Functional Assessment of Four Novel Immune-Related Biomarkers in the Pathogenesis of Clear Cell Renal Cell Carcinoma

Overview

Journal Front Cell Dev Biol

Specialty Cell Biology

Date 2021 Apr 2

PMID 33796525

Citations 6

Authors

Daojun Lv

Xiangkun Wu

Ming Wang

Wenzhe Chen

Shuxin Yang

Yongda Liu

Guohua Zeng

Di Gu

Affiliations

Soon will be listed here.

Abstract

Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma whose pathogenesis is not well understood. We aimed at identifying novel immune-related biomarkers that could be valuable in the diagnosis and prognosis of ccRCC.

Methods: The Robust Rank Aggregation (RRA) method was used to integrate differently expressed genes (DEGs) of 7 Gene Expression Omnibus (GEO) datasets and obtain robust DEGs. Weighted gene co-expression network analyses (WGCNA) were performed to identify hub genes associated with clinical traits in The Cancer Genome Atlas (TCGA) database. Comprehensive bioinformatic analyses were used to explore the role of hub genes in ccRCC.

Results: Four hub genes IFI16, LMNB1, RHBDF2 and TACC3 were screened by the RRA method and WGCNA. These genes were found to be up-regulated in ccRCC, an upregulation that could be due to their associations with late TNM stages and tumor grades. The Receiver Operating Characteristic (ROC) curve and Kaplan-Meier survival analysis showed that the four hub genes had great diagnostic and prognostic values for ccRCC, while Gene Set Enrichment Analysis (GSEA) showed that they were involved in immune signaling pathways. They were also found to be closely associated with multiple tumor-infiltrating lymphocytes and critical immune checkpoint expressions. The results of Quantitative Real-time PCR (qRT-PCR) and immunohistochemical staining (IHC) analysis were consistent with bioinformatics analysis results.

Conclusion: The four hub genes were shown to have great diagnostic and prognostic values and played key roles in the tumor microenvironment of ccRCC.

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References

Irianto J, Pfeifer C, Ivanovska I, Swift J, Discher D . Nuclear lamins in cancer. Cell Mol Bioeng. 2016; 9(2):258-267. PMC: 4999255. DOI: 10.1007/s12195-016-0437-8. View

Unterholzner L, Keating S, Baran M, Horan K, Jensen S, Sharma S . IFI16 is an innate immune sensor for intracellular DNA. Nat Immunol. 2010; 11(11):997-1004. PMC: 3142795. DOI: 10.1038/ni.1932. View

Barascu A, Le Chalony C, Pennarun G, Genet D, Imam N, Lopez B . Oxidative stress induces an ATM-independent senescence pathway through p38 MAPK-mediated lamin B1 accumulation. EMBO J. 2012; 31(5):1080-94. PMC: 3297999. DOI: 10.1038/emboj.2011.492. View

Guo F, Liu Y . Knockdown of TACC3 Inhibits the Proliferation and Invasion of Human Renal Cell Carcinoma Cells. Oncol Res. 2017; 26(2):183-189. PMC: 7844598. DOI: 10.3727/096504017X14837020772250. View

Wolff I, May M, Hoschke B, Zigeuner R, Cindolo L, Hutterer G . Do we need new high-risk criteria for surgically treated renal cancer patients to improve the outcome of future clinical trials in the adjuvant setting? Results of a comprehensive analysis based on the multicenter CORONA database. Eur J Surg Oncol. 2016; 42(5):744-50. DOI: 10.1016/j.ejso.2016.01.009. View

Hellmann M, Friedman C, Wolchok J . Combinatorial Cancer Immunotherapies. Adv Immunol. 2016; 130:251-77. DOI: 10.1016/bs.ai.2015.12.005. View

Ishimoto T, Miyake K, Nandi T, Yashiro M, Onishi N, Huang K . Activation of Transforming Growth Factor Beta 1 Signaling in Gastric Cancer-associated Fibroblasts Increases Their Motility, via Expression of Rhomboid 5 Homolog 2, and Ability to Induce Invasiveness of Gastric Cancer Cells. Gastroenterology. 2017; 153(1):191-204.e16. DOI: 10.1053/j.gastro.2017.03.046. View

Galon J, Bruni D . Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov. 2019; 18(3):197-218. DOI: 10.1038/s41573-018-0007-y. View

Langfelder P, Horvath S . WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008; 9:559. PMC: 2631488. DOI: 10.1186/1471-2105-9-559. View

10.

Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A . Frequency of regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma. BJU Int. 2010; 107(9):1500-6. DOI: 10.1111/j.1464-410X.2010.09555.x. View

11.

Cai H, Yan L, Liu N, Xu M, Cai H . IFI16 promotes cervical cancer progression by upregulating PD-L1 in immunomicroenvironment through STING-TBK1-NF-kB pathway. Biomed Pharmacother. 2020; 123:109790. DOI: 10.1016/j.biopha.2019.109790. View

12.

Du Y, Liu L, Wang C, Kuang B, Yan S, Zhou A . TACC3 promotes colorectal cancer tumourigenesis and correlates with poor prognosis. Oncotarget. 2016; 7(27):41885-41897. PMC: 5173103. DOI: 10.18632/oncotarget.9628. View

13.

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu J . TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017; 77(21):e108-e110. PMC: 6042652. DOI: 10.1158/0008-5472.CAN-17-0307. View

14.

Yang Z, Sun Q, Guo J, Wang S, Song G, Liu W . GRSF1-mediated MIR-G-1 promotes malignant behavior and nuclear autophagy by directly upregulating TMED5 and LMNB1 in cervical cancer cells. Autophagy. 2018; 15(4):668-685. PMC: 6526811. DOI: 10.1080/15548627.2018.1539590. View

15.

Lemos H, Mohamed E, Huang L, Ou R, Pacholczyk G, Arbab A . STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation. Cancer Res. 2016; 76(8):2076-81. PMC: 4873329. DOI: 10.1158/0008-5472.CAN-15-1456. View

16.

Hutson T, Bellmunt J, Porta C, Szczylik C, Staehler M, Nadel A . Long-term safety of sorafenib in advanced renal cell carcinoma: follow-up of patients from phase III TARGET. Eur J Cancer. 2010; 46(13):2432-40. DOI: 10.1016/j.ejca.2010.06.121. View

17.

Hutson T, Lesovoy V, Al-Shukri S, Stus V, Lipatov O, Bair A . Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol. 2013; 14(13):1287-94. DOI: 10.1016/S1470-2045(13)70465-0. View

18.

Hsieh J, Purdue M, Signoretti S, Swanton C, Albiges L, Schmidinger M . Renal cell carcinoma. Nat Rev Dis Primers. 2017; 3:17009. PMC: 5936048. DOI: 10.1038/nrdp.2017.9. View

19.

Blaydon D, Etheridge S, Risk J, Hennies H, Gay L, Carroll R . RHBDF2 mutations are associated with tylosis, a familial esophageal cancer syndrome. Am J Hum Genet. 2012; 90(2):340-6. PMC: 3276661. DOI: 10.1016/j.ajhg.2011.12.008. View

20.

Remark R, Alifano M, Cremer I, Lupo A, Dieu-Nosjean M, Riquet M . Characteristics and clinical impacts of the immune environments in colorectal and renal cell carcinoma lung metastases: influence of tumor origin. Clin Cancer Res. 2013; 19(15):4079-91. DOI: 10.1158/1078-0432.CCR-12-3847. View