN that is downregulated by overexpressed miR-21, miR-130a, miR-205, miR-222 and miR-429 (Srivastava et al. 2017). Although much studied, there are currently no miRNA signatures in use for early detection and screening of gynecological cancers (Srivastava et al. 2017).
miRNAs in thyroid cancer
The identity and targets of miRNAs dysregulated in PTC and follicular thyroid carcinoma (FTC) have been recently reviewed (Pallante et al. 2013, Saiselet et al. 2016, Yoo et al. 2016, Celano et al. 2017, Lima et al. 2017, Pishkari et al. 2018). miRNAs upregulated in PTC include miR-21, miR-31, miR-99-3p, miR-128a, miR-128b, miR-139, miR-141, miR-146a, miR-146b-3p, miR-146b-5p, miR-155, miR-181a, miR-181b, miR-187, miR-191, miR-200a, miR-200b, miR-200c, miR-220, miR-221, miR-222, miR-222-5p, miR-224, miR-375, miR-551b (Pallante et al. 2013). Downregulated miRNAs in PTC include: let-7f, miR-1, miR-26a-1, miR-30, miR-30c, miR-138, miR-199, miR-219, miR-292, miR-300 and miR-345 (Pallante et al. 2013). With RNA-seq, the arm of each miRNA and isomiRNAs can be detected. Thus, RNA-seq has higher resolution and detected increased miR-21-3p, miR-21-5p, miR-31-3p, miR-31-5p, miR-34a-5p, miR-146-3p, miR-146-5p, miR-182-5p, miR-183-5p, miR-221-3p, miR-221-5p, miR-222-3p and miR-551b-3p in PTC (Saiselet et al. 2016). RNA-seq identified miRNAs upregulated in FTC include miR-96-5p, miR-182-5p, miR-221-3p, miR-183-5p and miR-222-3p, whereas miR-31-5p, miR-199a-5p and miR-199b-5p showed consistent downregulation in three independent studies (reviewed in Saiselet et al. 2016).
miRNAs in mitochondria
Mitochondrial function is critical for metabolic homeostasis. NGS has identified several miRNAs imported into mitochondria including miR-34, miR-181c-5p and miR-146a-5p (Kim et al. 2017b). The identity and roles of miRNAs in mitochondrial biology were recently reviewed (Vendramin et al. 2017). The term ‘mitomiRs’ refers to miRNAs functioning in mitochondria, whether nuclear- or mtDNA-encoded (Duarte et al. 2015). mitomiRs are 17–25 nt vs the canonical 22 nt for most miRNAs. The exact function and identity of mitomiRs remains unknown and caution is advised since cytoplasmic contamination of mitochondrial extracts is problematic (Vendramin et al. 2017). Many ncRNAs appear to be involved in rapid cell stress responses and may be involved in anterograde and retrograde signaling between the nucleus and mitochondria to regulate energy homeostasis and apoptosis. For example, miRNAs appear to provide anterograde regulation of mitochondrial function, apoptosis and cancer cell metabolism (Duarte et al. 2015, Cha et al. 2017). However, although mitochondrial dysfunction is a hallmark of cancer, the role of ncRNAs in the mitochondrial unfolded protein response (UPRmt) in cancer (reviewed in Kenny & Germain 2017) remains to be examined.
miRNAs in circulation
Screening of free and exosomal-associated miRNAs by high-throughput sequencing platforms has identified changes in breast, ovarian and prostate cancers (Smith et al. 2017) and in thyroid cancer (Saiselet et al. 2016). The release of exosomes containing miRNAs (as well as other ncRNAs, protein and lipids) and endocytic uptake of the exosomes in recipient cells results in altered regulation of gene translation and has implicated miRNAs as hormones (reviewed in Bayraktar et al. 2017). In addition, circulating miRNAs can be transported between cells by microvesicles, apoptotic bodies, lipoproteins (HDL) and ribonucleoproteins, e.g., nucleophosmin 1 and AGO2. Exosomes derived from patients with CRPCa have increased expression of miR-1290 and miR-375 and correlate with decreased overall survival (reviewed in Kanwal et al. 2017). CAFs stimulate cancer progression by secreting chemokines, cytokines and growth factors that create the extracellular matrix (ECM) and CAFs secrete EVs containing a different spectrum of miRNAs compared to normal fibroblasts (Bayraktar et al. 2017). Among the miRNAs secreted by CAFs that regulate cancer cells are miR-21, miR-143 and miR-378 in BCa (Donnarumma et al. 2017); miR-210, miR-409-3p/5p (Yang et al. 2017a) and miR-409 (Josson et al. 2014) in PCa cells; and miR-21 in ovarian cancer (Au Yeung et al. 2016). Tumor-associated macrophages (TAMs) are also donors of miRNAs in cancer (reviewed in Bayraktar et al. 2017). Increased TAMs is associated with poor survival in advanced thyroid cancer (Ryder et al. 2008).
