The tyrosine kinase c-Src is frequently overexpressed and activated in a wide variety of human cancers. However, the molecular mechanisms responsible for the upregulation of c-Src remain elusive. To examine whether microRNA-mediated c-Src upregulation promotes cancer progression, we screened miRNAs with complementarity to the 3'-UTR of c-Src mRNA. Among these miRNAs, down-regulation of miR-137 was tightly associated with c-Src-mediated tumor progression of human colon cancer cells/tissues. Re-expression of miR-137 in human colon cancer cells suppressed tumor growth and caused the disruption of focal contacts, suppression of cell adhesion, and invasion, although restoration of c-Src in miR-137-treated cells could not fully rescue the tumor-suppressive effect of miR-137. We found that miR-137 targets AKT2 and paxillin also and miR-137-mediated regulation of c-Src /AKT2 is crucial for controlling tumor growth, whereas that of c-Src/paxillin contributes to malignancy. miR-137 suppressed Src-related oncogenic signaling and changed the expression of miRNAs that are regulated by Src activation. miR-137 controls the expression of c-Src/AKT2/paxillin and synergistically suppresses Src oncogenic signaling evoked from focal adhesions. In various human cancers that harbor c-Src upregulation, the dysfunction of this novel mechanism would serve as a critical trigger for tumor progression.
Keywords: AKT2; Src; colon cancer; malignancy; miR-137; paxillin; tumor growth.
© 2018 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.