Dysregulation of the miRNA biogenesis components DICER1, DROSHA, DGCR8 and AGO2 in clear cell renal cell carcinoma in both a Korean cohort and the cancer genome atlas kidney clear cell carcinoma cohort

Abstract

Impairment of microRNA (miRNA) biogenesis may be involved in clear cell renal cell carcinoma (ccRCC). The objective of the present study was to investigate the mRNA levels of important miRNA machinery components, DICER1, DROSHA, DiGeroge syndrome critical region gene 8 (DGCR8), and Argonaute 2 (AGO2), and their correlations with clinicopathological characteristics of ccRCC using mRNA expression data from The Cancer Genome Atlas kidney clear cell carcinoma (TCGA KIRC) cohort and a Korean ccRCC cohort. mRNA levels of DICER1, DROSHA, and DGCR8 were significantly decreased in both cohorts. However, AGO2 was significantly downregulated only in the Korean ccRCC cohort. Additionally, positive correlations were observed between the altered mRNA levels of DICER1 and DROSHA as well as DROSHA and DGCR8 in both cohorts. In the TCGA KIRC cohort, alterations in the mRNA levels of DICER1 were significantly correlated with histological grade. Furthermore, the altered mRNA levels of DGCR8 showed significant associations with sex and histologic grades. However, in the Korean ccRCC cohort, no factors were significantly associated with any clinicopathological parameters, including sex, age, T stage, Fuhrman grade/The International Society of Urological Pathology grade, lymphovascular invasion, and peri-renal fat invasion. Taken together, these findings indicate that DICER1, DROSHA, DGCR8 and AGO2 are significantly dysregulated in ccRCC, suggesting that they are important in the pathophysiology of this malignancy.

Keywords: clear cell renal cell carcinoma; miRNA biogenesis; the cancer genome atlas.

Figure 1.

Heat map presenting the mRNA expression of the miRNA biogenesis-related genes in the TCGA KIRC cohort. The data are presented in matrix format in which each row represents an individual gene and each column represents a single tissue. Each cell in the matrix represents the expression level of a gene feature in an individual tissue. Expression levels have been standardized (centered and scaled) within columns for visualization. The red and green colors in cells reflect relative high and low expression levels, respectively, as indicated in the scale bar. Images were obtained by re-analysis of the raw data of the TCGA KIRC cohort. ccRCC tissues were ordered from STs to ccRCC tissues according to the standardized expression level of each gene as indicated. TCGA KIRC, The Cancer Genome Atlas kidney clear cell carcinoma; ccRCC, clear cell renal cell carcinoma; ST, adjacent non-neoplastic surround tissues.

Figure 2.

(A) Heat map presenting significantly differential mRNA expression of the miRNA biogenesis-related genes in ccRCC tissues compared with the ST of TCGA KIRC cohort. The data are presented in matrix format in which each row represents an individual gene and each column represents a single tissue. Each cell in the matrix represents the expression level of a gene feature in an individual tissue. Expression levels have been standardized (centered and scaled) within columns for visualization. The red and green colors in cells reflect relative high and low expression levels, respectively, as indicated in the scale bar. Images were obtained by re-analysis of the raw data of the TCGA KIRC cohort. ccRCC tissues were ordered from STs to ccRCC tissues according to the standardized expression level of each gene as indicated. *P<0.05 (ST vs. ccRCC). (B) Relative mRNA levels of various miRNA biogenesis-related genes in ccRCC tissues and their corresponding ST. *P<0.001, **P=0.029 and ***P=0.002, as indicated. TCGA KIRC, The Cancer Genome Atlas kidney clear cell carcinoma; ccRCC, clear cell renal cell carcinoma; ST, adjacent non-neoplastic surround tissues.

Figure 3.

Relative mRNA levels of various microRNA biogenesis-related genes in ccRCC tissues and their corresponding ST of the Korean ccRCC cohort. *P<0.001, as indicated. ccRCC, clear cell renal cell carcinoma; ST, adjacent non-neoplastic surround tissues; DGCR8, DiGeroge syndrome critical region gene 8; AGO2, Argonaute 2.

Figure 4.

Correlation between inter-individual mRNA levels of microRNA biogenesis components in TCGA KIRC cohort and the Korean ccRCC cohort. DICER1 and RNASEN (DROSHA) and DGCR8 and RNASEN (DROSHA) in (A) TCGA KIRC cohort and the (B) Korean ccRCC cohort. TCGA KIRC, The Cancer Genome Atlas kidney clear cell carcinoma; ccRCC, clear cell renal cell carcinoma; ST, adjacent non-neoplastic surround tissues; DGCR8, DiGeroge syndrome critical region gene 8; RNASEN (DROSHA), RNase III endonuclease DROSHA.