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The lncRNA XIST/miR-125b-2-3p Axis Modulates Cell Proliferation and Chemotherapeutic Sensitivity via Targeting Wee1 in Colorectal Cancer
55 Pages Posted: 22 Aug 2019
More...Abstract
Background: Accumulating evidence has demonstrated that microRNAs regulate diverse tumorigenic processes and play important roles in tumor metastasis and growth. Recently, miR-125b-2-3p was identified as a meaningful prognostic factor for predicting chemotherapeutic sensitivity in advanced colorectal cancer (CRC). However, the biological functions and molecular mechanisms of miR-125b-2-3p in the chemotherapy of advanced CRC have yet to be elucidated.
Methods: MiR-125b-2-3p expression was detected by real-time PCR in CRC tissues. Gain-of-function experiments were performed to assess the effect of miR-125b-2-3p on CRC growth, metastasis, invasion and drug sensitivity in vitro and in vivo. Based on multiple databases, the competitive endogenous RNAs (ceRNAs) and target genes for miR-125b-2-3p were predicted and have been confirmed by bioinformatic analysis, luciferase reporter assays, rescue experiments and western blot assays.
Findings: MiR-125b-2-3p expression was significantly downregulated in CRC tissues and cell lines. MiR-125b-2-3p overexpression was correlated with lower proliferation rates, fewer metastases and better chemotherapeutic sensitivity in vitro and in vivo. Mechanistically, miR-125b-2-3p was regulated by lncRNA XIST and influenced the expression of the WEE1 G2 checkpoint kinase (WEE1).
Interpretation: These findings suggested that the lncRNA XIST-miR-125b-2-3p-WEE1 axis not only regulated CRC growth and metastasis but also contributed to chemotherapeutic resistance, thus identifying a potential therapeutic target for CRC.
Funding: National Natural Science Foundation of China (81572392), Guangdong special support program (2016TQ03R614), National Key R&D Program of China (2018YFC1313300); Natural Science Foundation of Guangdong Province (2014A030312015); Science and Technology Program of Guangdong (2019B020227002); Science and Technology Program of Guangzhou (201904020046, 201803040019, 201704020228).
Declaration of Interest: The authors declare no conflicts of interest.
Ethical Approval: This study was approved by the institutional ethics review board of SYSUCC (Guangzhou, China). Our animal study was approved by the Institutional Animal Care and Use Committee of Sun Yat-sen University.
Keywords: colorectal cancer (CRC), miR-125b-2-3p, chemotherapeutic sensitivity, drug resistance
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