Bairong Xia

miR-211 suppresses epithelial ovarian cancer proliferation and cell-cycle progression by targeting Cyclin D1 and CDK6

BackgroundEpithelial ovarian cancer (EOC) is a significant cause of morbidity and mortality. MicroRNAs play important roles in cancer development and progression. The microRNA miR-211 is localized on intron 6 of the Trpm1 gene at 15q13-q14, a locus that is frequently lost in neoplasms. Its function and loss-of-function have been described in normal and cancer cells and tissues. miR-211 is known to be dysregulated in ovarian cancer: however, its function and the downstream effect of its loss-of-function in ovarian cancer have not been described before.MethodsWe analyzed miR-211 expression in clinical samples of primary EOC tissues compared to normal epithelial ovarian tissues and in the EOC cell lines: OVCAR3, Caov3, OVCA429, SKOV3 and A2780 compared to human ovarian surface epithelial cells. We then investigated the effect of miR-211 on EOC cell proliferation and apoptosis by counting cell numbers, MTT, colony formation, cell cycle, and PI/Annexin V staining assays. A luciferase reporter system was developed to assess miR-211 regulation of the predicted targets. Expression level of discovered targets and correlation with miR-211 expression were analyzed in EOC tissues. Finally, OVCAR3 stably expressing miR-211 or control cells were injected subcutaneously into mice to determine in vivo effect of miR-211 on tumorigenesis.ResultsWe found that the expression of miR-211 is downregulated in EOC tissues and cell lines compared to normal epithelial ovarian tissue and human ovarian surface epithelial cells, respectively. miR-211 was found to arrest cells in the G0/G1-phase, inhibit proliferation and induce apoptosis. Cyclin D1 and CDK6 were found to be direct targets of miR-211, and when overexpressed in miR-211-expressing EOC cells, could restore proliferative ability. Finally, in vitro investigation confirmed that miR-211 is a tumor suppressor that controls Cyclin D1 and CDK6 expression.ConclusionsOur results demonstrate that miR-211 is a tumor suppressor that controls expression of Cyclin D1 and CDK6, and that its downregulation results in overexpression of Cyclin D1 and CDK6 which increases proliferation ability of EOC cells to proliferate compared to normal cells.

Long noncoding RNA CCHE1 promotes cervical cancer cell proliferation via upregulating PCNA

Long noncoding RNAs (lncRNAs) have been shown to play important roles in carcinogenesis and progression. However, the roles and functional mechanisms of lncRNAs in cervical cancer remain largely unknown. In this study, we found that cervical carcinoma high-expressed lncRNA 1 (lncRNA-CCHE1) was significantly upregulated in cervical cancer tissues. The higher expression of CCHE1 was significantly correlated with large tumor size, advanced Federation of Gynecology and Obstetrics stage, uterine corpus invasion, and poor survival. Gain-of-function and loss-of-function experiments demonstrated that CCHE1 overexpression promotes the proliferation of cervical cancer cell. By contrast, the depletion of CCHE1 inhibits the proliferation of cervical cancer cells. RNA pull-down assays confirmed that CCHE1 physically associates with proliferating cell nuclear antigen (PCNA) messenger RNA, consequently enhances the expression of PCNA. The expression of CCHE1 and PCNA is significantly correlated in cervical cancer tissues. The depletion of PCNA abolishes the effects of CCHE1 on the proliferation of cervical cancer cells. Taken together, these findings indicate that CCHE1 plays a pivotal role in cervical cancer cell proliferation via increasing PCNA expression and serves as a potential prognostic biomarker and therapeutic target in human cervical cancer.

miR-133a suppresses ovarian cancer cell proliferation by directly targeting insulin-like growth factor 1 receptor

The microRNA miR-133a is dysregulated in many types of cancer, but the underlying mechanism remains largely unknown. In this study, we showed that the expression level of miR-133a was reduced in ovarian cancer tissues compared with normal ovaries. Ectopic expression of miR-133a significantly inhibited ovarian cancer cell proliferation and colony formation, and induced G1-phase cell cycle arrest, whereas decreased miR-133a expression dramatically enhanced cell proliferation and colony formation. Importantly, miR-133a overexpression suppressed in vivo tumor growth in nude mice models. Through in silico search, we found that the 3′-untranslated region (UTR) of insulin-like growth factor 1 receptor (IGF1R) contains an evolutionarily conserved miR-133a binding site. miR-133a overexpression repressed IGF1R-3′UTR reporter activity, and reduced the mRNA and protein levels of endogenous IGF1R. Rescue experiments showed that ectopic expression of IGF1R significantly promoted the proliferation of ovarian cancer cells stably overexpressing miR-133a. Taken together, these findings indicate that miR-133a is an important regulator in ovarian cancer, and that its suppressive effects are mediated by targeting IGF1R.

