Abstract
The nuclear factor (erythroid-derived 2)-like 2 (NFE2L2/NRF2) plays a critical role in the expression of multiple antioxidant and detoxifying enzymes. Herein, we provide evidence of the molecular links between NRF2 and oncogenic signaling hepatocyte growth factor receptor (HGFR/c-MET) and epidermal growth factor receptor (EGFR). Interfering RNA-induced stable inhibition of NRF2 in ovarian carcinoma SKOV3 and renal carcinoma A498 reduced the levels of c-MET and EGFR. MicroRNA-206 (miR-206) that was increased in both NRF2-silenced cells was predicted as a dual regulator of c-MET and EGFR. As experimental evidence, miR-206 decreased c-MET and EGFR levels through a direct binding to the 3′-untranslated region of the c-MET and EGFR genes. The treatment of NRF2-knockdown cells with the miR-206 inhibitor could restore c-MET and EGFR levels. The miR-206-mediated c-MET/EGFR repression resulted in two outcomes. First, presumably through the inhibition of c-MET/EGFR-dependent cell proliferation, overexpression of miR-206 inhibited tumor growth in SKOV3-inoculated nude mice. Second, reduced c-MET/EGFR in NRF2-silenced cells affected breast cancer resistance protein (BCRP/ABCG2) levels. The pharmacological and genetic inhibition of c-MET or EGFR, as well as the miR-206 mimic treatment, repressed BCRP levels and increased cellular accumulation of doxorubicin. In line with these, treatment of NRF2-silenced SKOV3 with the miR-206 inhibitor elevated BCRP levels and consequently made these cells more resistant to doxorubicin treatment. Collectively, our results demonstrated that the NRF2 silencing-inducible miR-206 targeted both c-MET and EGFR, and subsequently suppressed the BCRP level in cancer cells.
Highlights
Dysregulation of receptor tyrosine kinases (RTKs), including hepatocyte growth factor receptor (HGFR/c-MET) and epidermal growth factor receptor (EGFR), has been implicated in cancer development and progression through a wide range of signaling pathways such as phosphatidylinositol 3-kinase (PI3K)-AKT and mitogen-activated protein kinase (MAPK) [1, 2]
SKOV3 and A498 were chosen because these cell lines expressed high levels of both c-MET and EGFR when compared to the other cell lines (Supplementary Figure 1A and 1B)
We demonstrated that the inhibition of NRF2 expression in ovarian and renal carcinoma cells led to the suppression of c-MET/ EGFR levels through miR-206 upregulation, and the NRF2-silencing-induced miR-206 could reduce breast cancer resistance protein (BCRP) expression, resulting in chemosensitization to anticancer drug treatment
Summary
Dysregulation of receptor tyrosine kinases (RTKs), including hepatocyte growth factor receptor (HGFR/c-MET) and epidermal growth factor receptor (EGFR), has been implicated in cancer development and progression through a wide range of signaling pathways such as phosphatidylinositol 3-kinase (PI3K)-AKT and mitogen-activated protein kinase (MAPK) [1, 2]. HGF treatment in lung cancer cells induced cisplatin resistance via c-MET activation [10]. In non-adherent ovarian cancer cells, c-MET overexpression caused acquired resistance to cisplatin and paclitaxel through PI3K/AKT and extracellular signal-regulated kinase (ERK) 1/2 signaling [11]. In www.impactjournals.com/oncotarget anticancer drug resistant small-cell lung cancer cells, c-MET expression was high and treatment with a c-METspecific inhibitor SU11274 (SU112) sensitized cancer cells to cisplatin and paclitaxel [12]. Lung cancer cells that were initially sensitive to the EGFR kinase inhibitor gefitinib developed resistance via the amplification of c-MET. C-MET amplification was observed in 22% of lung cancer samples that had developed anti-EGFR therapy [13]. Tumor samples from patients with resistance to anti-EGFR therapy such as gefitinib and erlotinib retained EGFR gene mutations such as T790M or exon 20 insertion [14, 15]
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