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.
"Alterations in the TGF-β signaling pathway occur in almost all pancreatic cancers . In preclinical models, TGF-β has been shown to play a central role in tumor invasion, EMT transition and resistance to therapy . "
[Show abstract][Hide abstract] ABSTRACT: Hypoxia-inducible factors (HIFs) and NF-κB play essential roles in cancer cell growth and metastasis by promoting angiogenesis. Heat shock protein 90 (Hsp90) serves as a regulator of HIF-1α and NF-κB protein. We hypothesized that curcumin and its analogues EF31 and UBS109 would disrupt angiogenesis in pan-creatic cancer (PC) through modulation of HIF-1α and NF-κB. Conditioned medium from MIA PaCa-2 or PANC-1 cells exposed to curcumin and its analogues in vitro significantly impaired angiogenesis in an egg CAM assay and blocked HUVEC tube assembly in comparison to untreated cell medium. In vivo, EF31 and UBS109 blocked the vascularization of subcutaneous matrigel plugs developed by MIA PaCa-2 in mice. Significant inhibition of VEGF, angiopoietin 1, angiopoietin 2, platelet derived growth factor, COX-2, and TGFβ secretion was observed in PC cell lines treated with UBS109, EF31 or curcumin. Treatment with UBS109, EF31 or curcumin inhibited HSP90, NF-κB, and HIF-1α transcription in PC cell lines. UBS109 and EF31 inhibited HSP90 and HIF-1α expression even when elevated due to NF-κB (p65) overexpression. Finally, we demonstrate for the first time that curcumin analogues EF31 and UBS109 induce the downregulation of HIF-1α, Hsp90, COX-2 and VEGF in tumor samples from xenograft models compared to untreated xenografts. Altogether, these results suggest that UBS109 and EF31 are potent curcumin ana-logues with antiangiogenic activities.
Cancer Letters 12/2014; 357(2). DOI:10.1016/j.canlet.2014.12.007 · 5.62 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The transforming growth factor-beta (TGF-β) signaling pathway plays critical roles in the development of various diseases. The current study investigated whether TGF-β was involved in the pathogenesis of osteosarcoma from the genetic polymorphism perspective and serum level perspective. We first examined two TGF-β1 polymorphisms, rs1800469C/T and rs1800470T/C, in 202 osteosarcoma patients and 216 healthy controls. Data revealed that the prevalence of rs1800470TT genotype and T allele was significantly elevated in patients than in controls (odds ratio [OR]=2.28, 95% confidence interval [CI]: 1.30-3.98, p<0.001, and OR=1.49, 95% CI: 1.14-1.96, p<0.001). Function analyses showed that healthy controls carrying rs1800470TT genotype had a significantly higher serum level of TGF-β than those carrying the rs1800470CC genotype (191.1±15.7 pg/mL vs. 129.4±10.9 pg/mL, p=0.003). We then compared the serum level of TGF-β between osteosarcoma patients and healthy controls. Results demonstrated a significantly increased serum level of TGF-β in patients than in controls. Further analyses identified that patients with metastasis had augmented levels of serum TGF-β than those without metastasis. These data indicate that TGF-β may be closely involved in the pathogenesis of osteosarcoma.
DNA and Cell Biology 08/2014; 33(11). DOI:10.1089/dna.2014.2527 · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an extremely severe disease where the mortality and incidence rates are almost identical. This is mainly due to late diagnosis and limited response to current treatments. The tumor macroenvironment/microenvironment have been frequently reported as the major contributors to chemoresistance in PDAC, preventing the drugs from reaching their intended site of action (i.e., the malignant duct cells). However, the recent discovery of microRNAs (miRNAs) has provided new directions for research on mechanisms underlying response to chemotherapy. Due to their tissue-/disease-specific expression and high stability in tissues and biofluids, miRNAs represent new promising diagnostic and prognostic/predictive biomarkers and therapeutic targets. Furthermore, several studies have documented that selected miRNAs, such as miR-21 and miR-34a, may influence response to chemotherapy in several tumor types, including PDAC. In this review, we summarize the current knowledge on the role of miRNAs in PDAC and recent advances in understanding their role in chemoresistance through multiple molecular mechanisms.
BioMed Research International 08/2014; 2014:678401. DOI:10.1155/2014/678401 · 2.71 Impact Factor
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