MiR-381 inhibits epithelial ovarian cancer malignancy via YY1 suppression

Epithelial ovarian cancer (EOC) is a common type of gynecologic cancer, which accounts for the majority of deaths among all gynecologic malignant tumors in developed countries. A series of recent studies suggested that miR-381 might play important roles in the development of various cancer types. However, the biological function of miR-381 in EOC remains to be investigated. We examined the levels of miR-381 expression in EOC tissues and cell lines. We identified miR-381 target genes by bioinformatic prediction. We also characterized the phenotype regarding cell proliferation, cell migration, and cell invasion in EOC cells lines with altered expression levels of both miR-381 and its target gene, YY1. The expression levels of miR-381 were downregulated in EOC tissues and cell lines. Overexpression of miR-381 significantly inhibited EOC cell proliferation, migration, and invasion. Restoration of YY1 expression partially reversed the phenotype induced by miR-381 overexpression. Knockdown of miR-381 target gene, YY1, mimicked the phenotype induced by miR-381 overexpression. MiR-381 regulated EOC cell through miR-381/YY1/p53 and miR-381/YY1/Wnt signaling axis. We concluded that miR-381 inhibited EOC cell proliferation, migration, and invasion, at least in part, via suppressing YY1 expression.

Long non-coding RNA ZFAS1 interacts with miR-150-5p to regulate Sp1 expression and ovarian cancer cell malignancy

We reported that long non-coding RNA ZFAS1 was upregulated in epithelial ovarian cancer tissues, and was negatively correlated to the overall survival rate of patients with epithelial ovarian cancer in this study. While depletion of ZFAS1 inhibited proliferation, migration, and development of chemoresistance, overexpression of ZFAS1 exhibited an even higher proliferation rate, migration activity, and chemoresistance in epithelial ovarian cancer cell lines. We further found miR-150-5p was a potential target of ZFAS1, which was downregulated in epithelial ovarian cancer tissue. MiR-150-5p subsequently inhibited expression of transcription factor Sp1, as evidence by luciferase assays. Inhibition of miR-150-5p rescued the suppressed proliferation and migration induced by depletion of ZFAS1 in epithelial ovarian cancer cells, at least in part. Taken together, our findings revealed a critical role of ZFAS1/miR-150-5p/Sp1 axis in promoting proliferation rate, migration activity, and development of chemoresistance in epithelial ovarian cancer. And ZFAS1/miR-150-5p may serve as novel markers and therapeutic targets of epithelial ovarian cancer.

Overexpression of multiple myeloma SET domain (MMSET) is associated with advanced tumor aggressiveness and poor prognosis in serous ovarian carcinoma

Abstract Multiple myeloma SET domain (MMSET) has been shown to be overexpressed in many different cancer tissues. Our study was to investigate the expression of MMSET in serous ovarian carcinoma and to evaluate its clinical significance in patients with serous ovarian carcinoma. Immunohistochemistry was performed to determine the expression of MMSET in 132 serous ovarian carcinoma, 32 normal ovarian and fallopian tube specimens. The high expression of MMSET was observed in 49.2% (65/132) in patients with serous ovarian carcinoma. MMSET high expression correlated with the advanced extent of serous ovarian carcinoma and poor outcome. MMSET may serve as a new molecular marker to predict the prognosis of serous ovarian carcinoma in the clinic.

