Transcription factor 7 like 2 promotes metastasis in hepatocellular carcinoma via NEDD9-mediated activation of AKT/mTOR signaling pathway.

IF 6 2区医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Molecular Medicine Pub Date : 2024-07-25 DOI:10.1186/s10020-024-00878-9

Linsong Tang, Shengjun Xu, Rongli Wei, Guanghan Fan, Junbin Zhou, Xuyong Wei, Xiao Xu

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Abstract

Background: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors of the digestive system, and the exact mechanism of HCC is still unclear. Transcription factor 7 like 2 (TCF7L2) plays a pivotal role in cell proliferation and stemness maintenance. However, the exact mechanism of TCF7L2 in HCC remains unclear.

Methods: Clinical samples and public databases were used to analyze the expression and prognosis of TCF7L2 in HCC. The function of TCF7L2 in HCC was studied in vitro and in vivo. ChIP and luciferase assays were used to explore the molecular mechanism of TCF7L2. The relationship between TCF7L2 and NEDD9 was verified in HCC clinical samples by tissue microarrays.

Results: The expression of TCF7L2 was upregulated in HCC, and high expression of TCF7L2 was associated with poor prognosis of HCC patients. Overexpression of TCF7L2 promoted the metastasis of HCC in vitro and in vivo, while Knockdown of TCF7L2 showed the opposite effect. Mechanically, TCF7L2 activated neural precursor cell expressed developmentally downregulated protein 9 (NEDD9) transcription by binding to the -1522/-1509 site of the NEDD9 promoter region, thereby increasing the phosphorylation levels of AKT and mTOR. The combination of TCF7L2 and NEDD9 could distinguish the survival of HCC patients.

Conclusions: This study demonstrated that TCF7L2 promotes HCC metastasis by activating AKT/mTOR pathway in a NEDD9-dependent manner, suggesting that potential of TCF7L2 and NEDD9 as prognostic markers and therapeutic targets for HCC.

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转录因子7 like 2通过NEDD9介导的AKT/mTOR信号通路的激活促进肝细胞癌的转移。

背景：肝细胞癌（HCC）是消化系统最常见的恶性肿瘤之一，其确切的发病机制尚不清楚。转录因子 7 like 2（TCF7L2）在细胞增殖和干性维持中起着关键作用。然而，TCF7L2在HCC中的确切机制仍不清楚：方法：利用临床样本和公共数据库分析TCF7L2在HCC中的表达和预后。在体外和体内研究了TCF7L2在HCC中的功能。利用 ChIP 和荧光素酶实验探讨了 TCF7L2 的分子机制。通过组织芯片验证了TCF7L2和NEDD9在HCC临床样本中的关系：结果：TCF7L2在HCC中表达上调，TCF7L2的高表达与HCC患者的不良预后相关。过表达 TCF7L2 会促进 HCC 的体外和体内转移，而敲除 TCF7L2 则会产生相反的效果。在机制上，TCF7L2通过与NEDD9启动子区的-1522/-1509位点结合，激活神经前体细胞表达的发育下调蛋白9（NEDD9）的转录，从而增加AKT和mTOR的磷酸化水平。TCF7L2和NEDD9的联合作用可以区分HCC患者的存活率：本研究表明，TCF7L2通过激活AKT/mTOR通路以NEDD9依赖的方式促进HCC转移，这表明TCF7L2和NEDD9有可能成为HCC的预后标志物和治疗靶点。

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

Molecular Medicine 医学-生化与分子生物学

CiteScore

8.60

自引率

0.00%

发文量

137

审稿时长

1 months

期刊介绍： Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.