The Contributions of HIF-Target Genes to Tumor Growth in RCC

• Published in: PloS one Vol. 8; no. 11; p. e80544
• Main Authors: Zhang, Ting, Niu, Xiaohua, Liao, Lili, Cho, Eun-Ah, Yang, Haifeng
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.11.2013; Public Library of Science (PLoS)
• Subjects: Analysis; Angiopoietin-like 4 Protein; Angiopoietins - genetics; Angiopoietins - metabolism; Animals; Apoptosis; Biology; Breast cancer; Cancer; Cancer therapies; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell culture; Cell cycle; Cell Line, Tumor; Clear cell-type renal cell carcinoma; Cyclin D1 - genetics; Cyclin D1 - metabolism; Depletion; Development and progression; Disease Models, Animal; Disease susceptibility; Gene expression; Gene Expression Regulation, Neoplastic; Gene Knockout Techniques; Genes; Genetic research; Glucose; Glucose Transporter Type 1 - genetics; Glucose Transporter Type 1 - metabolism; Growth; Humans; Hypoxia; Hypoxia-Inducible Factor 1 - metabolism; Hypoxia-Inducible Factor-Proline Dioxygenases - genetics; Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism; Immunoglobulins; Insulin; Insulin-Like Growth Factor Binding Protein 3 - genetics; Insulin-Like Growth Factor Binding Protein 3 - metabolism; Insulin-like growth factor I receptors; Insulin-like growth factor-binding protein 3; Insulin-like growth factors; Kidney cancer; Kidneys; Kinases; Metabolism; Mice; Mutation; Pathology; Phosphopyruvate Hydratase - genetics; Phosphopyruvate Hydratase - metabolism; Proteins; Receptor, IGF Type 1 - genetics; Receptor, IGF Type 1 - metabolism; RNA; Transcriptional Activation; Tumor Burden - genetics; Tumor suppressor genes; Tumors; Vascular endothelial growth factor; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; VHL protein; Von Hippel-Lindau Tumor Suppressor Protein - genetics; Von Hippel-Lindau Tumor Suppressor Protein - metabolism; Xenograft Model Antitumor Assays; Xenografts; Cleveland Ohio; Ohio; United States > US; Pennsylvania
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0080544

Somatic mutations or loss of expression of tumor suppressor VHL happen in the vast majority of clear cell Renal Cell Carcinoma, and it's causal for kidney cancer development. Without VHL, constitutively active transcription factor HIF is strongly oncogenic and is essential for tumor growth. However, the contribution of individual HIF-responsive genes to tumor growth is not well understood. In this study we examined the contribution of important HIF-responsive genes such as VEGF, CCND1, ANGPTL4, EGLN3, ENO2, GLUT1 and IGFBP3 to tumor growth in a xenograft model using immune-compromised nude mice. We found that the suppression of VEGF or CCND1 impaired tumor growth, suggesting that they are tumor-promoting genes. We further discovered that the lack of ANGPTL4, EGLN3 or ENO2 expression did not change tumor growth. Surprisingly, depletion of GLUT1 or IGFBP3 significantly increased tumor growth, suggesting that they have tumor-inhibitory functions. Depletion of IGFBP3 did not lead to obvious activation of IGFIR. Unexpectedly, the depletion of IGFIR protein led to significant increase of IGFBP3 at both the protein and mRNA levels. Concomitantly, the tumor growth was greatly impaired, suggesting that IGFBP3 might suppress tumor growth in an IGFIR-independent manner. In summary, although the overall transcriptional activity of HIF is strongly tumor-promoting, the expression of each individual HIF-responsive gene could either enhance, reduce or do nothing to the kidney cancer tumor growth.