Oxidative stress is considered to be involved in the pathophysiology of all cancers. In order to evaluate the total oxidant/antioxidant status in patients with thyroid cancer and to investigate the relationship between oxidative stress parameters and serum thyroid profiles among thyroid cancer patients and various controls, we determined oxidative status including total antioxidant status (TAS) and total oxidant status (TOS) and calculation of oxidative stress index (OSI) in sera in 82 thyroid cancer patients, 56 benign thyroid disease patients, and 50 healthy controls. It was found that serum TAS levels were significantly lower in patients with thyroid cancer than in controls (P<0.001), while serum TOS levels and OSI values were significantly higher (both P<0.001) in the cancer patients. No significant correlations were observed between various oxidative stress markers and thyroid profiles in either the thyroid cancer patients or the controls. Receiver operating characteristic curve analysis demonstrated that OSI was the best indicator for distinguishing cancer patients from benign thyroid diseased or healthy controls, followed by TOS and TAS. Risk estimate statistics also indicated that TOS and/or OSI were good risk factors to discriminate patients with thyroid cancer from two controls. These findings suggested that oxidants are increased and antioxidants are decreased in patients with thyroid cancer. OSI may be a more useful oxidative stress biomarker than TAS and TOS for monitoring the clinical status of thyroid cancer patients.
Dong Wang, Jia-Fu Feng, Ping Zeng, Yun-Hong Yang, Jun Luo and Yu-Wei Yang
Jay H Fowke, Charles E Matthews, Herbert Yu, Qiuyin Cai, Sarah Cohen, Maciej S Buchowski, Wei Zheng and William J Blot
African–American (AA) race/ethnicity, lower body mass index (BMI), and higher IGF1 levels are associated with premenopausal breast cancer risk. This cross-sectional analysis investigated whether BMI or BMI at age 21 years contributes to racial differences in IGF1, IGF2, IGF-binding protein 3 (IGFBP3), or free IGF1. Participants included 816 white and 821 AA women between ages 40 and 79 years across a wide BMI range (18.5–40 kg/m2). Compared with white women, AA women had higher mean IGF1 (146.3 vs 134.4 ng/ml) and free IGF1 (0.145 vs 0.127) levels, and lower IGF2 (1633.0 vs 1769.3 ng/ml) and IGFBP3 (3663.3 vs 3842.5 ng/ml) levels (all P<0.01; adjusted for age, height, BMI, BMI at age 21 years, and menopausal status). Regardless of race, IGF1 and free IGF1 levels rose sharply as BMI increased to 22–24 kg/m2, and then declined thereafter, while IGF2 and IGFBP3 levels tended to rise with BMI. In contrast, BMI at age 21 years was inversely associated with all IGF levels, but only among white women (P-interaction=0.01). With the decline in IGF1 with BMI at age 21 years among whites, racial differences in IGF1 significantly increased among women who were obese in early adulthood. In summary, BMI was associated with IGF1 levels regardless of race/ethnicity, while obesity during childhood or young adulthood may have a greater impact on IGF1 levels among white women. The effects of obesity throughout life on the IGF axis and racial differences in breast cancer risk require study.
