The TGFβ-miR200-MIG6 pathway orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors. Cancer Res. 2014;74:3995–4005. Erratum in

Cancer Research (Impact Factor: 9.33). 05/2014; 74(14). DOI: 10.1158/0008-5472.CAN-14-0110
Source: PubMed


While specific mutations in the tyrosine kinase domain of epidermal growth factor receptor (EGFR) identify tumors that are responsive to EGFR tyrosine kinase inhibitors (TKIs), these genetic alterations are present in only a minority of patients. Patients with tumors expressing wild-type (wt) EGFR lack reliable predictive markers of their clinical response to EGFR TKIs. Although epithelial-mesenchymal transition (EMT) has been inversely correlated with the response of cancers to EGFR-targeted therapy, the precise molecular mechanisms underlying this association have not been defined and no specific EMT-associated biomarker of clinical benefit has been identified. Here we show that during transforming growth factor-β (TGFβ)-mediated EMT, inhibition of the microRNAs 200 (miR200) family results in upregulated expression of mitogen-inducible gene 6 (Mig6), a negative regulator of EGFR. The Mig6-mediated reduction of EGFR occurs concomitantly with a TGFβ-induced EMT-associated kinase switch of tumor cells to an AKT-activated EGFR-independent state. In a panel of 25 cancer cell lines of different tissue origins, we find that the ratio of the expression levels of Mig6 and miR200c is highly correlated with EMT and resistance to erlotinib. Analyses of primary tumor xenografts of patient-derived lung and pancreatic cancers carrying wild type EGFR showed that the tumor Mig6(mRNA)/miR200 ratio was inversely correlated with response to erlotinib in vivo. Our data demonstrate that the TGFβ-miR200-Mig6 network orchestrates the EMT-associated kinase switch that induces resistance to EGFR inhibitors, and identify a low ratio of Mig6 to miR200 as a promising predictive biomarker of the response of tumors to EGFR TKIs.

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    • "Further investigation into this question is clearly needed. The finding that inhibition of miR-200c strongly elevates the Gene 33 protein level is consistent with the existence of multiple consensus binding element for miR200 and the previous findings (Figure 2G) [35]. However, we did not detect a role of miR-200c in Cr(VI)mediated suppression of Gene 33 despite the increase in miR-200c expression upon Cr(VI) treatment (Figure 2G and 2I). "
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    ABSTRACT: Hexavalent Chromium [Cr(VI)] compounds are human lung carcinogens and environmental/occupational hazards. The molecular mechanisms of Cr(VI) carcinogenesis appear to be complex and are poorly defined. In this study, we investigated the potential role of Gene 33 (ERRFI1, Mig6), a multifunctional adaptor protein, in Cr(VI)-mediated lung carcinogenesis. We show that the level of Gene 33 protein is suppressed by both acute and chronic Cr(VI) treatments in a dose- and time-dependent fashion in BEAS-2B lung epithelial cells. The inhibition also occurs in A549 lung bronchial carcinoma cells. Cr(VI) suppresses Gene 33 expression mainly through post-transcriptional mechanisms, although the mRNA level of gene 33 also tends to be lower upon Cr(VI) treatments. Cr(VI)-induced DNA damage appears primarily in the S phases of the cell cycle despite the high basal DNA damage signals at the G2M phase. Knockdown of Gene 33 with siRNA significantly elevates Cr(VI)-induced DNA damage in both BEAS-2B and A549 cells. Depletion of Gene 33 also promotes Cr(VI)-induced micronucleus (MN) formation and cell transformation in BEAS-2B cells. Our results reveal a novel function of Gene 33 in Cr(VI)-induced DNA damage and lung epithelial cell transformation. We propose that in addition to its role in the canonical EGFR signaling pathway and other signaling pathways, Gene 33 may also inhibit Cr(VI)-induced lung carcinogenesis by reducing DNA damage triggered by Cr(VI).
    Full-text · Article · Jan 2016 · Oncotarget
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    • "Alterations in the TGF-β signaling pathway occur in almost all pancreatic cancers [22]. In preclinical models, TGF-β has been shown to play a central role in tumor invasion, EMT transition and resistance to therapy [23]. Elevated levels of TGF-β in plasma were associated with worse outcomes in patients with pancreatic cancer [24]. "

    Full-text · Article · Aug 2015 · Cancer Research
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    • "On the contrary, blockage of TGF-β signaling can inhibit or reverse EMT by up-regulating miR-200c and miR-205, down-regulating MIG6 levels, and increasing erlotinib sensitivity. Izumchenko et al. (2014) also concluded that the elevated ratio of MIG6/miR-200 expression is associated with erlotinib resistance in cancer cell lines and can be used as a predictor of response to erlotinib in vivo. SMAD4 is a tumor suppressor gene for PDAC. "
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is considered to be the most lethal and aggressive malignancy with high mortality and poor prognosis. Their responses to current multimodal therapeutic regimens are limited. It is urgently needed to identify the molecular mechanism underlying pancreatic oncogenesis. Twelve core signaling cascades have been established critical in PDAC tumorigenesis by governing a wide variety of cellular processes. MicroRNAs (miRNAs) are aberrantly expressed in different types of tumors and play pivotal roles as post-transcriptional regulators of gene expression. Here, we will describe how miRNAs regulate different signaling pathways that contribute to pancreatic oncogenesis and progression.
    Preview · Article · Aug 2015 · Journal of Genetics and Genomics
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