Tumor microenvironment immune subtypes for classification of novel clear cell renal cell carcinoma profiles with prognostic and therapeutic implications.

ABSTRACT: Currently, no effective prognostic model of clear cell renal cell carcinoma (ccRCC) based on immune cell infiltration has been developed. Recent studies have identified 6 immune groups (IS) in 33 solid tumors. We aimed to characterize the expression pattern of IS in ccRCC and evaluate the potential in predicting patient prognosis. The clinical information, immune subgroup, somatic mutation, copy number variation, and methylation score of patients with TCGA ccRCC cohort were downloaded from UCSC Xena for further analysis. The most dominant IS in ccRCC was the inflammatory subgroup (immune C3) (86.5%), regardless of different pathological stages, pathological grades, and genders. In the C3 subgroup, stage IV (69.1%) and grade 4 (69.9%) were the least presented. Survival analysis showed that the IS could effectively predict the overall survival (OS) (P < .0001) and disease-specific survival (DSS) (P < .0001) of ccRCC alone, of which group C3 (OS, HR = 2.3, P < .001; DSS, HR = 2.84, P < .001) exhibited the best prognosis. Among the most frequently mutated ccRCC genes, only VHL and PBRM1 were found to be common in the C3 group. The homologous recombination deficiency score was also lower. High heterogeneity was observed in immune cells and immunoregulatory genes of IS. Notably, CD4+ memory resting T cells were highly infiltrating, regulatory T cells (Treg) showed low infiltration, and most immunoregulatory genes (such as CX3CL1, IFNA2, TLR4, SELP, HMGB1, and TNFRSF14) were highly expressed in the C3 subgroup than in other subgroups. Enrichment analysis showed that adipogenesis, apical junction, hypoxia, IL2 STAT5 signaling, TGF-beta signaling, and UV response DN were activated, whereas E2F targets, G2M checkpoint, and MYC targets V2 were downregulated in the C3 group. Immune classification can more accurately classify ccRCC patients and predict OS and DSS. Thus, IS-based classification may be a valuable tool that enables individualized treatment of patients with ccRCC.

Prognostic Implications of Immune-Related Gene Pairs Signatures in Bladder Cancer.

Compelling evidence indicates that immune function is correlated with the prognosis of bladder cancer (BC). Here, we aimed to develop a clinically translatable immune-related gene pairs (IRGPs) prognostic signature to estimate the overall survival (OS) of bladder cancer. From the 251 prognostic-related IRGPs, 37 prognostic-related IRGPs were identified using LASSO regression. We identified IRGPs with the potential to be prognostic markers. The established risk scores divided BC patients into high and low risk score groups, and the survival analysis showed that risk score was related to OS in the TCGA-training set (p < 0.001; HR = 7.5 [5.3, 10]). ROC curve analysis showed that the AUC for the 1-year, 3-year, and 5-year follow-up was 0.820, 0.883, and 0.879, respectively. The model was verified in the TCGA-testing set and external dataset GSE13507. Multivariate analysis showed that risk score was an independent prognostic predictor in patients with BC. In addition, significant differences were found in gene mutations, copy number variations, and gene expression levels in patients with BC between the high and low risk score groups. Gene set enrichment analysis showed that, in the high-risk score group, multiple immune-related pathways were inhibited, and multiple mesenchymal phenotype-related pathways were activated. Immune infiltration analysis revealed that immune cells associated with poor prognosis of BC were upregulated in the high-risk score group, whereas immune cells associated with a better prognosis of BC were downregulated in the high-risk score group. Other immunoregulatory genes were also differentially expressed between high and low risk score groups. A 37 IRGPs-based risk score signature is presented in this study. This signature can efficiently classify BC patients into high and low risk score groups. This signature can be exploited to select high-risk BC patients for more targeted treatment.

miR-19a promotes the metastasis and EMT through CUL5 in prostate cancer cell line PC3.

PURPOSE: Prostate cancer is an epithelial malignancy that occurs in the prostate and metastasis is a challenge of the treatment of prostate cancer. MicroRNA (miR)-19a was usually upregulated in several cancers at the roles of miR-19a in the metastasis in prostate cancer are still unclear. METHODS: A normal prostate epithelial cell line P69 and two prostate cancer cell lines PC3 and DU145 were used in this study. The mRNA levels of miR-19a and CUL5 were measured using qRT-PCR assay. Transwell and Western blot assays were conducted to calculate cell metastasis and epithelial-mesenchymal transition (EMT) properties in PC3 cells. Luciferase reporter assay was applied to validate that miR-19a targeted to CUL5. RESULTS: The expression of miR-19a was high in prostate cancer and its overexpression predicted poor outcome of prostate cancer patients. miR-19a regulated the expression of CUL5 by directly targeting its mRNA 3'-UTR in PC3 cells. The expression of CUL5 was lower in prostate cancer tissues and cell lines than in non-tumor tissues and normal cells. Downregulation of CUL5 predicted worse outcome of prostate cancer patients. miR-19a promoted cell migration, invasion and EMT in prostate cancer by directly binding to CUL5 mRNA 3'-UTR. CUL5 partially reversed the roles of miR-19a on the metastasis in prostate cancer. CONCLUSION: miR-19a promoted migratory, invasive and EMT abilities by binding to CUL5 in prostate cancer. The newly identified miR-19a/CUL5 axis provides novel insight into the pathogenesis of prostate cancer.