PPM1G-mediated TBL1X mRNA splicing promotes cell migration in hepatocellular carcinoma.

IF 5.7 2区医学 Q1 Medicine Cancer Science Pub Date : 2024-10-27 DOI:10.1111/cas.16372

Liling Hu, Xinyu Shi, Xiaoyi Yuan, Danya Liu, Dandan Zheng, Yuying Li, Fujin Shi, Meifang Zhang, Shu-Guang Su, Chris Zhiyi Zhang

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Abstract

The progression of hepatocellular carcinoma (HCC) is coincident with aberrant splicing of numerous tumor-related genes. Identification of the tumor-specific splice variants that facilitate HCC metastasis may provide a more comprehensive insight into the mechanisms of HCC metastasis. Through RNA sequencing and bioinformatic analyses, PPM1G was identified as a biomarker associated with HCC metastasis. Our data mapped a transcriptome-wide landscape of alternative splicing events modulated by PPM1G in HCC. Notably, we characterized the exon six-skipping transcript of TBL1X as an onco-splice variant regulated by PPM1G. Experimental validation revealed the enrichment of TBL1X-S in response to PPM1G overexpression. Moreover, mRNA stability analyses revealed that PPM1G prolonged the half-life of the TBL1X-S transcript. Both PPM1G and TBL1X-S exhibited metastasis-promoting phenotypes, with PPM1G-driven metastasis in HCC being partially dependent on TBL1X-S. Mechanistically, different TBL1X splice variants showed varying affinities for ZEB1, with TBL1X-S significantly enhancing ZEB1 activation and repressing CDH1 transcription, potentially accelerating the epithelial-mesenchymal transition (EMT) process. In conclusion, our study highlights the biological role of PPM1G and TBL1X-S in tumor metastasis. The PPM1G/TBL1X-S signaling axis presents a new view for investigating liver cancer metastasis mechanisms.

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PPM1G 介导的 TBL1X mRNA 剪接可促进肝细胞癌的细胞迁移。

肝细胞癌（HCC）的进展与许多肿瘤相关基因的剪接异常有关。鉴定促进 HCC 转移的肿瘤特异性剪接变异可能有助于更全面地了解 HCC 转移的机制。通过 RNA 测序和生物信息学分析，PPM1G 被鉴定为与 HCC 转移相关的生物标志物。我们的数据绘制了整个转录组范围内受 PPM1G 调节的替代剪接事件图谱。值得注意的是，我们将 TBL1X 的外显子六跳转转录本表征为受 PPM1G 调控的共剪接变体。实验验证表明，TBL1X-S 在 PPM1G 过表达时富集。此外，mRNA稳定性分析表明，PPM1G延长了TBL1X-S转录本的半衰期。PPM1G和TBL1X-S都表现出促进转移的表型，PPM1G驱动的HCC转移部分依赖于TBL1X-S。从机理上讲，不同的TBL1X剪接变体对ZEB1的亲和力不同，TBL1X-S能显著增强ZEB1的活化并抑制CDH1的转录，从而可能加速上皮-间质转化（EMT）过程。总之，我们的研究强调了 PPM1G 和 TBL1X-S 在肿瘤转移中的生物学作用。PPM1G/TBL1X-S信号轴为研究肝癌转移机制提供了新的视角。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cancer Science ONCOLOGY-

CiteScore

9.90

自引率

3.50%

发文量

406

审稿时长

17 weeks

期刊介绍： Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.