Citation: Tomi´ c, T.; Tomi´ c, D.; Vukoja, M.; Kraljevi´ c, M.; Ljevak, I.; Glamoˇ clija, U.; Tomi´ c, V.; Vukojevi´ c, K.; Beljan Perak, R.; Šolji´ c, V. Clinical Significance and Expression Pattern of RIP5 and VGLL4 in Clear Cell Renal Cell Carcinoma Patients Treated with Sunitinib. Biomedicines 2024, 12, 149. https://doi.org/10.3390/ biomedicines12010149 Academic Editors: Anca-Maria Cimpean and Parham Jabbarzadeh Kaboli Received: 4 December 2023 Revised: 18 December 2023 Accepted: 8 January 2024 Published: 10 January 2024 Copyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). biomedicines Article Clinical Significance and Expression Pattern of RIP5 and VGLL4 in Clear Cell Renal Cell Carcinoma Patients Treated with Sunitinib Tanja Tomi´ c 1,† , Davor Tomi´ c 2,3,† , Martina Vukoja 3 , Marija Kraljevi´ c 4 , Ivona Ljevak 1 , Una Glamoˇ clija 5 , Vajdana Tomi´ c 1,3,6 , Katarina Vukojevi´ c 1,3,7, * , Renata Beljan Perak 8 and Violeta Šolji´ c 1,3 1 Faculty of Health Studies, University of Mostar, Bijeli Brijeg bb, 88000 Mostar, Bosnia and Herzegovina; tanja.tomic@fzs.sum.ba (T.T.); ivona.ljevak@fzs.sum.ba (I.L.); vajdana.tomic@fzs.sum.ba (V.T.); violeta.soljic@fzs.sum.ba (V.Š.) 2 Department of Urology, University Hospital Center Mostar, Bijeli Brijeg bb, 88000 Mostar, Bosnia and Herzegovina; sven.tomic@gmail.com 3 Laboratory of Morphology, Department of Histology and Embryology, School of Medicine, University of Mostar, Bijeli Brijeg bb, 88000 Mostar, Bosnia and Herzegovina; martina.vukoja@mef.sum.ba 4 Department of Oncology, University Hospital Center Mostar, Bijeli Brijeg bb, 88000 Mostar, Bosnia and Herzegovina; marija.kraljevicc91@gmail.com 5 Faculty of Pharmacy, University of Sarajevo, Zmaja od Bosne 8, 71000 Sarajevo, Bosnia and Herzegovina; una.glamoclija@ffsa.unsa.ba 6 Department of Gynecology, University Hospital Center Mostar, Bijeli Brijeg bb, 88000 Mostar, Bosnia and Herzegovina 7 Department of Anatomy, Histology and Embryology, University of Split School of Medicine, Šoltanska 2, 21000 Split, Croatia 8 Department of Pathology, Forensic Medicine and Cytology, University Hospital of Split, Spinˇ ci´ ceva 1, 21000 Split, Croatia; renatavonbe@gmail.com * Correspondence: katarina.vukojevic@mefst.hr † These authors contributed equally to the work. Abstract: While clear cell renal cell carcinoma (ccRCC) is curable, advanced metastatic (mRCC) remains a clinical challenge. We analyzed clinical, pathohistological, and molecular data (Receptor Interacting Protein 5—RIP5 and Vestigial Like Family Member 4—VGLL4 expression) of 55 mRCC patients treated with first-line treatment with sunitinib. The trend of linear increase in the protein expression of RIP5 was observed with the progression of tumor grade. Overall, 80% of RIP5-positive cells were in the control kidneys and high-grade mRCC. On the contrary, RIP5 displayed low expression in grade 2 mRCC (5.63%). The trend of linear decrease in the expression of VGLL4 was observed with the progression of tumor grade. The highest protein expression of VGLL4 was observed in grade 2 (87.82%) in comparison to grade 3 and 4 and control. High expression of RIP5 mRNA was associated with longer first-line overall survival and longer progression-free survival in mRCC. In addition, a high VGLL4 mRNA expression showed better overall survival in patients with ccRCC. In conclusion, high mRNA expression of RIP5 and VGLL4 are important markers of better survival rates in mRCC patients. Keywords: ccRCC; RIP 5; VGLL 4; sunitinib; progression-free survival; mRCC 1. Introduction Clear cell renal cell carcinoma (ccRCC) is the most common type of renal cell carcinoma, accounting for about 75 to 80% of renal cell carcinomas [1]. The remaining 20 to 25% are papillary renal cell carcinoma (pRCC), chromophobe RCC (cRCC), and others, while about 5% of renal tumors remain unclassified [2]. ccRCC is responsible for the death of 180,000 people a year worldwide [3]. ccRCC arises from the proximal epithelium of the renal tubules and is characterized by genetic diversity and chromosomal complexity. Loss of heterozygosity of chromosome 3p, where the von Hippel-Lindau (VHL) gene is located, is found in more than 90% of cases of ccRCC and is considered a critical genetic event [4–6]. Biomedicines 2024, 12, 149. https://doi.org/10.3390/biomedicines12010149 https://www.mdpi.com/journal/biomedicines