Cancer-associated fibroblasts promote the proliferation and metastasis of colon cancer by mediating the RLIM/PML axis through paracrine COMP.

Abstract

Background and aim: Cancer-associated fibroblasts (CAFs) are abundant in colon cancer (CC) patients with a poor prognosis. Here, the molecular regulatory mechanism of CAFs on CC growth and metastasis was explored.

Methods: The genes' expression was monitored using RT-qPCR, immunoblotting, and immunohistochemistry. Cell viability and proliferation were found using CCK-8 and clone formation assays. The cell migration and invasion were probed using wound healing and Transwell. Co-IP was utilized for ascertaining the interaction between AKT and the ring finger protein, LIM domain interacting (RLIM). The in vivo murine subcutaneous tumor model and the metastasis model were built to further ascertain the axis.

Results: The result showed that CAFs motivate the growth and activate the PI3K/AKT pathway of CC cells via paracrine cartilage oligomeric matrix protein (COMP). Moreover, RLIM promoted the growth of CC cells, and its protein stability was regulated by AKT through its phosphorylation. Further, RLIM facilitated the ubiquitination and degradation of promyelocytic leukemia protein (PML). The in vitro and in vivo tests found that PML overexpression could inhibit CC's growth and metastasis, which were enhanced by CAFs.

Conclusion: The COMP excreted from CAFs enhances the CC's growth and metastasis through regulating the RLIM/PML axis, supplying a new potential target for the cure of CC.