BackgroundThe epithelial-mesenchymal transition (EMT) is a key developmental program that is often activated during cancer progression and may promote resistance to therapy. An analysis of patients (n = 71) profiled with both gene expression and a global microRNA assessment (∼415 miRs) identified miR-147 as highly anti-correlated with an EMT gene expression signature score and postulated to reverse EMT (MET).Methods and FindingsmiR-147 was transfected into colon cancer cells (HCT116, SW480) as well as lung cancer cells (A-549). The cells were assessed for morphological changes, and evaluated for effects on invasion, motility, and the expression of key EMT markers. Resistance to chemotherapy was evaluated by treating cells with gefitinib, an EGFR inhibitor. The downstream genes regulated by miR-147 were assayed using the Affymetrix GeneChip U133 Plus2.0 platform. miR-147 was identified to: 1. cause MET primarily by increasing the expression of CDH1 and decreasing that of ZEB1; 2. inhibit the invasion and motility of cells; 3. cause G1 arrest by up-regulating p27 and down-regulating cyclin D1. miR-147 also dramatically reversed the native drug resistance of the colon cancer cell line HCT116 to gefitinib. miR-147 significantly repressed Akt phosphorylation, and knockdown of Akt with siRNA induced MET. The morphologic effects of miR-147 on cells appear to be attenuated by TGF-B1, promoting a plastic and reversible transition between MET and EMT.ConclusionmiR-147 induced cancer cells to undergo MET and induced cell cycle arrest, suggesting a potential tumor suppressor role. miR-147 strikingly increased the sensitivity to EGFR inhibitor, gefitinib in cell with native resistance. We conclude that miR-147 might have therapeutic potential given its ability to inhibit proliferation, induce MET, as well as reverse drug sensitivity.
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
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