Dataset Information

Mir20a/106a-WTX axis regulates RhoGDIa/CDC42 signaling and colon cancer progression.

ABSTRACT: Wilms tumor gene on the X chromosome (WTX) is a putative tumor suppressor gene in Wilms tumor, but its expression and functions in other tumors are unclear. Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in women and the second leading cause in men in the United States. We demonstrated that WTX frequently lost in CRC which was highly correlated with cell proliferation, tumor invasion and metastasis. Mechanistically, WTX loss disrupts the interaction between RhoGDI? and CDC42 by losing of the binding with RhoGDI? and triggers the activation of CDC42 and its downstream cascades, which promotes CRC development and liver metastasis. The aberrant upregulation of miR-20a/miR-106a were identified as the reason of WTX loss in CRC both in vivo and in vitro. These study defined the mechanism how miR-20a/miR-106a-mediated WTX loss regulates CRC progression and metastasis, and provided a potential therapeutic target for preventing CRC progression.

SUBMITTER: Zhu GF

PROVIDER: S-EPMC6328557 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Mir20a/106a-WTX axis regulates RhoGDIa/CDC42 signaling and colon cancer progression.

Zhu Gui-Fang GF Xu Yang-Wei YW Li Jian J Niu Hui-Lin HL Ma Wen-Xia WX Xu Jia J Zhou Pei-Rong PR Liu Xia X Ye Dan-Li DL Liu Xiao-Rong XR Yan Tao T Zhai Wei-Ke WK Xu Zhi-Jun ZJ Liu Chun C Wang Lei L Wang Hao H Luo Jia-Mao JM Liu Li L Li Xuan-Qi XQ Guo Suiqun S Jiang Hui-Ping HP Shen Peng P Lin Hui-Kuan HK Yu Di-Hua DH Ding Yan-Qing YQ Zhang Qing-Ling QL

Nature communications 20190110 1

Wilms tumor gene on the X chromosome (WTX) is a putative tumor suppressor gene in Wilms tumor, but its expression and functions in other tumors are unclear. Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in women and the second leading cause in men in the United States. We demonstrated that WTX frequently lost in CRC which was highly correlated with cell proliferation, tumor invasion and metastasis. Mechanistically, WTX loss disrupts the interaction between RhoGDIα a ...[more]

PMID: 30631060

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Project description:BackgroundThe linear long non-coding RNA P14AS has previously been reported to be dysregulated in colon cancer, but the mechanistic role that P14AS plays in colon cancer progression has yet to be clarified. Accordingly, this study was developed to explore the regulatory functions of ANRIL linear transcript-P14AS in cancer.MethodsThe expression of P14AS, ANRIL, miR-23a-5p and their target genes were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot. Cell supernatants of IL6 and IL8 were measured by Enzyme linked immunosorbent (ELISA) assay. Dual-luciferase reporter assays, RNA immunoprecipitation, or pull-down assays were used to confirm the target association between miR-23a-5p and P14AS or UBE2D3. Cell proliferation and chemosensitivity of NF-κB inhibitor BAY 11-7085 were evaluated by cell counting kit 8 (CCK8).ResultsWhen P14AS was overexpressed in colon cancer cell lines, enhanced TNF-NF-κB signaling pathway activity was observed together with increases in IL6 and IL8 expression. The Pita, miRanda, and RNA hybrid databases revealed the ability of miR-23a-5p to interact with P14AS, while UBE2D3 was further identified as a miR-23a-5p target gene. The results of dual-luciferase reporter, RNA pull-down, and RNA immunoprecipitation experiments confirmed these direct interactions among P14AS/miR-23a-5p/UBE2D3. The degradation of IκBa mediated by UBE2D3 may contribute to enhanced NF-κB signaling in these cells. Moreover, the beneficial impact of P14AS on colon cancer cell growth was eliminated when cells were treated with miR-23a-5p inhibitors or UBE2D3 was silenced. As such, these findings strongly supported a role for the UBE2D3/IκBa/NF-κB signaling axis as a mediator of the ability of P14AS to promote colon cancer progression.ConclusionsThese data suggested a mechanism through which the linear ANRIL transcript P14AS can promote inflammation and colon cancer progression through the sequestration of miR-23a-5p and the modulation of NF-κB signaling activity, thus highlighting P14AS as a promising target for therapeutic intervention efforts.

Dataset Information

Mir20a/106a-WTX axis regulates RhoGDIa/CDC42 signaling and colon cancer progression.

Publications

Mir20a/106a-WTX axis regulates RhoGDIa/CDC42 signaling and colon cancer progression.

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