POU6F2通过SNAI1转录上调和IGF2/PI3K/AKT信号诱导肝星状细胞转化为癌症相关成纤维细胞的双重机制促进胃腺癌的肝转移。

POU6F2 promotes liver metastasis of gastric adenocarcinoma by dual mechanism of transcriptional upregulation of SNAI1 and IGF2/PI3K/AKT signaling-induced conversion of hepatic stellate cells into cancer-associated fibroblasts.

作者信息

Yang Chunxiao, Gao Zhiqing, Tang Ruiming, Zhou Lihuan, Zhou Ping, Shi Wangpan, Ren Dong, Chen Han, Zhang Zhuojun, Xie Xiaoyi, Lin Jiaqian, Ye Yingming, Feng Zhengfu, Feng Xiaoli, He Yaoming, Zhi Yaofeng, Liu Dongmei, Zhang Xin, Jiang Lili

机构信息

The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, China.

Guangzhou Municipal and Guangdong Provincial Key Laboratory of Protein Modification and Disease, Guangzhou Medical University, Guangzhou, China.

出版信息

Br J Cancer. 2025 Apr 29. doi: 10.1038/s41416-025-03017-1.

DOI:10.1038/s41416-025-03017-1

PMID:40301686

Abstract

BACKGROUND

Activation of cancer-associated fibroblasts (CAFs) plays an important role in tumor metastasis. The purpose of this study is to investigate the role of POU6F2 in conversion of hepatic stellate cells (HSCs) into CAFs in liver metastasis of gastric adenocarcinoma (GAC).

METHODS

POU6F2 expression was examined by real-time PCR, Western blot and immunohistochemical staining. The functional roles of POU6F2 in GAC liver metastasis were investigated both cellular experiments in vitro and in vivo using a mouse model of subcutaneous splenic injection. ChIP and ELISA assays were used to explore the underlying molecular mechanism of POU6F2 in liver metastasis of GAC.

RESULTS

Here we reported that POU6F2 was upregulated in GAC tissue with liver metastasis, which predicted poor early liver metastasis. Upregulating POU6F2 promoted EMT, invasion and migration of GAC cells in vitro, and the liver metastasis of GAC cells in vivo. Mechanic investigation further revealed that upregulating POU6F2 promoted the invasion and metastasis of GAC by transcriptional upregulation of EMT-inducer SNAI1, and promoting the conversion of HSCs into CAFs dependent on transcriptional upregulation of IGF2-induced activation of PI3K/AKT signaling.

CONCLUSION

Our findings uncover a novel dual mechanism by which POU6F2 promotes liver metastasis of GAC.

摘要

背景

癌症相关成纤维细胞（CAFs）的激活在肿瘤转移中起重要作用。本研究旨在探讨POU6F2在胃腺癌（GAC）肝转移中肝星状细胞（HSCs）向CAFs转化过程中的作用。

方法

采用实时PCR、蛋白质免疫印迹和免疫组织化学染色检测POU6F2表达。使用皮下脾注射小鼠模型，通过体外和体内细胞实验研究POU6F2在GAC肝转移中的功能作用。采用染色质免疫沉淀（ChIP）和酶联免疫吸附测定（ELISA）试验探讨POU6F2在GAC肝转移中的潜在分子机制。

结果

我们发现，在发生肝转移的GAC组织中POU6F2表达上调，这预示着早期肝转移情况较差。上调POU6F2可促进体外GAC细胞的上皮-间质转化（EMT）、侵袭和迁移，以及体内GAC细胞的肝转移。机制研究进一步表明，上调POU6F2通过转录上调EMT诱导因子SNAI1促进GAC的侵袭和转移，并通过依赖IGF2诱导的PI3K/AKT信号激活的转录上调促进HSCs向CAFs的转化。