Bioinformatic Analysis Identifying PSMB 1/2/3/4/6/8/9/10 as Prognostic Indicators in Clear Cell Renal Cell Carcinoma

Abstract

Renal cancer incidence has been increasing across the world, clear cell renal cell carcinoma (ccRCC) represents the major subtype of renal cancer. The proteasome is involved in onset, metabolism and survival of tumor and has been recognized as a therapeutic target for various malignancies, while the role of β subunits of proteasome, PSMB gene family, in ccRCC has not been fully unveiled. Herein we investigated the expression and the prognostic role of PSMBs in ccRCC by analyzing a series of databases, including ONCOMINE, UALCAN, cBioPortal, STRING, GEPIA, GO and KEGG. Over-expressions of PSMB1/2/4/7/8/9/10 mRNA were found in ccRCC tissues compared to normal tissues, transcriptional levels of PSMB2/3/4/6/8/9/10 were significantly positively associated with patients' individual cancer stages and grades. Similar or higher levels of proteins encoded by PSMB1/2/3/7/8/9/10 were observed in tumor tissues compared to normal renal tissues. Further, high mRNA levels of PSMB1/2/3/4/6/10 were correlated with shorter overall survival in univariate analysis. Taken together, the results of our analysis implied that overexpression of PSMB1/2/3/4/6/8/9/10 were indicative of worse prognosis of ccRCC. However, further researches were required to validate our findings.

Keywords: PSMB; bioinformatic analysis; clear cell renal cell carcinoma; prognosis.

Figure 1

Transcriptional expression of PSMB1-10 in 20 different types of cancers (ONCOMINE database). Difference of transcriptional levels was compared by Student's t-test. Cut-off of p value and fold change: p value: 0.01, fold change: 1.5, data type: mRNA.

Figure 2

mRNA expression of PSMBs in ccRCC tissues and adjacent normal renal tissues (UALCAN). mRNA expressions of PSMB1, PSMB2, PSMB4, PSMB7-10 were found to be significantly elevated in RCC tissues compared to normal samples while mRNA expressions of PSMB5, PSMB6 were significantly reduced, no statistically differences of PSMB3 mRNA expressions were observed between cancer tissues and normal tissues. *** p<0.001.

Figure 3

Representative immunohistochemistry images of PSMB1-10 in ccRCC tissues and normal tissues (glomeruli and tubules) (Human Protein Atlas). PSMB9 proteins were not detected in normal renal tissues, whereas their expressions were observed high in ccRCC tissues. Lower PSMB1/2/3/7/8 proteins expressions were observed in normal glomeruli compared with cancer tissues, lower PSMB8/10 proteins levels were observed in normal tubules compared with cancer tissues. PSMB5 proteins were detected staining medium in normal renal tissues and were not detected in cancer tissues. Staining of PSMB4/6 proteins was observed as medium in both normal tissues and cancer tissues.

Figure 4

RNA levels of PSMB1-10 in different single cell type clusters of the kidney (Human Protein Atlas). PSMB1-7 levels are higher in proximal tubular cells in kidney tissues, while PSMB8-10 are higher expressed in immune cells such as T cells, B cells and macrophages.

Figure 5

Relationship between mRNA expression of PSMB1-10 and cancer stages and grades of ccRCC patients. A: Higher mRNA levels of PSMB1/2/3/4/6/8/9/10 were associated with higher tumor stages significantly. B: Higher mRNA levels of PSMB2/3/4/6/8/9/10 were associated with higher tumor grades significantly. *p<0.05, **p<0.01, ***p<0.001.

Figure 6

Prognostic value of mRNA PSMB1-10 in patients with ccRCC. Higher mRNA expressions of PSMB1/2/3/4/6/10 were significantly associated with shorter overall survival (OS). Higher mRNA expressions of PSMB7 were significantly associated with longer OS. No statistically significant correlations were observed between mRNA expressions of PSMB5/8/9 and OS of the patients.

Figure 7

Genetic mutations in PSMB1-10 and their association with OS of ccRCC patients (cBioPortal) and the enrichment analysis of mutations in PSMB1-10 and 50 similar genes (DAVID). A: Genetic alterations in PSMBs were associated with shorter OS of ccRCC patients. B: PSMB1, PSMB6, PSMB4 and PSMB5 ranked the highest four genes of genetic alterations, and their mutation rates were 10%, 9%, 8% and 7%, respectively. C: GO biological process. D: GO cellular component. E: GO molecular function. F: Pathway enrichment based on KEGG.

Figure 8

Major molecular function and regulation pathway based on GO functional enrichment analysis and KEGG pathway analysis (DAVID) and the STRING interaction network of PSMB1-10 (STRING). A: GO biological process: antigen processing and presentation. B: KEGG pathway: proteasome. C: STRING interaction network of PSMB1-10.