Mir-147 Is A Novel Tumor Suppressor That Reverses Emt And Native Resistance To Egfr Inhibitors By Inactivating Akt And Activating Stat3

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Background: The epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer invasion and metastasis, and resistance to chemotherapy. The EGFRi class of reagents are thought to target tumors with the epithelial phenotype. Hypothesis: We hypothesized that reversing this biological process through a mesenchymal to epithelial transition (MET), using a recently identified miR-147, might also lead to a reversal of resistance to EGFR inhibitors (EGFRi). Methods/Results: Following a screen of > 400 miRs, we recently identified miR-147 as highly correlated with an “intrinsic” and prognostic EMT gene expression signature derived from an unsupervised analysis of >2000 colorectal cancers. This suggested miR-147 might regulate the EMT program. We have shown that miR-147 is capable of reversing the EMT phenotype in vitro and converting EGFRi-resistant cells to sensitive cells. To further understand the mechanism underpinning this observation, we analyzed the genes affected by miR-147 over-expression in colon cancer cells using a global gene expression survey (Affymetrix). Among significantly altered genes, Akt expression was down-regulated (>2 fold) and Stat3 expression was up-regulated (>2 fold) by miR-147. Subsequent knock down of Akt with siRNA did induce MET and significantly increased EGFRi sensitivity. Western analysis showed increased Stat3 protein levels and total Stat3 phosphorylation with miR-147 transfection. Interestingly, knockdown of Stat3 inhibited the capacity of miR147 to reverse native EGFRi resistance. Conclusion: miR-147 induced MET and reversed resistance to EGFRi. This observation appears to be related to both the inhibition of Akt and to the induction of Stat3 activity. Understanding the precise mechanisms by which miRs regulate chemosensitivity and resistance will be important in designing more effective EGFRi therapies. Citation Format: Chang Gong Lee, Michael Gruidl, Cindy R. Timmee, Susan McCarthy, Timothy J. Yeatman. MiR-147 is a novel tumor suppressor that reverses EMT and native resistance to EGFR inhibitors by inactivating Akt and activating Stat3. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-43. doi:10.1158/1538-7445.AM2013-LB-43