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HNRNPC 通过 FOXM1 的 m6A 依赖性可变剪接介导宫颈癌的淋巴转移。

HNRNPC mediates lymphatic metastasis of cervical cancer through m6A-dependent alternative splicing of FOXM1.

机构信息

Department of Obstetrics and Gynecology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.

Guangdong Provincial Clinical Research Center for Obstetrical and Gynecological Diseases, Guangzhou, Guangdong, China.

出版信息

Cell Death Dis. 2024 Oct 7;15(10):732. doi: 10.1038/s41419-024-07108-4.

DOI:10.1038/s41419-024-07108-4
PMID:39375330
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11458786/
Abstract

Cervical cancer (CCa) patients with lymph node (LN) metastasis face poor prognoses and have limited treatment options. Aberrant N6-methyladenosine (mA) modification of RNAs are known to promote tumor metastasis, but their role in CCa remains unclear. Our study reveals that HNRNPC, an alternative splicing (AS) factor and mA reader, increases tumor-related variants through mA-dependent manner, thereby promoting lymphatic metastasis in CCa. We found that HNRNPC overexpression correlates with lymphatic metastasis and poorer prognoses in CCa patients. Functionally, knocking down HNRNPC markedly inhibited the migration and invasion of several CCa cell lines, while supplementing HNRNPC restored the malignant phenotypes of these cells. Mechanistically, HNRNPC regulates exon skipping of FOXM1 by binding to its m6A-modified motif. Mutating the mA site on FOXM1 weakened the interaction between HNRNPC and FOXM1 pre-RNA, leading to a reduction in the metastasis-related FOXM1-S variant. In conclusion, our findings demonstrate that mA-dependent alternative splicing mediated by HNRNPC is essential for lymphatic metastasis in CCa, potentially providing novel clinical markers and therapeutic strategies for patients with advanced CCa.

摘要

宫颈癌（CCa）患者发生淋巴结（LN）转移后预后较差，且治疗选择有限。已知 RNA 上的异常 N6-甲基腺苷（mA）修饰可促进肿瘤转移，但它们在 CCa 中的作用尚不清楚。我们的研究表明，剪接因子和 mA 阅读器 HNRNPC 通过 mA 依赖性方式增加肿瘤相关变体，从而促进 CCa 中的淋巴转移。我们发现 HNRNPC 过表达与 CCa 患者的淋巴转移和预后不良相关。功能上，敲低 HNRNPC 可显著抑制几种 CCa 细胞系的迁移和侵袭，而补充 HNRNPC 可恢复这些细胞的恶性表型。在机制上，HNRNPC 通过结合其 m6A 修饰基序来调节 FOXM1 的外显子跳跃。改变 FOXM1 上的 mA 位点会削弱 HNRNPC 和 FOXM1 前 RNA 之间的相互作用，从而减少与转移相关的 FOXM1-S 变体。总之，我们的研究结果表明，HNRNPC 介导的 mA 依赖性可变剪接对 CCa 的淋巴转移至关重要，这可能为晚期 CCa 患者提供新的临床标志物和治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7448/11458786/4e48d4531148/41419_2024_7108_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7448/11458786/63a37480ae27/41419_2024_7108_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7448/11458786/354e76b576f0/41419_2024_7108_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7448/11458786/cfe34a65b29c/41419_2024_7108_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7448/11458786/b19cfbe22a97/41419_2024_7108_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7448/11458786/729cb32bda1f/41419_2024_7108_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7448/11458786/f615342eac74/41419_2024_7108_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7448/11458786/4e48d4531148/41419_2024_7108_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7448/11458786/63a37480ae27/41419_2024_7108_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7448/11458786/354e76b576f0/41419_2024_7108_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7448/11458786/cfe34a65b29c/41419_2024_7108_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7448/11458786/b19cfbe22a97/41419_2024_7108_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7448/11458786/729cb32bda1f/41419_2024_7108_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7448/11458786/f615342eac74/41419_2024_7108_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7448/11458786/4e48d4531148/41419_2024_7108_Fig7_HTML.jpg

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