Downregulating hypoxia‐inducible factor‐2α improves the efficacy of doxorubicin in the treatment of hepatocellular carcinoma

Abstract

The hypoxic microenvironment inside solid tumors, including hepatocellular carcinoma (HCC), is a major cause of tumor resistance to chemotherapy. The recently identified hypoxia‐inducible factor (HIF)‐2 executes the hypoxia response. Its expression feature and transcriptional targets indicate a possible dominance of HIF‐2 in regulating genes in HCC. The aim of the present study was to determine whether transfection of siRNA targeting HIF‐2α could enhance the efficacy of doxorubicin, the most commonly used drug in the treatment of HCC. Transfection of HIF‐2 siRNA into human HCC cells downregulated the expression of HIF‐2α, vascular endothelial growth factor (VEGF), transforming growth factor (TGF)‐α, and cyclin D1, but had little effect on the expression of HIF‐1α, fms‐related tyrosine kinase‐1 (Flt‐1), the glucose transporter (GLUT)‐1, and lactate dehydrogenase A (LDHA). Doxorubicin itself only downregulated VEGF expression. Furthermore, HIF‐2 siRNA inhibited proliferation, induced cell cycle arrest at the G0/G1 phase, and acted synergistically with doxorubicin to inhibit the growth of human HCC cells in vitro. Transfection of HIF‐2 siRNA also downregulated tumoral expression of HIF‐2α, VEGF, TGF‐α, and cyclin D1 in vivo, and acted synergistically with doxorubicin to suppress the growth of HepG2 tumors established in immunodeficient mice by inhibiting cell proliferation, tumor angiogenesis and microvessel perfusion. The results of the present study suggest that targeting HIF‐2α with siRNA warrants investigation as a potential strategy to enhance the efficacy of doxorubicin in the treatment of HCC. (Cancer Sci 2012; 103: 528–534)

Mechanisms of resistance to sorafenib and the corresponding strategies in hepatocellular carcinoma

“…Particularly, sorafenib has been uniquely recommended as the first line treatment for advanced HCC [2] . Despite the encouraging achievement, the worry about drug resistance to sorafenib is increasing as the OS of HCC patients after sorafenib treatment was only 2-3 mo longer than placebo and sorafenib was shown to result in a limited increase in median time to symptomatic progression and a low partial response rate due to drug resistance [3,4] . Although the exact rate of resistance to sorafenib has not been reported, considering the dilemma that no effective systemic therapy is available so far for patients after failure of sorafenib therapy, studies on the mechanisms of sorafenib resistance are urgently required [5][6][7] .…”

The Role of Hypoxia-Inducible Factors in Cancer Resistance

“…Tumor hypoxia is involved in each hallmark and enabling characteristic displayed by cancer cells. Cellular adaptation to hypoxia is mediated by the HIF family of transcription factors: three oxygen-dependent different alpha subunits HIF1, HIF2 and HIF3 and two oxygen-independent HIFβ subunits [96][97][98][99][100][101][102][103][104][105]. In contrast to the well-established importance of HIF1α and HIF2α in cancer biology, the functional significance of HIF3α is remarkably understudied.…”

“…Glucose transport RCC [91,92,93] ADRP Lipid metabolism RCC [91] CAXII pH homeostasis RCC [91] FILAG Cytoskeletal structure RCC [91] IL-6 Inmmune cytokine RCC [91] ADM1 Angiogenesis RCC [91] VEGF Angiogenesis RCC [91 , 83,29] Hep3B [91,83,29] HepG2 [105] LOX cross-linking of extracellular matrix HEAK293T [112] PFKFB4 Metabolism HEAK293T [112] BNIP3 Autophagy, apoptosis HEAK293T; RCC [112,83] …”

“…Inhibitor of NO production Macrophages [97] EPO Erythropoiesis Kidney [98][99][100] , liver [100,101] OCT4 pluripotency Mouse ES [84] , hESC [99] SCGB3A1 Secretoglobin 3A1 NSCLC [103] TGFα Growth Factor RCC [83,104] , HCC (HepG2 [105 , Huh7 [12] cells)…”

“…Cell cycle progression RCC [83] , HCC (HepG2 cells [105] ) DLL4 NOTCH signaling, EC branching Mouse ECS [106] …”