FMRP promotes gastric cancer progression via m6A-dependent stabilization of DVL2 and activation of the Wnt/PCP-JNK pathway

Sep 22, 2026

N6-methyladenosine (m6A) modification drives gastric cancer progression, yet how m6A biology connects to specific oncogenic effectors remains unclear. Fragile X messenger ribonucleoprotein 1 (FMRP), an RNA-binding protein with tumorigenic potential, was investigated in gastric cancer. Using bioinformatics and tissue microarray-based immunohistochemistry, FMRP was found upregulated; knockdown suppressed growth and metastasis. Mechanistically, FMRP bound DVL2 mRNA and stabilized it in an m6A-dependent manner, activating noncanonical Wnt/PCP-JNK signaling.

LanguageEnglish

CategoryHealthcare

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Pages19

Reading Time48 min

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Abstract

Background

Methods

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Conclusions

Introduction

Hou et al. Journal of Translational Medicine (2026) 24:1139 [https://doi.org/10.1186/s12967-026-08834-3](https://doi.org/10.1186/s12967-026-08834-3) Journal of Translational Medicine RESEARCH Open Access FMRP promotes gastric cancer progression via m6A-dependent stabilization of DVL2 and activation oftheWnt/PCP-JNK pathway Xiaoyu Hou1†, Jinlan Gao1†, Xuesha Xing1, Qi Liu1, Ming Yi1, Chen Liu1, Qi Chu1, Mengdie Zou1, Meirong Hu 1 and Yang Luo 1* Abstract Background N6-methyladenosine (m6A) modification has emerged as a critical regulator in gastric cancer progression. Fragile X messenger ribonucleoprotein 1 (FMRP), an RNA-binding protein with tumorigenic potential, remains poorly characterized in gastric cancer. Methods FMRP expression in gastric cancer was assessed through bioinformatic analyses and tissue microarraybased immunohistochemistry. Its biological functions were examined through loss-of-function experiments in vitro and in vivo. Mechanistic investigations, including RNA interaction, m6A site mutation, and RNA stability analyses, were performed to identify downstream targets and pathways regulated by FMRP. Results Bioinformatic analyses and tissue microarray-based immunohistochemistry showed that FMRP was significantly upregulated in gastric cancer tissues. FMRP depletion suppressed tumor growth and metastasis. Subsequently, Dishevelled segment polarity protein 2 (DVL2) was identified as a candidate downstream target of FMRP. DVL2 was also significantly upregulated in gastric cancer tissues, and its expression positively correlated with FMRP expression. Mechanistically, FMRP bound to DVL2 mRNA and enhanced its stability in an m6A-dependent manner. Among the candidate sites tested, mutation of 1271A attenuated FMRP-mediated regulation of DVL2 reporter activity, supporting the involvement of this site. Functionally, FMRP promoted activation of the noncanonical Wnt/planar cell polarity (PCP) signaling pathway and enhanced the proliferative, migratory, and invasive capacities of gastric cancer cells via DVL2 . Conclusions These results define FMRP as an oncogenic driver in gastric cancer that operates via the DVL2/Wnt/PCP axis. Targeting this pathway may provide a potential therapeutic strategy for gastric cancer. Keywords FMRP, DVL2, m6A, Wnt/PCP-JNK pathway, Gastric cancer †Xiaoyu Hou and Jinlan Gao contributed equally to this work asco-first authors. *Correspondence: Yang Luo [yluo@cmu.edu.cn](yluo@cmu.edu.cn) 1The Research Center for Medical Genomics, Key Laboratory of Medical Cell Biology, Ministry of Education, School of Life Science, China Medical University, No. 77 Puhe Road, Shenyang North New Area, Shenyang, China © The Author(s) 2026. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creati](http://creati)[vecommons.org/licenses/by-nc-nd/4.0/](vecommons.org/licenses/by-nc-nd/4.0/.)[.](vecommons.org/licenses/by-nc-nd/4.0/.) Hou et al. Journal of Translational Medicine (2026) 24:1139 Introduction Global annual estimates by the International Agency for Research on C

FAQs

What role does m6A modification play in gastric cancer progression?

m6A modification is described as a critical regulator in gastric cancer progression, influencing RNA functions relevant to carcinogenesis.

How was FMRP evaluated in gastric cancer in this study?

FMRP expression was assessed using bioinformatic analyses and tissue microarray-based immunohistochemistry. Functional effects were tested with loss-of-function experiments in vitro and in vivo.

What mechanism links FMRP to DVL2 and Wnt/PCP-JNK signaling?

FMRP binds DVL2 mRNA and enhances its stability in an m6A-dependent manner. This upregulates DVL2 and promotes activation of the noncanonical Wnt/PCP signaling pathway, leading to increased proliferation, migration, and invasion.

Sep 22, 2026

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