The mandate from NIH in the Precision Medicine Initiate is to have data-driven care for patients. A current goal of clinical trials is to determine if miRNA signatures obtained in fine needle aspiration biopsies and blood (serum or plasma) or urine will provide early diagnosis and track with therapeutic responses in cancer patients. However, the miRNA expression profile identified in blood samples depends on the processing of the sample, the miRNA extraction method, contamination, including by lysis of blood cells, and which normalizers are used (Saiselet et al. 2016). In addition to the ongoing efforts to standardize exosome and miRNA purification from biological fluids, factors that impact variability in miRNAs detected in circulation include diet, physical activity and circadian rhythms (reviewed in Smith et al. 2017). Most of the clinical trials involving mRNAs are observational, i.e., examining circulating in PCa, ovarian and breast cancers to monitor therapeutic responses to chemotherapy or other treatment strategies (reviewed in Smith et al. 2017).
miRNA therapeutics
Despite the large body of literature supporting miRNAs as biomarkers for diagnosis, prognosis and follow-up in patients with malignancies, the application of miRNA therapeutics into the clinical practice has a number of technical obstacles to overcome include clearance and optimization of bioavailability (reviewed in Chen et al. 2015). Nanoformulations of miRNAs, miRNA mimics, miRNA sponges, anti-miR oligonucleotides (AMOs) and small-molecule inhibitors are being tested in animal models. miRNA mimics to replace the expression of downregulated miRNAs by synthetic oligonucleotides that are combined with hydrogels, liposomes, minicells, nanoparticles, synthetic polymers or viral carriers for better delivery are under investigation (Drusco & Croce 2017). Recently, a folate-miR-34a-5p conjugate was shown to be taken by MDA-MB-231 cells, which have high folate receptor levels and to inhibit MDA-MB-231 xenograft tumor growth in mice (Orellana et al. 2017). ‘AntagomiRs’ serve to inhibit oncomiR function, e.g., a miR-10b antagomiR to mice did not inhibit primary mammary tumor growth, but inhibited lung metastasis (Ma et al. 2010) and intraperitoneal injection of a miR-92a-LNA inhibitor inhibited human EC cell xenograft growth in mice with no evidence of overt toxicity or metastatic spread (Torres et al. 2016). However, many challenges remain for therapeutics with or against miRNAs, notably the contradictory nature of miRNAs.
Conclusions
lncRNAs and miRNAs dysregulated in endocrine cancers, and they serve as biomarkers and potential therapeutic targets and agents in various cancers and other diseases, e.g., cardiovascular disease and type II diabetes. These and other ncRNAs are interconnected and have complex molecular roles in regulating protein-coding and non-coding nuclear gene transcription: RNA stability, epigenetic processes, chromatin accessibility, translation, gene expression in mitochondria, anterograde and retrograde signaling and intracellular and intercellular signaling. The study of lncRNAs is less mature than that of miRNAs. For example, new lncRNAs continue to be discovered, relatively few studies on any specific lncRNA have been published, and each lncRNA may have multiple isoforms that can be post-transcriptionally modified, adding complexity to evaluating their cellular and physiologic function. lncRNA structures are functionally important, but only a few lncRNAs’ structures are known. Identification of cell-specific lncRNA-interacting proteins and other RNAs and their subcellular distribution is needed. Both miRNAs and lncRNAs are being actively evaluated as tumor biopsy, plasma, serum, blood and urine biomarkers in the diagnosis and management of endocrine-related cancers as well as therapeutic targets. In addition, lncRNAs and miRNAs may serve as therapeutic agents. Many challenges remain in elucidating the biogenesis and function of ncRNAs in endocrine-related cancers. Our understanding of the functional roles of miRNAs and lncRNAs and their molecular targets is expanding rapidly. However, individual miRNAs and lncRNAs, and their combinations, may have different sets of targets and activities depending on the cell type, microenvironment, microbiome and hormonal milieu; thus, further investigation is required to fully elucidate miRNA and lncRNA function in endocrine-related cancers.
Supplementary data
This is linked to the online version of the paper at https://doi.org/10.1530/ERC-17-0548.
Declaration of interest
The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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