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Wei Zhang, Hang Zhang and Xudong Zhao

Papillary thyroid carcinoma (PTC) is one of the most prevalent tumors in endocrine system. CircRNAs (circular RNAs) are widely known as critical regulators in tumorigenesis of papillary thyroid carcinoma (PTC). The present study focused on the functional investigation and potential molecular mechanism toward circ_0005273 in PTC progression. Gene Expression Omnibus datasets (GSE93522) and qRT-PCR (quantitative real-time PCR) analyses showed that circ_0005273 were upregulated in PTC tissues and cell lines. Moreover, circ_0005273 was located in the cytoplasm of PTC cells and suggested poor prognosis in PTC patients. In vivo and in vitro functional assays indicated that knockdown of circ_0005273 inhibited PTC tumor growth and progression, respectively. Mechanistically, miR-1183 was identified as functional target of circ_0005273, and circ_0005273 could directly bind to miR-1138 and relieve inhibition of SRY (sex-determining region Y)-box 2 (SOX2). Data from Cell Counting Kit-8, colony formation assays and transwell assays revealed that the oncogenic role of circ_0005273 on PTC progression dependent on miR-1183-mediated SOX2 expression. In conclusion, circ_0005273 functioned as a tumor promoter of PTC via circ_0005273/miR-1183/SOX2 axis, suggesting a novel biomarker and therapeutic target for PTC.

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Anna Angelousi, Krystallenia I Alexandraki, George Kyriakopoulos, Marina Tsoli, Dimitrios Thomas, Gregory Kaltsas and Ashley Grossman

Endocrine organs are metastatic targets for several primary cancers, either through direct extension from nearby tumour cells or dissemination via the venous, arterial and lymphatic routes. Although any endocrine tissue can be affected, most clinically relevant metastases involve the pituitary and adrenal glands with the commonest manifestations being diabetes insipidus and adrenal insufficiency respectively. The most common primary tumours metastasing to the adrenals include melanomas, breast and lung carcinomas, which may lead to adrenal insufficiency in the presence of bilateral adrenal involvement. Breast and lung cancers are the most common primaries metastasing to the pituitary, leading to pituitary dysfunction in approximately 30% of cases. The thyroid gland can be affected by renal, colorectal, lung and breast carcinomas, and melanomas, but has rarely been associated with thyroid dysfunction. Pancreatic metastasis can lead to exo-/endocrine insufficiency with renal carcinoma being the most common primary. Most parathyroid metastases originate from breast and lung carcinomas and melanoma. Breast and colorectal cancers are the most frequent ovarian metastases; prostate cancer commonly affects the testes. In the presence of endocrine deficiencies, glucocorticoid replacement for adrenal and pituitary involvement can be life saving. As most metastases to endocrine organs develop in the context of disseminated disease, surgical resection or other local therapies should only be considered to ameliorate symptoms and reduce tumour volume. Although few consensus statements can be made regarding the management of metastases to endocrine tissues because of the heterogeneity of the variable therapies, it is important that clinicians are aware of their presence in diagnosis.

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Veronica R Placencio-Hickok, Anisha Madhav, Sungjin Kim, Frank Duong, Bryan Angara, Zhenqiu Liu and Neil A Bhowmick

While the overall 5-year survival rate for prostate cancer is near 100%, up to 35% of patients will develop recurrent disease. At the time of prostatectomy, prostate-specific antigen (PSA) is used to guide primary therapy with the goal of curative intervention. It can be valuable to know when primary therapy may not in fact be curative, so that subsequent adjuvant therapy can be administered at an early stage to limit progression. We examined prostate cancer patients with PSA ≤10 ng/mL that were all subjected to prostatectomy with at least 5 years of follow-up (n = 181). Based on data that endoglin (CD105) signaling in the tumor can contribute to prostate cancer progression, we examined the expression of soluble CD105 (sCD105) in the patient plasma. To determine the relation of plasma sCD105 measures to cellular CD105 in tissues, we tested an independent set of prostate cancer tissues and paired plasma (n = 31). Elevated sCD105 was found to be associated with recurrence-free survival of prostate cancer patients. Further, sCD105 levels in patient plasma were inversely correlated with cellular CD105 expression. This translational study supported preclinical data demonstrating the pro-tumorigenic capacity of cellular CD105 and provide a blood-based biomarker, sCD105, for prostate cancer recurrence in prostatectomy patients with PSA levels ≤10 ng/mL.

