Unveiling of the mechanism by which Cancer-associated fibroblasts affect colorectal cancer cell

Cancer cells are in a close communication with the fibroblast cells in cancer microenvironment, Cancer-associated fibroblasts (CAFs). The CAFs play an important role in malignant behaviors of colorectal cancer (CRC) cells. To gain insight into the underlying mechanism, we treated SW480 cells with conditioned medium from CRC CAFs (CAF-CM) and evaluated its effects on EMT, invasion, and migration characteristics of the treated CRC cell. Moreover, the expression pattern of UCA1/mTOR/miR-143/KRAS signaling pathway was studied by qRT-PCR and western blotting. Our study indicated that CAFs dramatically stimulated invasion and migration of CRC cell. Furthermore, CAFs induced the EMT phenotype in CRC cell, with an associated change in the expression of EMT markers including vimentin, E-cadherin, N-cadherin, and incited metastasis-related genes (MMPs). The following mechanism investigation revealed that CAFs induced overexpression of UCA1, which leads to upregulation of mTOR. Overexpression of UCA1/mTOR axis suppressed miR-143 while KRAS was significantly upregulated in mRNA and protein level compared with control group. Moreover, UCA1 silencing in treated CRC cell suggested that overexpression of UCA1, which was induced by CAFs, regulates the expression of downstream key effectors. Taken together, these findings provide a better discernment of intercellular communication whereby CAFs incite the UCA1/mTOR axis to direct CRC cell invasive manner. These study support the hypothesis that CAFs may be a prominent therapeutic target of stroma-based therapy in CRC treatment, besides the critical role of cooperation between UCA1 and mTOR in cancer metastasis.

Keywords:

Cancer-associated fibroblasts (CAFs) , UCA1 , Metastasis , mTOR , miR-143