Vitamin D receptor upregulates lncRNA TOPORS-AS1 which inhibits the Wnt/β-catenin pathway and associates with favorable prognosis of ovarian cancer

AbstractLong non-coding RNAs (lncRNAs) have important biological functions, but their involvement in ovarian cancer remains elusive. We analyzed high-throughput data to identify lncRNAs associated with ovarian cancer outcomes. Our search led to the discovery of lncRNA TOPORS Antisense RNA 1 (TOPORS-AS1). Patients with high TOPORS-AS1 expression had favorable overall survival compared to low expression. This association was replicated in our study and confirmed by meta-analysis. In vitro experiments demonstrated that overexpressing TOPORS-AS1 in ovarian cancer cells suppressed cell proliferation and inhibited aggressive cell behaviors, including migration, invasion, and colony formation. Analysis of tumor cell transcriptomes indicated TOPORS-AS1′s influence on the Wnt/β-catenin signaling. Additional experiments revealed that TOPORS-AS1 increased the phosphorylation of β-catenin and suppressed the expression of CTNNB1, disrupting the Wnt/β-catenin pathway. Our experiments further discovered that vitamin D receptor (VDR) upregulated TOPORS-AS1 expression and that inhibition of β-catenin by TOPORS-AS1 required a RNA binding protein, hnRNPA2B1 (heterogeneous nuclear ribonucleoprotein A2B1). Taken together, these findings suggest that TOPORS-AS1 may behave like a tumor suppressor in ovarian cancer through interrupting the Wnt/β-catenin signaling and that VDR upregulates the expression of TOPORS-AS1. Assessing TOPORS-AS1 expression in ovarian cancer may help predict disease prognosis and develop treatment strategy

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Vitamin D receptor rs2228570 polymorphism and susceptibility to ovarian cancer: An updated meta-analysis

Journal of Obstetrics and Gynaecology Research ◽

10.1111/jog.13534 ◽

2017 ◽

Vol 44 (3) ◽

pp. 556-565 ◽

Cited By ~ 8

Author(s):

Hongmei Chen ◽

Jin Zhu

Keyword(s):

Ovarian Cancer ◽

Vitamin D ◽

Vitamin D Receptor ◽

Meta Analysis

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Role of Rb Family in Vitamin D Receptor-Mediated Anti-Tumor Effects in Ovarian Cancer Cells.

10.1210/endo-meetings.2010.part1.p1.p1-9 ◽

2010 ◽

pp. P1-9-P1-9

Author(s):

J Tang ◽

P Li ◽

AKW Tse ◽

SV Nicosia ◽

X Zhang ◽

...

Keyword(s):

Ovarian Cancer ◽

Vitamin D ◽

Cancer Cells ◽

Vitamin D Receptor ◽

Ovarian Cancer Cells

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1α,25‑Dihydroxyvitamin�D3 restrains stem cell‑like properties of ovarian cancer cells by enhancing vitamin�D receptor and suppressing CD44

Oncology Reports ◽

10.3892/or.2019.7116 ◽

2019 ◽

Cited By ~ 4

Author(s):

Mintao Ji ◽

Lizhi Liu ◽

Yongfeng Hou ◽

Bingyan Li

Keyword(s):

Ovarian Cancer ◽

Vitamin D ◽

Stem Cell ◽

Cancer Cells ◽

Vitamin D Receptor ◽

Ovarian Cancer Cells ◽

Dihydroxyvitamin D3

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CPEB4-Promoted Paclitaxel Resistance in Ovarian Cancer In Vitro Relies on Translational Regulation of CSAG2

Frontiers in Pharmacology ◽

10.3389/fphar.2020.600994 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yaqing Zhang ◽

