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TCN1 通过调控 ITGB4 通路抑制结直肠癌细胞的恶性转化。

TCN1 Deficiency Inhibits the Malignancy of Colorectal Cancer Cells by Regulating the ITGB4 Pathway.

机构信息

Department of General Surgery, The Second Affiliated Hospital of Soochow University, Suzhou, China.

Department of General Surgery, The Affiliated Suqian Hospital of Xuzhou Medical University, Suqian, China.

出版信息

Gut Liver. 2023 May 15;17(3):412-429. doi: 10.5009/gnl210494. Epub 2022 Jun 10.

DOI:10.5009/gnl210494
PMID:35686504
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10191790/
Abstract

BACKGROUND/AIMS: This study aimed to investigate the biological function and regulatory mechanism of TCN1 in colorectal cancer (CRC).

METHODS

We studied the biological function of TCN1 by performing gain-of-function and loss-of-function analyses in HCT116 cell lines; examined the effects of TCN1 on the proliferation, apoptosis, and invasion of CRC cells; and determined potential molecular mechanisms using HCT116 and SW480 CRC lines and mouse xenotransplantation models. Tumor xenograft and colonization assays were performed to detect the tumorigenicity and metastatic foci of cells .

RESULTS

TCN1 knockdown attenuated CRC cell proliferation and invasion and promoted cell apoptosis. Overexpression of TCN1 yielded the opposite effects. In addition, TCN1-knockdown HCT116 cells failed to form metastatic foci in the peritoneum after intravenous injection. Molecular mechanism analyses showed that TCN1 interacted with integrin subunit β4 (ITGB4) to positively regulate the expression of ITGB4. TCN1 knockdown promoted the degradation of ITGB4 and increased the instability of ITGB4 and filamin A. Downregulation of ITGB4 at the protein level resulted in the disassociation of the ITGB4/plectin complex, leading to cytoskeletal damage.

CONCLUSIONS

TCN1 might play an oncogenic role in CRC by regulating the ITGB4 signaling pathway.

摘要

背景/目的：本研究旨在探究 TCN1 在结直肠癌（CRC）中的生物学功能和调控机制。

方法

我们通过在 HCT116 细胞系中进行功能获得和功能丧失分析来研究 TCN1 的生物学功能；检测 TCN1 对 CRC 细胞增殖、凋亡和侵袭的影响；并使用 HCT116 和 SW480 CRC 细胞系和小鼠异种移植模型来确定潜在的分子机制。进行肿瘤异种移植和定植实验以检测细胞的致瘤性和转移灶。

结果

TCN1 敲低可减弱 CRC 细胞的增殖和侵袭，并促进细胞凋亡。TCN1 的过表达则产生相反的效果。此外，TCN1 敲低的 HCT116 细胞在静脉注射后未能在腹膜中形成转移灶。分子机制分析表明，TCN1 与整合素亚基 β4（ITGB4）相互作用，正向调节 ITGB4 的表达。TCN1 敲低促进了 ITGB4 的降解，并增加了 ITGB4 和细丝蛋白 A 的不稳定性。ITGB4 蛋白水平的下调导致 ITGB4/网蛋白复合物的解离，从而导致细胞骨架损伤。

结论

TCN1 可能通过调节 ITGB4 信号通路在 CRC 中发挥致癌作用。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17fe/10191790/33bd0f77c0c5/gnl-17-3-412-f6a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17fe/10191790/1af4a47314cb/gnl-17-3-412-f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17fe/10191790/c6732fa2f7e5/gnl-17-3-412-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17fe/10191790/b304018aa5e6/gnl-17-3-412-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17fe/10191790/ad5e956a4590/gnl-17-3-412-f5a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17fe/10191790/33bd0f77c0c5/gnl-17-3-412-f6a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17fe/10191790/1af4a47314cb/gnl-17-3-412-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17fe/10191790/8e7c599dfcf3/gnl-17-3-412-f2a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17fe/10191790/c6732fa2f7e5/gnl-17-3-412-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17fe/10191790/b304018aa5e6/gnl-17-3-412-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17fe/10191790/ad5e956a4590/gnl-17-3-412-f5a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/17fe/10191790/33bd0f77c0c5/gnl-17-3-412-f6a.jpg

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