Fabia De Oliveira Andrade, Wei Yu, Xiyuan Zhang, Elissa Carney, Rong Hu, Robert Clarke, Kevin FitzGerald and Leena Hilakivi-Clarke
Resistance to endocrine therapy remains a clinical challenge in the treatment of estrogen receptor-positive (ER+) breast cancer. We investigated if adding a traditional Asian herbal mixture consisting of 12 herbs, called Jaeumkanghwa-tang (JEKHT), to tamoxifen (TAM) therapy might prevent resistance and recurrence in the ER+ breast cancer model of 7,12-dimethylbenz[a]anthracene (DMBA)-exposed Sprague–Dawley rats. Rats were divided into four groups treated as follows: 15 mg/kg TAM administered via diet as TAM citrate (TAM only); 500 mg/kg JEKHT administered via drinking water (JEKHT only group); TAM + JEKHT and no treatment control group. The study was replicated using two different batches of JEKHT. In both studies, a significantly higher proportion of ER+ mammary tumors responded to TAM if animals also were treated with JEKHT (experiment 1: 47% vs 65%, P = 0.015; experiment 2: 43% vs 77%, P < 0.001). The risk of local recurrence also was reduced (31% vs 12%, P = 0.002). JEKHT alone was mostly ineffective. In addition, JEKHT prevented the development of premalignant endometrial lesions in TAM-treated rats (20% in TAM only vs 0% in TAM + JEKHT). Co-treatment of antiestrogen-resistant LCC9 human breast cancer cells with 1.6 mg/mL JEKHT reversed their TAM resistance in dose–response studies in vitro. Several traditional herbal medicine preparations can exhibit anti-inflammatory properties and may increase anti-tumor immune activities in the tumor microenvironment. In the tumors of rats treated with both JEKHT and TAM, expression of Il-6 (P = 0.03), Foxp3/T regulatory cell (Treg) marker (P = 0.033) and Tgfβ1 that activates Tregs (P < 0.001) were significantly downregulated compared with TAM only group. These findings indicate that JEKHT may prevent TAM-induced evasion of tumor immune responses.
Xianhui Ruan, Xianle Shi, Qiman Dong, Yang Yu, Xiukun Hou, Xinhao Song, Xi Wei, Lingyi Chen and Ming Gao
There is no effective treatment for patients with poorly differentiated papillary thyroid cancer or anaplastic thyroid cancer (ATC). Anlotinib, a multi-kinase inhibitor, has already shown antitumor effects in various types of carcinoma in a phase I clinical trial. In this study, we aimed to better understand the effect and efficacy of anlotinib against thyroid carcinoma cells in vitro and in vivo. We found that anlotinib inhibits the cell viability of papillary thyroid cancer and ATC cell lines, likely due to abnormal spindle assembly, G2/M arrest, and activation of TP53 upon anlotinib treatment. Moreover, anlotinib suppresses the migration of thyroid cancer cells in vitro and the growth of xenograft thyroid tumors in mice. Our data demonstrate that anlotinib has significant anticancer activity in thyroid cancer, and potentially offers an effective therapeutic strategy for patients of advanced thyroid cancer type.
Yu-fang Bi, Rui-xin Liu, Lei Ye, Hai Fang, Xiao-ying Li, Wei-qing Wang, Ji Zhang, Kan-Kan Wang, Lei Jiang, Ting-wei Su, Zhong-yuan Chen and Guang Ning
Although there has been increased knowledge about the molecular biology of neuroendocrine tumors (NETs), little is known about thymic carcinoids and even less about those with excessive hormone disorders, such as ectopic ACTH syndrome. This study was designed to gain insights into the molecular networks underlying the tumorigenesis of thymic carcinoids with ACTH secretion. By an approach integrating cDNA microarray and methods of computational biology, we compare gene expression profile between ACTH-producing thymic carcinoids and the normal thymus. In total, there are 63 biological categories increased and 108 decreased in thymic carcinoids. Cell proliferation was stimulated, which may explain the relatively uncontrolled cell growth of the tumor. Dysregulation of the Notch-signaling pathway was likely to be underlying the neuroendocrine features of this type of tumors. Moreover, inhibition of immunity and increased neuropeptide signaling molecules (POMC and its sorting molecule CPE) made the clinical manifestation reasonable and thus validated the array data. In conclusion, thymic carcinoids have a distinct gene expression pattern from the normal thymus, and they are characterized by deregulations of a series of biofunctions, which may be involved in the development of NETs. Hence, this study has provided not only a detailed comprehension of the molecular pathogenesis of thymic carcinoids with ectopic ACTH syndrome, but also a road map to approach thymic NETs at the system level.
