Abstract
Emerging evidence demonstrates that platelet-derived growth factor-D (PDGF-D) plays a critical role in epithelial-mesenchymal transition (EMT) and drug resistance in hepatocellular carcinoma (HCC) cells. However, the underlying mechanism has not been fully elucidated. The objective is to explore the molecular mechanism of PDGF-D-mediated EMT in drug resistance HCC cells. To achieve our goal, we used multiple approaches including Western blotting, real-time RT-PCR, wound healing assay, invasion assay, luciferase activity assay, transfection, and immunohistochemistry. We found that PDGF-D is highly expressed in gemcitabine-resistant (GR) HCC cells. Moreover, PDGF-D markedly inhibited miR-106a expression and subsequently upregulated Twist1 expression. Notably, PDGF-D expression was associated with miR-106a and Twist1 in HCC patients. Our findings provide a possible molecular mechanism for understanding GR chemoresistance in HCC cells. Therefore, inactivation of PDGF-D/Twist or activation of miR-106a could be a novel strategy for the treatment of HCC.
Highlights
Hepatocellular carcinoma (HCC) is one of commonly diagnosed malignancies [1]
We have found that platelet-derived growth factor-D (PDGF-D) regulates miR-106a expression and Twist1 is a target of miR-106a
The data presented here demonstrated that PDGF-D mediated epithelial-mesenchymal transition (EMT) through inhibition of miR-106a and subsequent upregulation of Twist1 in hepatocellular carcinoma (HCC) GR cells
Summary
Hepatocellular carcinoma (HCC) is one of commonly diagnosed malignancies [1]. The standard of care for patients with advanced HCC, improved the median survival in advanced HCC; the median overall survival is less than one year [2, 3]. Several other drugs targeting signaling cascades such as brivanib, sunitinib, erlotinib, and linifanib encountered setbacks in clinical trials in advanced HCC [4, 5]. Infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) as palliative chemotherapy to patients with advanced HCC conferred some benefit [6]. It has been shown that gemcitabine and oxaliplatin are effective with manageable toxicity in advanced HCC patients [7]. Tumor cells acquire resistance to these chemotherapeutic drugs, leading to treatment failure and high mortality of HCC [8]
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