Comprehensive analysis of the expression, prognostic value and biological importance of OVO‑like proteins in clear cell renal cell carcinoma

Lin,Jinfang; Lin,Jinfang; Jiang,Ming; Jiang,Ming; Chen,Ru; Chen,Ru; Zheng,Ping; Zheng,Ping; Chen,Guoxian; Chen,Guoxian

doi:10.3892/ol.2023.13765

Comprehensive analysis of the expression, prognostic value and biological importance of OVO‑like proteins in clear cell renal cell carcinoma

Authors:
- Jinfang Lin
- Ming Jiang
- Ru Chen
- Ping Zheng
- Guoxian Chen
View Affiliations

Affiliations: Department of Urology, The First Hospital of Putian City, Putian, Fujian 351100, P.R. China, Department of Urology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Urology, Shangrao Municipal Hospital, Shangrao, Jiangxi 334000, P.R. China
Published online on: March 17, 2023 https://doi.org/10.3892/ol.2023.13765
Article Number: 179
Copyright: © Lin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

This study examined the expression levels of OVO‑like proteins (OVOLs) in clear cell renal cell carcinoma (ccRCC) tissues and their value in predicting disease prognosis. The transcript levels, genetic alterations, and biological functions of OVOLs and their correlation with tumor immune cell infiltration and drug sensitivity and survival outcomes, as well as their prognostic values, in patients with ccRCC were analyzed based on data obtained from The Cancer Genome Atlas, Gene Expression Profiling Interactive Analysis, cBioPortal, and GSCALite databases. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses were performed using R software (Bioconductor, clusterProfiler packages). A protein‑protein interaction network was established and visualized using the R software with the ggplots package. The ggstatsplot package was used to plot the correlation between gene expression and immune cell infiltration. The mRNA expression levels of OVOL1 and OVOL2 were significantly downregulated in patients with ccRCC, whereas those of OVOL3 were upregulated. OVOL1 expression was correlated with tumor stage and histological grades. The OVOL1, OVOL2, and OVOL3 levels were significantly correlated with the prognosis of patients with ccRCC, the infiltration of immune cells, and drug sensitivity. Multivariate and univariate analyses showed that the expression of OVOL1 was an independent prognostic factor for the overall survival (OS) of patients with ccRCC. The OVOL proteins were associated with various pathways, including tight junction, cell adhesion molecules, and ether lipid metabolism. Additionally, OVOL3 upregulation, and OVOL1 and OVOL2 downregulation in clinical ccRCC samples were experimentally verified. Thus, OVOL1 and OVOL2 are potential therapeutic targets and prognostic markers for ccRCC. Additionally, OVOL1 can serve as an independent prognostic factor for OS in patients with ccRCC.

