c‐Src promotes tumor progression through downregulation of microRNA‐129‐1‐3p

• Published in: Cancer science 2020-02, Vol.111 (2), p.418-428
• Main Authors: Okuzaki, Daisuke, Yamauchi, Tomoe, Mitani, Fumie, Miyata, Mamiko, Ninomiya, Yuichi, Watanabe, Risayo, Akamatsu, Hiroki, Oneyama, Chitose
• Format: Article
• Language: English
• Subjects: Animals; Cancer; Cell adhesion; Cell adhesion & migration; Cell Movement; Cell Proliferation; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Colon cancer; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; CSK Tyrosine-Protein Kinase - metabolism; Disease Progression; Down-Regulation; Doxycycline; Epidermal growth factor; Fibroblasts; Gene expression; Gene Expression Regulation, Neoplastic; Genetic transformation; HCT116 Cells; HT29 Cells; Humans; Kinases; malignancy; Mice; microRNA; MicroRNAs; MicroRNAs - genetics; miRNA; Molecular modelling; Morphology; Neoplasm Transplantation; Original; Protein-tyrosine kinase; Proto-Oncogene Proteins pp60(c-src) - metabolism; signaling; Src
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.14269

MicroRNAs (miRNAs) fine‐tune cellular signaling by regulating expression of signaling proteins, and aberrant expression of miRNAs is observed in many cancers. The tyrosine kinase c‐Src is upregulated in various human cancers, but the molecular mechanisms underlying c‐Src‐mediated tumor progression remain unclear. In previous investigations of miRNA‐mediated control of c‐Src‐related oncogenic pathways, we identified miRNAs that were downregulated in association with c‐Src transformation and uncovered the signaling networks by predicting their target genes, which might act cooperatively to control tumor progression. Here, to further elucidate the process of cell transformation driven by c‐Src, we analyzed the expression profiles of miRNAs in a doxycycline‐inducible Src expression system. We found that miRNA (miR)‐129‐1‐3p was downregulated in the early phase of c‐Src‐induced cell transformation, and that reexpression of miR‐129‐1‐3p disrupted c‐Src‐induced cell transformation. In addition, miR‐129‐1‐3p downregulation was tightly associated with tumor progression in human colon cancer cells/tissues. Expression of miR‐129‐1‐3p in human colon cancer cells caused morphological changes and suppressed tumor growth, cell adhesion, and invasion. We also identified c‐Src and its critical substrate Fer, and c‐Yes, a member of the Src family of kinases, as novel targets of miR‐129‐1‐3p. Furthermore, we found that miR‐129‐1‐3p‐mediated regulation of c‐Src/Fer and c‐Yes is important for controlling cell adhesion and invasion. Downregulation of miR‐129‐1‐3p by early activation of c‐Src increases expression of these target genes and synergistically promotes c‐Src‐related oncogenic signaling. Thus, c‐Src‐miR‐129‐1‐3p circuits serve as critical triggers for tumor progression in many human cancers that harbor upregulation of c‐Src. We found that microRNA (miR)‐129‐1‐3p was repressed in the early phase of c‐Src‐induced cell transformation, and that reexpression of miR‐129‐1‐3p disrupted c‐Src‐induced cell transformation. MicroRNA‐129‐1‐3p was repressed in various colon cancer tissues. In addition, we showed that miR‐129‐1‐3p directly targets c‐Src, Fer, and c‐Yes, which are required for cancer cell adhesion and invasion. These findings indicate that downregulation of miR‐129‐1‐3p by early activation of c‐Src synergistically promotes c‐Src‐related oncogenic signaling.