Yu-Tang Chin, Po-Li Wei, Yih Ho, André Wendindondé Nana, Chun A Changou, Yi-Ru Chen, Yu-Chen SH Yang, Meng-Ti Hsieh, Aleck Hercbergs, Paul J Davis, Ya-Jung Shih and Hung-Yun Lin
Thyroid hormone, l-thyroxine (T4), has been shown to promote ovarian cancer cell proliferation via a receptor on plasma membrane integrin αvβ3 and to induce the activation of ERK1/2 and expression of programmed death-ligand 1 (PD-L1) in cancer cells. In contrast, resveratrol binds to integrin αvβ3 at a discrete site and induces p53-dependent antiproliferation in malignant neoplastic cells. The mechanism of resveratrol action requires nuclear accumulation of inducible cyclooxygenase (COX)-2 and its complexation with phosphorylated ERK1/2. In this study, we examined the mechanism by which T4 impairs resveratrol-induced antiproliferation in human ovarian cancer cells and found that T4 inhibited resveratrol-induced nuclear accumulation of COX-2. Furthermore, T4 increased expression and cytoplasmic accumulation of PD-L1, which in turn acted to retain inducible COX-2 in the cytoplasm. Knockdown of PD-L1 by small hairpin RNA (shRNA) relieved the inhibitory effect of T4 on resveratrol-induced nuclear accumulation of COX-2- and COX-2/p53-dependent gene expression. Thus, T4 inhibits COX-2-dependent apoptosis in ovarian cancer cells by retaining inducible COX-2 with PD-L1 in the cytoplasm. These findings provide new insights into the antagonizing effect of T4 on resveratrol’s anticancer properties.
Yu-Li Chen, Cheng-Yang Chou, Ming-Cheng Chang, Han-Wei Lin, Ching-Ting Huang, Shu-Feng Hsieh, Chi-An Chen and Wen-Fang Cheng
Aside from tumor cells, ovarian cancer-related ascites contains the immune components. The aim of this study was to evaluate whether a combination of clinical and immunological parameters can predict survival in patients with ovarian cancer. Ascites specimens and medical records from 144 ovarian cancer patients at our hospital were used as the derivation group to select target clinical and immunological factors to generate a risk-scoring system to predict patient survival. Eighty-two cases from another hospital were used as the validation group to evaluate this system. The surgical status and expression levels of interleukin 17a (IL17a) and IL21 in ascites were selected for the risk-scoring system in the derivation group. The areas under the receiver operating characteristic (AUROC) curves of the overall score for disease-free survival (DFS) of the ovarian cancer patients were 0.84 in the derivation group, 0.85 in the validation group, and 0.84 for all the patients. The AUROC curves of the overall score for overall survival (OS) of cases were 0.78 in the derivation group, 0.76 in the validation group, and 0.76 for all the studied patients. Good correlations between overall risk score and survival of the ovarian cancer patients were demonstrated by sub-grouping all participants into four groups (P for trend <0.001 for DFS and OS). Therefore, acombination of clinical and immunological parameters can provide a practical scoring system to predict the survival of patients with ovarian carcinoma. IL17a and IL21 can potentially be used as prognostic and therapeutic biomarkers.
Han-Wei Lin, Ying-Cheng Chiang, Nai-Yun Sun, Yu-Li Chen, Chi-Fang Chang, Yi-Jou Tai, Chi-An Chen and Wen-Fang Cheng
The role of chitinase-3-like protein 1 (CHI3L1) in ovarian cancer and the possible mechanisms were elucidated. CHI3L1 is a secreted glycoprotein and associated with inflammation, fibrosis, asthma, extracellular tissue remodeling and solid tumors. Our previous study showed CHI3L1 could be a potential prognostic biomarker for epithelial ovarian cancer and could protect cancer cells from apoptosis. Therefore, clinical data and quantitation of CHI3L1 of ovarian cancer patients, tumor spheroid formation, side-population assays, Aldefluor and apoptotic assays, ELISA, RT-PCR, immunoblotting and animal experiments were performed in two ovarian cancer cells lines, OVCAR3 and CA5171, and their CHI3L1-overexpressing and -knockdown transfectants. High expression of CHI3L1 was associated with poor outcome and chemoresistance in ovarian cancer patients. The mRNA expression of CHI3L1 in CA5171 ovarian cancer stem-like cells was 3-fold higher than in CA5171 parental cells. CHI3L1 promoted the properties of ovarian cancer stem-like cells including generating more and larger tumor spheroids and a higher percentage of ALDH+ in tumor cells and promoting resistance to cytotoxic drug-induced apoptosis. CHI3L1 could induce both the Akt (essential) and Erk signaling pathways, and then enhance expression of β-catenin followed by SOX2, and finally promote tumor spheroid formation and other properties of ovarian cancer stem-like cells. OVCAR3 CHI3L1-overexpressing transfectants were more tumorigenic in vivo, whereas CA5171 CHI3L1-knockdown transfectants were not tumorigenic in vivo. CHI3L1 critically enhances the properties of ovarian cancer stem-like cells. CHI3L1 or CHI3L1-regulated signaling pathways and molecules could be potential therapeutic targets in ovarian cancer.
