Cancer Genetics and Epigenetics 2024, Vol.12, No.4, 223-233 http://medscipublisher.com/index.php/cge 224 development of targeted therapies for metastatic RCC (Kim et al., 2021). The identification of VHLmutations can aid in the early diagnosis of RCC and provide insights into the prognosis and potential therapeutic strategies (Carlo et al., 2019; Carlo et al., 2023). This study aims to explore the application and prospects of the VHL gene in the diagnosis of kidney cancer. By examining the current understanding of the VHL-HIF pathway and its role in RCC, this study seeks to highlight the potential of VHL as a genetic biomarker for early detection and targeted therapy. The scope of this study includes an analysis of recent advancements in the molecular characterization of RCC, the clinical implications of VHLmutations, and the future directions for research and treatment in this field. Through a comprehensive review of the literature, this study will provide valuable insights into the role of the VHL gene in kidney cancer diagnosis and its potential to improve patient outcomes. 2The VHLGene and Kidney Cancer Pathogenesis 2.1 Biological function of the VHLgene The von Hippel-Lindau (VHL) gene plays a crucial role in cellular oxygen sensing and the regulation of hypoxia-inducible factors (HIFs). The VHL protein (pVHL) is a component of the E3 ubiquitin ligase complex, which targets the α-subunits of HIFs for proteasomal degradation under normoxic conditions. This degradation prevents the accumulation of HIFs, thereby regulating the cellular response to oxygen levels (Turner et al., 2002; Gossage et al., 2015; Schödel et al., 2016). In normoxia, pVHL binds to HIF-α subunits, leading to their ubiquitination and subsequent degradation by the proteasome. This process is essential for maintaining cellular homeostasis and preventing the inappropriate activation of hypoxia-responsive genes. However, under hypoxic conditions, HIF-α subunits escape degradation, accumulate, and translocate to the nucleus, where they dimerize with HIF-β subunits. This dimerization activates the transcription of various genes involved in angiogenesis, metabolism, and cell survival (Turner et al., 2002; Gossage et al., 2015; Schödel et al., 2016). Additionally, pVHL has HIF-independent functions, including the regulation of intercellular junctions and maintenance of epithelial cell morphology. VHL inactivation disrupts these processes, leading to a fibroblastic-like phenotype in renal cell carcinoma (RCC) cells, which is independent of HIF activity (Calzada et al., 2006). 2.2 VHLGene mutations and RCC development Mutations in the VHL gene are a hallmark of clear cell renal cell carcinoma (ccRCC). These mutations can be germline or somatic and often result in the loss of pVHL function. The inactivation of VHL leads to the stabilization and accumulation of HIF-α subunits, particularly HIF-2α, which promotes tumorigenesis by upregulating genes involved in angiogenesis, cell proliferation, and survival (Turner et al., 2002; Schödel et al., 2016; Kim et al., 2021). The types of VHL mutations associated with RCC include missense mutations, nonsense mutations, insertions, deletions, and splice site mutations. These mutations disrupt the normal function of pVHL, leading to the constitutive activation of HIF pathways even under normoxic conditions. This aberrant activation of HIF pathways contributes to the development and progression of RCC by promoting angiogenesis through the upregulation of vascular endothelial growth factor (VEGF) and other pro-angiogenic factors (Figure 1) (Turner et al., 2002; Schödel et al., 2016; Kim et al., 2021). Moreover, specific VHL mutations can influence the expression and activity of different HIF isoforms. For instance, some mutations preferentially stabilize HIF-2α over HIF-1α, which has been shown to have distinct and sometimes opposing effects on RCC biology. HIF-2α is often associated with promoting tumor growth, while HIF-1α can act as a tumor suppressor in certain contexts (Turner et al., 2002; Schödel et al., 2016; Ordóñez-Navadijo et al., 2016).
RkJQdWJsaXNoZXIy MjQ4ODYzNQ==