CLINICAL ONCOLOGY AND RESEARCH | ISSN 2613-4942 Available online at www.sciencerepository.org Science Repository * Correspondence to: Raviprakash T. Sitaram, B.V.Sc., M.V.Sc., Ph.D., Senior Researcher, Department of Medical Biosciences, Pathology, Umeå University, SE- 901 85 Umeå, Sweden; E-mail: RAVIPRAKASH@UMU.SE; ORCID: 0000-0002-2391-5903 © 2020 Raviprakash T. Sitaram This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Hosting by Science Repository. All rights reserved. http://dx.doi.org/10.31487/j.COR.2020.03.09 Review Article Role of Wnt Signaling Pathways in Clear Cell Renal Cell Carcinoma Pathogenesis in Relation to VHL and HIF Status Raviprakash T. Sitaram 1* , Marene Landström 1 , Göran Roos 1 and Börje Ljungberg 2 1 Department of Medical Biosciences, Pathology, Translation Research Center (TRC), Umeå University, SE-901 85 Umeå, Sweden. 2 Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, SE-901 85 Umeå, Sweden A R T I C L E I N F O Article history: Received: 16 March, 2020 Accepted: 2 April, 2020 Published: 10 April, 2020 Keywords: ccRCC VHL/HIF Wnt/β-catenin signaling pathway A B S T R A C T Renal cell carcinoma (RCC) encompasses various tumor types characterized by a variety of genetic abnormalities. The genetic changes, like mutations, deletions, and epigenetic alterations, can affect the signaling components and signaling networks, causing the modification of tumor pathogenesis and prognosis of RCC. The most prevalent RCC, clear cell RCC (ccRCC), is asymptomatic in the early stages, refractory to chemotherapy and radiation therapy, and has a poorer prognosis compared with the papillary and chromophobe ccRCC types. Loss of the VHL gene and upregulation of oxygen sensors, hypoxia- inducible factor alphas (HIF-α), which promote different growth factors, is a signature of sporadic ccRCC. The VHL-HIF-α and Wnt/β-catenin pathways are closely connected and contribute to the ontogeny of ccRCC. This review confines to ccRCC and the role of the Wnt/β-catenin signaling pathways and its crosstalk with VHL/HIF. © 2020 Raviprakash T. Sitaram. Hosting by Science Repository. All rights reserved. Introduction Renal cell carcinoma (RCC) is composed of a heterogeneous group of tumors originating from different parts of the nephron, maintaining distinct genetic and histological characteristics, which is more prevalent in men (5%) than in women (3%) worldwide [1]. The most commonly occurring RCC types are clear cell (ccRCC), papillary (pRCC), and chromophobe RCC (chRCC) [2]. The clear cell type represents 70–80% of RCC, and the 5-year overall survival rate is about 55-60%, whereas the non-ccRCC types, pRCC and chRCC, constitute about 15% and 10% of RCC, respectively with 5-year survival rates around 70–95% [3]. The non-ccRCC types show the aberrations of discrete genes and signaling pathways and display a hypovascular feature [4, 5]. Hence, non-ccRCC tumors differ in tumor progression and tumor behavior compared with ccRCC. The most common genetic aberrations encountered in ccRCCs are loss chromosome 3p25, leading to the inactivation of the von Hippel – Lindau (VHL) gene [6]. In sporadic ccRCC, loss of heterozygosity (LOH), mutation and deletion, or hypermethylation of the VHL gene demonstrate gene inactivation in 56%-91% of the cases [7-11]. In sporadic ccRCC, lack of pVHL activated the transcription factor hypoxia-inducible factor-alpha (HIF-) subunits and further modifies several growth factors, like epidermal growth factor (EGF), insulin-like growth factor (IGF), platelet-derived growth factor (PDGF), and vascular endothelial growth factor (VEGF) [12]. In ccRCC, VHL not only regulates the cellular oxygen sensing mechanism but is also involved in Wnt/β-catenin mediated signaling pathways [13, 14]. The Wnt signaling pathway is classified into the canonical or β-catenin- dependent or Wnt/β-catenin and non-canonical or β-catenin-independent pathway. The non-canonical pathway, which is not discussed further in this review, is linked with cytoskeleton remodeling and cell movement. The canonical signaling pathway is crucial for normal embryonic development and cell activities, such as cell proliferation and stem cell