Research Papers:

HAF mediates the evasive resistance of anti-angiogenesis TKI through disrupting HIF-1α and HIF-2α balance in renal cell carcinoma

Xiang-Me Lai, Shu-Yu Liu, Yi-Ta Tsai, Guang-Huan Sun, Sun-Yran Chang, Shih-Ming Huang and Tai-Lung Cha _

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Oncotarget. 2017; 8:49713-49724. https://doi.org/10.18632/oncotarget.17923

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Xiang-Me Lai1, Shu-Yu Liu2, Yi-Ta Tsai3, Guang-Huan Sun2, Sun-Yran Chang2,4, Shih-Ming Huang1,3,5 and Tai-Lung Cha1,2,3,5

1Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, R.O.C

2Division of Urology, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, R.O.C

3Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan, R.O.C

4Buddhist Tzu Chi General Hospital, Taipei, Taiwan, R.O.C

5Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, R.O.C

Correspondence to:

Tai-Lung Cha, email: [email protected]

Shih-Ming Huang, email: [email protected]

Keywords: tyrosine kinase inhibitor, hypoxia-inducible factor, hypoxia associated factor, angiogenesis, renal cell carcinoma

Received: April 07, 2017     Accepted: May 03, 2017     Published: May 17, 2017


Anti-angiogenesis has emerged as a standard of care for metastatic renal cell carcinoma. However, long-lasting efficacy is seldom reached, and evasive resistance eventually occurs under anti-angiogenic tyrosine kinase inhibitor (TKI) therapy. To establish new therapeutic strategies, investigating the molecular mechanism of resistance is critically important. In our study, human umbilical vascular endothelial cells (HUVECs) were incubated with TKI treatment in conditioned medium derived from renal cancer cells (RCCs) to demonstrate cell viability. Quantitative real time PCR or Western blotting analysis detected the fluctuation of transcriptional factors HIF-1α and HIF-2α in RCCs under TKI treatment. We demonstrated the alteration of a specific cytokine produced from RCCs under normoxia or hypoxia incubation by utilizing a cytokine RT-PCR primer array. We found that the anti-angiogenic TKI sunitinib disrupted the balance between HIF-1α and HIF-2α in RCCs and led to a protective effect on HUVECs against sunitinib treatment when cultured with conditioned medium. Mechanistically, RCCs treated with sunitinib resulted in down-regulation of HIF-1α, but not HIF-2α, through reduction of both mRNA and protein levels. The down-regulation of HIF-1α by sunitinib occurred via hypoxia associated factor (HAF), which also enhanced HIF-2α transactivation activity to increase the production of pro-angiogenic factors and cytokines and promote HUVEC proliferation. This phenomenon was observed in ACHN and A498 cells, which express both HIF-1α and HIF-2α, but was not observed in 786-O cells, which express only HIF-2α. Our results illustrated that targeting both angiogenesis and hypoxia pathways might provide a resolution to dealing with the devastating effects of anti-angiogenesis resistance.

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