MicroRNA‐137‐mediated Src oncogenic signaling promotes cancer progression |
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Authors: | Rie Kokuda Risayo Watanabe Daisuke Okuzaki Hiroki Akamatsu Chitose Oneyama |
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Institution: | 1. Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan;2. Division of Cancer Cell Regulation, Aichi Cancer Center Research Institute, Nagoya, Japan;3. DNA‐chip Developmental Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan;4. Surgery, Osaka Police Hospital, Osaka, Japan |
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Abstract: | 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. |
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Keywords: | AKT2 colon cancer malignancy miR‐137 paxillin Src tumor growth |
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