Imbalance of Hypoxia-Inducible Factors Involved in the Drug Resistance of Sunitinib treatment in Renal Cell Carcinoma

• Main Authors: Liu, Shu-Yu, 劉書瑜
• Other Authors: Cha, Tai-Lung
• Format: Others
• Language: zh-TW
• Published: 2012
• Online Access: http://ndltd.ncl.edu.tw/handle/77745891344857014723

碩士 === 國防醫學院 === 生物及解剖學研究所 === 100 === Renal cell carcinoma (RCC) is an angiogenesis-dependent disease and highly resistant to chemo- and radiation therapies. Therefore, anti-angiogenesis therapy has emerged as a pivotal treatment of metastatic RCC. Tyrosine kinases are important cellular signaling proteins that have a variety of biological activities including cell proliferation, migration and angiogenesis. Multiple kinases are involved in angiogenesis, including receptor tyrosine kinases such as the vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor (PDGFR), etc. Inhibition of angiogenic tyrosine kinases has been developed as a systemic treatment strategy for cancer. As an anti-angiogenic tyrosine kinase inhibitor (TKIs), Sunitinib is used in first-line therapies for metastatic clear cell RCC (ccRCC) and it has been shown to improve progression-free survival in patients with mRCC and caused clinically significant toxic effects. A biological rationale exists for treating ccRCC with Sunitinib. Since the von Hippel–Lindau tumor-suppressor gene (VHL) is inactivated in at least 75% of RCC. Under hypoxic condition or VHL inactivation, hypoxia inducible factor-α (HIF-α) accumulates and increases the expression of HIF-regulated genes, including genes encoding angiogenic factors which act in a paracrine loop on their cognate receptor tyrosine kinases, stimulating cell proliferation and angiogenesis. However, some patients are inherently resistant to these approaches and most, if not all, patients acquire resistance over time. Thus, a pressing clinical and scientific question arises about the mechanism of resistance to anti-angiogenic TKI therapies. In this study, we try to figure out whether HIF participates in TKI resistance of Sunitinib in RCC. Our data shows that Sunitinib treatment reduced hypoxia-induced rises HIF-1 on both mRNA and protein levels. In contrast, Sunitinib treatment can increase HIF-2, VEGF mRNA level and maintain HIF-2 protein level. In addition, we further investigate the effect of Suntinib treatment in RCC cells under mimicing tumor microenvironment. By co-culturing RCC cells with human umbilcal vessel endothelial cells (HUVEC), we found that RCC cells will provide HUVEC protection effect to against Sunitinib treatment. And the protection effect would be disappeared when we knockdown HIF-2 in ACHN upon Sunitinib treatment. This phenomenon provided us the possible mechanism of Sunitinib resistance in RCC through HIF-2regulation. Evaluating the mechanisms involved in HIF-mediated resistance to Sunitinib treatment in RCC could provide further resolution in dealing with the clinical obstacle upon TKI therapy.