YAP, a novel target regulates F-actin rearrangement-associated CAFs transformation and promotes colorectal cancer cell progression

Colorectal cancer (CRC) progression is strongly influenced by the tumor microenvironment (TME) in which cancer-associated fibroblasts (CAFs) are the major components influencing CRC growth and progression. The present study aimed to investigate the effect of YAP on F-actin arrangement in CAF transformation and the possibility of using YAP as a target for inhibiting CRC growth and progression. Conditioned media were collected from direct interaction between CRC cells and fibroblasts. CAF markers were investigated by flow cytometry, western blot analysis, and immunofluorescence assay in CM-treated fibroblasts. Promoting the CRC progression of conditioned media was determined in CRC cells by using MTT assay, fluorescence assay, wound healing assay, transwell migration assay, and tubulogenesis. The results showed that the conditioned media induced the expression of CAF markers associated with the central rearrangement of F-actin in colon fibroblasts, upregulating and promoting the nuclear translocation of YAP. The conditioned media also significantly promoted the pro-liferation, migration, invasion, and angiogenesis of CRC cells. Interestingly, Verteporfin, a YAP inhibitor during cocultivation, abolished the conversion of CAFs and inhibited proliferation, migration, invasion, and angio-genesis in CRC cells. Moreover, bioinformatics analysis was employed to determine the potential role of YAP as a prognostic marker in CRC patients from databases. The results suggested that YAP has higher expression in CRC patients and is associated with a poor prognosis. In conclusion, these findings demonstrate that YAP-related F -actin rearrangement may be a potential new target of combination therapy with a focus on targeting TME.

Automated summary

The progression of colorectal cancer (CRC) is affected by the tumor microenvironment (TME), where cancer-associated fibroblasts (CAFs) play a significant role. This study investigated the role of YAP in CAF transformation and its potential as a target for inhibiting CRC growth and progression. The results showed that conditioned media from CRC cells induced CAF marker expression and rearrangement of F-actin in colon fibroblasts, leading to upregulation and nuclear translocation of YAP. Additionally, the conditioned media promoted proliferation, migration, invasion, and angiogenesis of CRC cells. Interestingly, a YAP inhibitor, Verteporfin, inhibited CAF conversion and the aforementioned effects in CRC cells. Furthermore, bioinformatics analysis suggested that YAP could serve as a prognostic marker in CRC patients. In conclusion, YAP-related F-actin rearrangement may be a potential target for combination therapy in CRC.