View Figures

View References

1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
2	Siegel RL, Miller KD, Fuchs HE and Jemal A: Cancer statistics, 2022. CA Cancer J Clin. 72:7–33. 2022. View Article : Google Scholar : PubMed/NCBI
3	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
4	Moch H, Cubilla AL, Humphrey PA, Reuter VE and Ulbright TM: The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: Renal, penile, and testicular tumours. Eur Urol. 70:93–105. 2016. View Article : Google Scholar : PubMed/NCBI
5	Ljungberg B, Albiges L, Abu-Ghanem Y, Bensalah K, Dabestani S, Fernández-Pello S, Giles RH, Hofmann F, Hora M, Kuczyk MA, et al: European association of urology guidelines on renal cell carcinoma: The 2019 update. Eur Urol. 75:799–810. 2019. View Article : Google Scholar : PubMed/NCBI
6	Wong MCS, Goggins WB, Yip BHK, Fung FDH, Leung C, Fang Y, Wong SYS and Ng CF: Incidence and mortality of kidney cancer: Temporal patterns and global trends in 39 countries. Sci Rep. 7:156982017. View Article : Google Scholar : PubMed/NCBI
7	Padala SA and Barsouk A, Thandra KC, Saginala K, Mohammed A, Vakiti A, Rawla P and Barsouk A: Epidemiology of renal cell carcinoma. World J Oncol. 11:79–87. 2020. View Article : Google Scholar : PubMed/NCBI
8	Siegel RL, Miller KD and Jemal A: Cancer statistics, 2020. CA Cancer J Clin. 70:7–30. 2020. View Article : Google Scholar : PubMed/NCBI
9	Williamson TJ, Pearson JR, Ischia J, Bolton DM and Lawrentschuk N: Guideline of guidelines: Follow-up after nephrectomy for renal cell carcinoma. BJU Int. 117:555–562. 2016. View Article : Google Scholar : PubMed/NCBI
10	Jamil ML, Keeley J, Sood A, Dalela D, Arora S, Peabody JO, Trinh QD, Menon M, Rogers CG and Abdollah F: Long-term risk of recurrence in surgically treated renal cell carcinoma: A post hoc analysis of the eastern cooperative oncology group-American college of radiology imaging network E2805 trial cohort. Eur Urol. 77:277–281. 2020. View Article : Google Scholar : PubMed/NCBI
11	Unverzagt S, Moldenhauer I, Nothacker M, Roßmeißl D, Hadjinicolaou AV, Peinemann F, Greco F and Seliger B: Immunotherapy for metastatic renal cell carcinoma. Cochrane Database Syst Rev. 5:CD0116732017.PubMed/NCBI
12	Meyer E, Pasquier D, Bernadou G, Calais G, Maroun P, Bossi A, Theodore C, Albiges L, Stefan D, de Crevoisier R, et al: Stereotactic radiation therapy in the strategy of treatment of metastatic renal cell carcinoma: A study of the getug group. Eur J Cancer. 98:38–47. 2018. View Article : Google Scholar : PubMed/NCBI
13	Tsuji G, Ito T, Chiba T, Mitoma C, Nakahara T, Uchi H and Furue M: The role of the OVOL1-OVOL2 axis in normal and diseased human skin. J Dermatol Sci. 90:227–231. 2018. View Article : Google Scholar : PubMed/NCBI
14	Kumar A, Bhandari A, Sinha R, Sardar P, Sushma M, Goyal P, Goswami C and Grapputo A: Molecular phylogeny of OVOL genes illustrates a conserved C2H2 zinc finger domain coupled by hypervariable unstructured regions. PLoS One. 7:e393992012. View Article : Google Scholar : PubMed/NCBI
15	Watanabe K, Villarreal-Ponce A, Sun P, Salmans ML, Fallahi M, Andersen B and Dai X: Mammary morphogenesis and regeneration require the inhibition of EMT at terminal end buds by Ovol2 transcriptional repressor. Dev Cell. 29:59–74. 2014. View Article : Google Scholar : PubMed/NCBI
16	Roca H, Hernandez J, Weidner S, McEachin RC, Fuller D, Sud S, Schumann T, Wilkinson JE, Zaslavsky A, Li H, et al: Transcription factors OVOL1 and OVOL2 induce the mesenchymal to epithelial transition in human cancer. PLoS One. 8:e767732013. View Article : Google Scholar : PubMed/NCBI
17	Wang ZH, Li Z, Hu M, Yang QJ, Yan S, Wu RS, Li BA and Guo M: Ovol2 gene inhibits the epithelial-to-mesenchymal transition in lung adenocarcinoma by transcriptionally repressing Twist1. Gene. 600:1–8. 2017. View Article : Google Scholar : PubMed/NCBI
18	Jia D, Jolly MK, Boareto M, Parsana P, Mooney SM, Pienta KJ, Levine H and Ben-Jacob E: OVOL guides the epithelial-hybrid-mesenchymal transition. Oncotarget. 6:15436–15448. 2015. View Article : Google Scholar : PubMed/NCBI
19	Jolly MK, Jia D, Boareto M, Mani SA, Pienta KJ, Ben-Jacob E and Levine H: Coupling the modules of EMT and stemness: A tunable ‘stemness window’ model. Oncotarget. 6:25161–25174. 2015. View Article : Google Scholar : PubMed/NCBI
20	Nieto MA: The ins and outs of the epithelial to mesenchymal transition in health and disease. Annu Rev Cell Dev Biol. 27:347–376. 2011. View Article : Google Scholar : PubMed/NCBI
21	Liu J, Wu Q, Wang Y, Wei Y, Wu H, Duan L, Zhang Q and Wu Y: Ovol2 induces mesenchymal-epithelial transition via targeting ZEB1 in osteosarcoma. Onco Targets Ther. 11:2963–2973. 2018. View Article : Google Scholar : PubMed/NCBI
