Renal cell carcinoma (RCC) represents around 2–3% of all malignancies diagnosed in adult patients. Most frequent (around 70–80% cases) and the most aggressive subtype is clear cell RCC (ccRCC). Mutations in VHL (von Hippel Lindau) gene, characteristic for this cancer type, lead to altered activity of the trimeric VBC (pVHL‐elongin B‐C) complex and consequently to HIF‐1α stabilization. In this study, we present results of exhaustive investigation of HIF‐1α alternative transcript variants abundance in A498, CAKI‐1, and 786‐O ccRCC cell lines. We proved the existence of truncated HIF‐1α protein form (HIF1A∆‐6) in A498 and HIF1A gene rearrangements in 786‐O cell lines. Subsequently, we found that HIF1A∆2‐6 was more stable than the full‐length HIF‐1α. Moreover, the shorter HIF‐1α was insensitive for hypoxia and was overaccumulated after proteasome inhibitor treatment indicative of potential diversified roles of full‐length and truncated HIF‐1α forms in the cell. We also showed that A498, CAKI‐1, and 786‐O exhibit differential expression of various regulatory genes involved in the control of metabolic processes, that is, glucose and lipid metabolism, and encoding subunits of such machineries like SWI/SNF chromatin remodeling complex. Furthermore, these cell lines exhibited differential responses to axitinib, everolimus, and sunitinib—anticancer drugs—in normoxia and hypoxia as well as various alterations in metabolism‐related regulatory processes. Finally, we have shown that overexpression of truncated HIF1A∆2‐6 form may affect the protein level of endogenous full‐length HIF‐1α protein. Thus, our study proves an important role of HIF‐1α in the ccRCC development.

中文翻译：

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各种形式的 HIF-1α 蛋白表征透明细胞肾细胞癌细胞系

肾细胞癌 (RCC) 约占成人患者诊断出的所有恶性肿瘤的 2-3%。最常见（约 70-80% 的病例）和最具侵袭性的亚型是透明细胞 RCC (ccRCC)。VHL (von Hippel Lindau) 基因突变是这种癌症类型的特征，导致三聚体 VBC (pVHL-elongin B-C) 复合物的活性改变，从而导致 HIF-1α 稳定。在这项研究中，我们展示了对 A498、CAKI-1 和 786-O ccRCC 细胞系中 HIF-1α 替代转录变体丰度的详尽调查结果。我们证明了 A498 中存在截短的 HIF-1α 蛋白形式 (HIF1A∆-6) 和 786-O 细胞系中的 HIF1A 基因重排。随后，我们发现 HIF1A∆2-6 比全长 HIF-1α 更稳定。而且，较短的 HIF-1α 对缺氧不敏感，并且在蛋白酶体抑制剂处理后过度积累，表明全长和截短的 HIF-1α 形式在细胞中具有潜在的多样化作用。我们还表明，A498、CAKI-1 和 786-O 表现出各种调控基因的差异表达，这些基因参与控制代谢过程，即葡萄糖和脂质代谢，并编码 SWI/SNF 染色质重塑复合物等机制的亚基. 此外，这些细胞系对阿西替尼、依维莫司和舒尼替尼（抗癌药物）在常氧和缺氧以及代谢相关调节过程的各种改变中表现出不同的反应。最后，我们已经证明截短的 HIF1A∆2-6 形式的过表达可能会影响内源性全长 HIF-1α 蛋白的蛋白质水平。因此，