TCN1 Deficiency Inhibits The Malignancy of Colorectal Cancer Cells By Regulating The ITGB4 Pathway

Abstract

Background: This study aimed to investigate the biological function and regulatory mechanism of TCN1 in colorectal cancer (CRC). Methods: We studied the biological functions of TCN1 using gain-of-function and loss-of-function analysis in HCT116 cell lines, and examined the effects of TCN1 on the proliferation, apoptosis, and invasion of CRC cells and determined its potential molecular mechanisms using CRC lines and mouse xenotransplantation models. Tumor xenograft and tumor metastasis studies were performed to detect the tumorigenicity and metastasis of cells in vivo. Results: TCN1-knockdown attenuated CRC cell proliferation, 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 studies showed that TCN1 interacts 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 (FLNA). Downregulation of ITGB4 at the protein level resulted in the disassociation of the ITGB4/PLEC complex, leading to cytoskeletal damage. Conclusion: TCN1 might exert oncogenic role in CRC via regulating the ITGB4 signaling pathway.