Hongyun Gan ◽

Fei Zhao ◽

Xiaomei Ma ◽

Xiaofeng Xie ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Cell Lines ◽

Cancer Cell ◽

Rna Binding ◽

Ovarian Cancer Cells ◽

Drug Resistant ◽

Paclitaxel Resistance ◽

Cytoplasmic Polyadenylation

Background: Drug resistance is a major obstacle in chemotherapy for ovarian cancer, wherein the up regulation of drug-resistant genes plays an important role. The cytoplasmic polyadenylation element binding protein 4 (CPEB4) is an RNA binding protein that controls mRNA cytoplasmic polyadenylation and translation.Methods: The expression of CPEB4 in paclitaxel-resistant ovarian cancer cell lines and recurrent ovarian tumors relative to counterparts was determined by qRT-PCR, Western blotting and immunohistochemistry. The response to paclitaxel treatment was evaluated by cellular viability test and colony formation assay. RNA immunoprecipitation and poly(A) tail test were applied to examine the levels of RNA binding and cytoplasmic polyadenylation.Results: CPEB4 is elevated in paclitaxel-resistant ovarian cancer cells and recurrent ovarian tumors treated with paclitaxel-based chemotherapy. In addition, CPEB4 overexpression promotes paclitaxel resistance in ovarian cancer cells in vitro, and vice versa, CPEB4 knockdown restores paclitaxel sensitivity, indicating that CPEB4 confers paclitaxel resistance in ovarian cancer cells. Mechanistically, CPEB4 binds with the taxol (paclitaxel)-resistance-associated gene-3 (TRAG-3/CSAG2) mRNAs and induces its expression at a translational level. Moreover, CSAG2 expression is upregulated in paclitaxel-resistant ovarian carcinoma and cancer cell lines, and more importantly, siRNA-mediated CSAG2 knockdown overtly attenuates CPEB4-mediated paclitaxel resistance.Conclusion: This study suggests that the drug-resistant protein CSAG2 is translationally induced by CPEB4, which underlies CPEB4-promoted paclitaxel resistance in ovarian cancer in vitro. Thus, interfering CPEB4/CSAG2 axis might be of benefit to overcome paclitaxel-resistant ovarian cancer.

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Vitamin D Receptor BsmІ Polymorphism and Ovarian Cancer Risk: A Meta-Analysis

International Journal of Gynecological Cancer ◽

10.1097/igc.0b013e31829db839 ◽

2013 ◽

Vol 23 (7) ◽

pp. 1178-1183 ◽

Cited By ~ 7

Author(s):

Xue Qin ◽

Yu Lu ◽

Aiping Qin ◽

Zhiping Chen ◽

Qiliu Peng ◽

...

Keyword(s):

Ovarian Cancer ◽

Vitamin D ◽

Vitamin D Receptor ◽

Meta Analysis ◽

Asian Population ◽

European Population ◽

Ovarian Cancer Risk ◽

Bsmi Polymorphism ◽

Inheritance Model ◽

The Relationship

ObjectiveVitamin D receptor (VDR) FokI polymorphism has been reported to influence ovarian cancer (OC) susceptibility, but the association between VDR BsmI polymorphism and OC risk remains controversial. To clarify the relationship between them, we performed a meta-analysis.MethodsA comprehensive literature search was conducted to examine all the eligible studies of VDR BsmI polymorphism and OC risk. Odds ratios (OR) with 95% confidence intervals (95% CI) were used to assess the strength of this association.ResultsSeven separate comparisons consisting of 1977 OC cases and 2832 healthy controls were included in our meta-analysis. The pooled analyses showed no significant association between VDR BsmI G/A polymorphism and OC in all of the comparisons (AA vs GG: OR, 1.01; P = 0.919; AG vs GG: OR, 1.12; P = 0.087; AG + AA vs GG: OR, 1.10; P = 0.146; AA vs AG + GG: OR, 0.96; P = 0.629). However, subgroup analysis showed a significant contribution of the dominant inheritance model to OC development in the European group: AG + AA vs GG (OR, 1.43; P = 0.029); AG vs GG (OR, 1.46; P = 0.031).ConclusionsVitamin D receptor BsmI G/A gene variant might be a moderate risk factor of OC development in the European population instead of North America or Asian population.

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