Xiao-hui Luo, Jian-zhou Liu, Bo Wang, Qun-li Men, Yu-quan Ju, Feng-yan Yin, Chao Zheng and Wei Li
Insights into the mechanisms by which key factors stimulate cell growth under androgen-depleted conditions is a premise to the development of effective treatments with clinically significant activity in patients with castration-resistant prostate cancer (CRPC). Herein, we report that, the expression of Krüppel-like factor 14 (KLF14), a master transcription factor in the regulation of lipid metabolism, was significantly induced in castration-insensitive PCa cells and tumor tissues from a mouse xenograft model of CRPC. KLF14 upregulation in PCa cells, which was stimulated upstream by oxidative stress, was dependent on multiple pathways including PI3K/AKT, p42/p44 MAPK, AMPK and PKC pathways. By means of ectopic overexpression and genetic inactivation, we further show that KLF14 promoted cell growth via positive regulation of the antioxidant response under androgen-depleted conditions. Mechanistically, KLF14 coupled to p300 and CBP to enhance the transcriptional activation of HMOX1, the gene encoding the antioxidative enzyme heme oxygenase-1 (HO-1) that is one of the most important mechanisms of cell adaptation to stress. Transient knockdown of HMOX1 is sufficient to overcome KLF14 overexpression-potentiated PCa cell growth under androgen-depleted conditions. From a pharmacological standpoint, in vivo administration of ZnPPIX (a specific inhibitor of HO-1) effectively attenuates castration-resistant progression in the mouse xenograft model, without changing KLF14 level. Together, these results provide comprehensive insight into the KLF14-dependent regulation of antioxidant response and subsequent pathogenesis of castration resistance and indicate that interventions targeting the KLF14/HO-1 adaptive mechanism should be further explored for CRPC treatment.
Allison Sumis, Katherine L Cook, Fabia O Andrade, Rong Hu, Emma Kidney, Xiyuan Zhang, Dominic Kim, Elissa Carney, Nguyen Nguyen, Wei Yu, Kerrie B Bouker, Idalia Cruz, Robert Clarke and Leena Hilakivi-Clarke
Social isolation is a strong predictor of early all-cause mortality and consistently increases breast cancer risk in both women and animal models. Because social isolation increases body weight, we compared its effects to those caused by a consumption of obesity-inducing diet (OID) in C57BL/6 mice. Social isolation and OID impaired insulin and glucose sensitivity. In socially isolated, OID-fed mice (I-OID), insulin resistance was linked to reduced Pparg expression and increased neuropeptide Y levels, but in group-housed OID fed mice (G-OID), it was linked to increased leptin and reduced adiponectin levels, indicating that the pathways leading to insulin resistance are different. Carcinogen-induced mammary tumorigenesis was significantly higher in I-OID mice than in the other groups, but cancer risk was also increased in socially isolated, control diet-fed mice (I-C) and G-OID mice compared with that in controls. Unfolded protein response (UPR) signaling (GRP78; IRE1) was upregulated in the mammary glands of OID-fed mice, but not in control diet-fed, socially isolated I-C mice. In contrast, expression of BECLIN1, ATG7 and LC3II were increased, and p62 was downregulated by social isolation, indicating increased autophagy. In the mammary glands of socially isolated mice, but not in G-OID mice, mRNA expressions of p53 and the p53-regulated autophagy inducer Dram1 were upregulated, and nuclear p53 staining was strong. Our findings further indicated that autophagy and tumorigenesis were not increased in Atg7+/− mice kept in social isolation and fed OID. Thus, social isolation may increase breast cancer risk by inducing autophagy, independent of changes in body weight.