A Comprehensive Analysis of Metabolomics and Transcriptomics in Cervical Cancer

Cervical cancer (CC) still remains a common and deadly malignancy among females in developing countries. More accurate and reliable diagnostic methods/biomarkers should be discovered. In this study, we performed a comprehensive analysis of metabolomics (285 samples) and transcriptomics (52 samples) on the potential diagnostic implication and metabolic characteristic description in cervical cancer. Sixty-two metabolites were different between CC and normal controls (NOR), in which 5 metabolites (bilirubin, LysoPC(17:0), n-oleoyl threonine, 12-hydroxydodecanoic acid and tetracosahexaenoic acid) were selected as candidate biomarkers for CC. The AUC value, sensitivity (SE), and specificity (SP) of these 5 biomarkers were 0.99, 0.98 and 0.99, respectively. We further analysed the genes in 7 significantly enriched pathways, of which 117 genes, that were expressed differentially, were mainly involved in catalytic activity. Finally, a fully connected network of metabolites and genes in these pathways was built, which can increase the credibility of our selected metabolites. In conclusion, our biomarkers from metabolomics could set a path for CC diagnosis and screening. Our results also showed that variables of both transcriptomics and metabolomics were associated with CC.

Overexpression of eukaryotic initiation factor 5A2 (EIF5A2) is associated with cancer progression and poor prognosis in patients with early-stage cervical cancer

As one of the only two isoforms of the eukaryotic initiation factor (EIF)5A family, EIF5A2 plays an important role in tumour progression and prognosis evaluation. The aim of this study was to investigate EIF5A2 expression in International Federation of Gynecology and Obstetrics (FIGO) stage I–II cervical cancer and to evaluate its clinical significance.

Metabolic profiling and novel plasma biomarkers for predicting survival in epithelial ovarian cancer

Epithelial ovarian cancer (EOC) is one of the most lethal gynecological malignancies around the world, and patients with ovarian cancer always have an extremely poor chance of survival. Therefore, it is meaningful to develop a highly efficient model that can predict the overall survival for EOC. In order to investigate whether metabolites could be used to predict the survival of EOC, we performed a metabolic analysis of 98 plasma samples with follow-up information, based on the ultra-performance liquid chromatography mass spectrometry (UPLC/MS) systems in both positive (ESI+) and negative (ESI-) modes. Four metabolites: Kynurenine, Acetylcarnitine, PC (42:11), and LPE(22:0/0:0) were selected as potential predictive biomarkers. The AUC value of metabolite-based risk score, together with pathological stages in predicting three-year survival rate was 0.80. The discrimination performance of these four biomarkers between short-term mortality and long-term survival was excellent, with an AUC value of 0.82. In conclusion, our plasma metabolomics study presented the dysregulated metabolism related to the survival of EOC, and plasma metabolites could be utilized to predict the overall survival and discriminate the short-term mortality and long-term survival for EOC patients. These results could provide supplementary information for further study about EOC survival mechanism and guiding the appropriate clinical treatment.

KIAA0101, a target gene of miR-429, enhances migration and chemoresistance of epithelial ovarian cancer cells

BackgroundOvarian cancer is a common type of gynecological malignancies, and is the fifth leading cause of cancer-related death in women in the United States. MiR-429 and KIAA0101 have been found to be involved in several human malignancies, respectively. However, the role of miR-429 and KIAA0101, and the correlation between them during development of epithelial ovarian cancer (EOC) remain to be investigated.MethodsThe expression of KIAA0101 in EOC tissues and cells was measured by Quantitative real-time PCR, western blot, and immunochemistry. Cell proliferation assay, colony formation assay, and transwell assay was performed to assess the role of miR-429 and KIAA0101 in regulation of proliferation, migration, and chemoresistance of EOC cells. Luciferase assay was used to test the Wnt/β-catenin signaling activity in response to depletion of KIAA0101 and overexpression of miR-429.ResultsWe found that KIAA0101 was upregulated in metastatic EOC tissues, compared to primary EOC tissues, and KIAA0101 was required for the migration activity and chemoresistance of EOC cells by enhancing Wnt/β-catenin signaling. Furthermore, we revealed KIAA0101 is direct target of miR-429. Similar to knockdown of KIAA0101, overexpression of miR-429 reduced invasion and chemoresistance of EOC cells. Co-transfection of KIAA0101 partially abrogates the inhibitory effects on invasion and chemoresistance in EOC cells.ConclusionsKIAA0101, a target gene of miR-429, was upregulated in the metastatic EOC tissues, and enhanced the migration activity and chemoresistance of EOC cells. Both miR-429 and KIAA0101 may represent the potential therapeutic targets of EOC.