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Yuling Mao, Liuqing Zhu, Zhijian Huang, Chuanghua Luo, Ti Zhou, Lei Li, Guannan Wang, Zhonghan Yang, Weiwei Qi, Xia Yang and Guoquan Gao

Sorafenib, a small-molecule tyrosine kinase inhibitor with antiangiogenic activity, has been used in liver cancer and kidney cancer treatments. However, clinical trials with sorafenib for breast cancer were stopped in phase III due to limited efficacy. The existence of heterogeneous vasculatures involving tumor cells, such as vessel-like structures formed by vasculogenic mimicry and mosaic vessels, and their resistance to antiangiogenic therapy are thought to be a possible reason for failure of sorafenib therapy. Nevertheless, the features and mechanism of vasculogenesis by tumor cells remain unclear. In the present study, we found that breast cancer stem-like cells (BCSLCs, ALDH1+ cells) were involved in vasculogenic mimicry and mosaic vessel formation in triple-negative breast cancer tissues. Further, only ALDH1+ BCSLCs sorted from MDA-MB-231 could exhibit the tube formation and angiogenesis ability. Sorafenib could inhibit vascularization from endothelial cells rather than that from ALDH1+ cells. α-SMA was identified as a key molecule in vascular formation of BCSLCs. Mechanistically, HIF-1α enhanced the mRNA and protein levels of α-SMA by binding to the HRE element in the promoter directly and meanwhile increased the BCSLCs population. Interestingly, pigment epithelium-derived factor (PEDF), an endogenous angiogenesis inhibitor, could inhibit both endothelial cell-derived and tumor cell-derived angiogenesis by downregulating HIF-1α in breast cancer. Our finding clarified the possible reason for the poor outcome of anti-angiogenesis therapy and PEDF may have the therapeutic potential.

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Martin Almquist, Elin Isaksson and Naomi Clyne

Renal hyperparathyroidism (rHPT) is a complex and challenging disorder. It develops early in the course of renal failure and is associated with increased risks of fractures, cardiovascular disease and death. It is treated medically, but when medical therapy cannot control the hyperparathyroidism, surgical parathyroidectomy is an option. In this review, we summarize the pathophysiology, diagnosis, and medical treatment; we describe the effects of renal transplantation; and discuss the indications and strategies in parathyroidectomy for rHPT. Renal hyperparathyroidism develops early in renal failure, mainly as a consequence of lower levels of vitamin D, hypocalcemia, diminished excretion of phosphate and inability to activate vitamin D. Treatment consists of supplying vitamin D and reducing phosphate intake. In later stages calcimimetics might be added. RHPT refractory to medical treatment can be managed surgically with parathyroidectomy. Risks of surgery are small but not negligible. Parathyroidectomy should likely not be too radical, especially if the patient is a candidate for future renal transplantation. Subtotal or total parathyroidectomy with autotransplantation are recognized surgical options. Renal transplantation improves rHPT but does not cure it.

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Suzan Stelloo, Simon Linder, Ekaterina Nevedomskaya, Eider Valle-Encinas, Iris de Rink, Lodewyk Wessels, Henk van der Poel, Andries M. Bergman and Wilbert Zwart

Prostate cancer development and progression is largely dependent on androgen receptor (AR) signaling. AR is a hormone-dependent transcription factor, which binds to thousands of sites throughout the human genome to regulate expression of directly responsive genes, including pro-survival genes that enable tumor cells to cope with increased cellular stress. ERN1 and XBP1 – two key players of the unfolded protein response (UPR) – are among such stress-associated genes. Here, we show that XBP1 levels in primary prostate cancer are associated with biochemical recurrence in five independent cohorts. Patients who received AR-targeted therapies had significantly lower XBP1 expression, whereas expression of the active form of XBP1 (XBP1s) was elevated. In vitro results show that AR-induced ERN1 expression led to increased XBP1s mRNA and protein levels. Furthermore, ChIP-seq analysis revealed that XBP1s binds enhancers upon stress stimuli regulating genes involved in UPR processes, eIF2 signaling and protein ubiquitination. We further demonstrate genomic overlap of AR and XBP1s binding sites, suggesting genomic conversion of the two signaling cascades. Transcriptomic effects of XBP1 were further studied by knockdown experiments, which lead to decreased expression of androgen-responsive genes and UPR genes. These results suggest a two-step mechanism of gene regulation, which involves androgen-induced expression of ERN1, thereby enhancing XBP1 splicing and transcriptional activity. This signaling cascade may prepare the cells for the increased protein folding, mRNA decay and translation that accompanies AR-regulated tumor cell proliferation.