22	Xu C, Yan T and Yang J: OVOL1 inhibits oral squamous cell carcinoma growth and metastasis by suppressing zinc finger E-box binding homeobox 1. Int J Clin Exp Pathol. 12:2801–2808. 2019.PubMed/NCBI
23	Qi XK, Han HQ, Zhang HJ, Xu M, Li L, Chen L, Xiang T, Feng QS, Kang T, Qian CN, et al: OVOL2 links stemness and metastasis via fine-tuning epithelial-mesenchymal transition in nasopharyngeal carcinoma. Theranostics. 8:2202–2216. 2018. View Article : Google Scholar : PubMed/NCBI
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
25	Tang Z, Kang B, Li C, Chen T and Zhang Z: GEPIA2: An enhanced web server for large-scale expression profiling and interactive analysis. Nucleic Acids Res. 47:W556–W560. 2019. View Article : Google Scholar : PubMed/NCBI
26	Cerami E, Gao J, Dogrusoz U, Gross BE, Sumer SO, Aksoy BA, Jacobsen A, Byrne CJ, Heuer ML, Larsson E, et al: The cBio cancer genomics portal: An open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2:401–404. 2012. View Article : Google Scholar : PubMed/NCBI
27	Mermel CH, Schumacher SE, Hill B, Meyerson ML, Beroukhim R and Getz G: GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers. Genome Biol. 12:R412011. View Article : Google Scholar : PubMed/NCBI
28	Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, et al: STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 47:D607–D613. 2019. View Article : Google Scholar : PubMed/NCBI
29	Liu CJ, Hu FF, Xia MX, Han L, Zhang Q and Guo AY: GSCALite: A web server for gene set cancer analysis. Bioinformatics. 34:3771–3772. 2018. View Article : Google Scholar : PubMed/NCBI
30	Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, et al: Gene ontology: Tool for the unification of biology. The gene ontology consortium. Nat Genet. 25:25–29. 2000. View Article : Google Scholar : PubMed/NCBI
31	The Gene Ontology Consortium, . The gene ontology resource: 20 years and still GOing strong. Nucleic Acids Res. 47:D330–D338. 2019. View Article : Google Scholar : PubMed/NCBI
32	Kanehisa M and Goto S: KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28:27–30. 2000. View Article : Google Scholar : PubMed/NCBI
33	Yu G, Wang LG, Han Y and He QY: clusterProfiler: An R package for comparing biological themes among gene clusters. OMICS. 16:284–287. 2012. View Article : Google Scholar : PubMed/NCBI
34	Liu J, Lichtenberg T, Hoadley KA, Poisson LM, Lazar AJ, Cherniack AD, Kovatich AJ, Benz CC, Levine DA, Lee AV, et al: An integrated TCGA pan-cancer clinical data resource to drive high-quality survival outcome analytics. Cell. 173:400–416.e11. 2018. View Article : Google Scholar : PubMed/NCBI
35	Fu H, Qi L, Chen L, He Y, Zhang N and Guo H: Expression of ovol2 is related to epithelial characteristics and shows a favorable clinical outcome in hepatocellular carcinoma. Onco Targets Ther. 9:5963–5973. 2016. View Article : Google Scholar : PubMed/NCBI
36	Fan C, Wang Q, van der Zon G, Ren J, Agaser C, Slieker RC, Iyengar PV, Mei H and Ten Dijke P: OVOL1 inhibits breast cancer cell invasion by enhancing the degradation of TGF-beta type I receptor. Signal Transduct Target Ther. 7:1262022. View Article : Google Scholar : PubMed/NCBI
37	Mitoma C, Nakahara T, Uchi H, Ito T, Inatomi Y, Ide T, Jinnai S, Jinnai N, Iwasaki N, Sakamoto K, et al: Preferential expression of OVOL1 in inner root sheath of hair, sebaceous gland, eccrine duct and their neoplasms in human skin. Fukuoka Igaku Zasshi. 105:166–173. 2014.PubMed/NCBI
38	Li J, Yu T, Cao J, Liu L, Liu Y, Kong HW, Zhu MX, Lin HC, Chu DD, Yao M and Yan MX: MicroRNA-148a suppresses invasion and metastasis of human non-small-cell lung cancer. Cell Physiol Biochem. 37:1847–1856. 2015. View Article : Google Scholar : PubMed/NCBI
39	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
40	Zhang R, Geng GJ, Guo JG, Mi YJ, Zhu XL, Li N, Liu HM, Lin JF, Wang JW, Zhao G, et al: An NF-κB/OVOL2 circuit regulates glucose import and cell survival in non-small cell lung cancer. Cell Commun Signal. 20:402022. View Article : Google Scholar : PubMed/NCBI
41	Ye GD, Sun GB, Jiao P, Chen C, Liu QF, Huang XL, Zhang R, Cai WY, Li SN, Wu JF, et al: OVOL2, an inhibitor of WNT signaling, reduces invasive activities of human and mouse cancer cells and is down-regulated in human colorectal tumors. Gastroenterology. 150:659–671.e16. 2016. View Article : Google Scholar : PubMed/NCBI
42	Wu RS, Lin J, Xing YM, Gao WL, Jiang YX, Chen LX, Zhang XP and Dai ZL: OVOL2 inhibits macrophage M2 polarization by regulating IL-10 transcription, and thus inhibits the tumor metastasis by modulating the tumor microenvironment. Immunol Lett. 242:17–26. 2022. View Article : Google Scholar : PubMed/NCBI