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Alastair H Davies, Amina Zoubeidi and Luke A. Selth

Tumours adapt to increasingly potent targeted therapies by transitioning to alternative lineage states. In prostate cancer, the widespread clinical application of androgen receptor pathway inhibitors has led to the insurgence of tumours relapsing with a neuroendocrine phenotype, termed neuroendocrine prostate cancer (NEPC). Recent evidence suggests that this lineage reprogramming is driven largely by dysregulation of the epigenome and transcriptional networks. Indeed, aberrant DNA methylation patterning and altered expression of epigenetic modifiers, such as EZH2, transcription factors and RNA-modifying factors, are hallmarks of NEPC tumours. In this review, we explore the nature of the epigenetic and transcriptional landscape as prostate cancer cells lose their AR-imposed identity and transition to the neuroendocrine lineage. Beyond addressing the mechanisms underlying epithelial-to-neuroendocrine lineage reprogramming, we discuss how oncogenic signaling and metabolic shifts fuel epigenetic/transcriptional changes as well as the current state of epigenetic therapies for NEPC.

Open access

Rajeev Mishra, Subhash Haldar, Surabhi Suchanti and Neil A Bhowmick

Genomic changes that drive cancer initiation and progression contribute to the co-evolution of the adjacent stroma. The nature of the stromal reprogramming involves differential DNA methylation patterns and levels that change in response to the tumor and systemic therapeutic intervention. Epigenetic reprogramming in carcinoma-associated fibroblasts are robust biomarkers for cancer progression and have a transcriptional impact that support cancer epithelial progression in a paracrine manner. For prostate cancer, promoter hypermethylation and silencing of the RasGAP, RASAL3 that resulted in the activation of Ras signaling in carcinoma-associated fibroblasts. Stromal Ras activity initiated a process of macropinocytosis that provided prostate cancer epithelia with abundant glutamine for metabolic conversion to fuel its proliferation and a signal to transdifferentiate into a neuroendocrine phenotype. This epigenetic oncogenic metabolic/signaling axis seemed to be further potentiated by androgen receptor signaling antagonists and contributed to therapeutic resistance. Intervention of stromal signaling may complement conventional therapies targeting the cancer cell.

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Wei-Chun Chang, Hsiao-Ching Wang, Wei-Chung Cheng, Juan-Cheng Yang, Wei-Min Chung, Yen-Pin Ho, Lumin Chen, Yao-Ching Hung and Wen-Lung Ma

Platinum-based therapy remains the cornerstone for cancer therapy; however, its efficacy varies. The role of lipoprotein receptors-mediated lipid entry for cancer development has been reported. Yet, the roles and mechanism of the low-density lipoprotein receptor (LDLR) in chemo-sensitivities are unknown. In the current report, we used epithelial ovarian cancer (EOC), composed of various cellularity, to study this issue. Using public cDNA microarray database and single cohort study, LDLR expressions were positively associated with epithelial ovarian carcinomas (EOCs) platinum-based chemotherapy patients disease prognosis. In vitro and in vivo add-in/silencing LDLR were introduced to determines cisplatin sensitivity and cancer growth. Result revealed knocked-down LDLR could sensitize while overexpressed LDLR could insensitize EOC cells to the cytotoxic effects of cisplatin. Moreover, the trans-omics approaches depicted an LDLR-->LPC (Lyso-phosphatidylcholine)-->FAM83B (phospholipase-related)-->FGFRs (cisplatin sensitivity and phospholipase-related) regulatory axis. Finally, the manipulation of LDLR expression in EOC cells was found to determine the efficacy of cisplatin therapy in terms of tumor suppression. In conclusion, the LDLR-->LPC-->FAM83B-->FGFRs axis is an example of tumor macroenvironmental regulation of therapy outcomes. Relatedly, LDLR expression could serve as a biomarker of chemotherapy sensitivity in EOCs.