Hexokinase 3 dysfunction promotes tumorigenesis and immune escape by upregulating monocyte/macrophage infiltration into the clear cell renal cell carcinoma microenvironment.

Purpose: This study aimed to identify the potential prognostic role of HK3 and provide clues about glycolysis and the microenvironmental characteristics of ccRCC. Methods: Based on the Cancer Genome Atlas (TCGA, n = 533) and Gene expression omnibus (GEO) (n = 127) databases, real-world (n = 377) ccRCC cohorts, and approximately 15,000 cancer samples, the prognostic value and immune implications of HK3 were identified. The functional effects of HK3 in ccRCC were analyzed in silico and in vitro. Results: The large-scale findings suggested a significantly higher HK3 expression in ccRCC tissues and the predictive efficacy of HK3 for tumor progression and a poor prognosis. Next, the subgroup survival and Cox regression analyses showed that HK3 serves as a promising and independent predictive marker for the prognosis and survival of patients with ccRCC from bioinformatic databases and real-world cohorts. Subsequently, we found that HK3 could be used to modulate glycolysis and the malignant behaviors of ccRCC cells. The comprehensive results suggested that HK3 is highly correlated with the abundance of immune cells, and specifically stimulates the infiltration of monocytes/macrophages presenting surface markers, regulates the immune checkpoint molecules PD-1 and CTLA-4 of exhaustive T cells, restrains the immune escape of tumor cells, and prompts the immune-rejection microenvironment of ccRCC. Conclusion: In conclusion, the large-scale data first revealed that HK3 could affect glycolysis, promote malignant biologic processes, and predict the aggressive progression of ccRCC. HK3 may stimulate the abundance of infiltrating monocytes/macrophages presenting surface markers and regulate the key molecular subgroups of immune checkpoint molecules of exhaustive T cells, thus inducing the microenvironmental characteristics of active anti-tumor immune responses.

Xu W ，Liu WR ，Xu Y ，Tian X ，Anwaier A ，Su JQ ，Zhu WK ，Shi GH ，Wei GM ，Huang YP ，Qu YY ，Zhang HL ，Ye DW ... -  《International Journal of Biological Sciences》

Comprehensive Multi-Omics Identification of Interferon-γ Response Characteristics Reveals That RBCK1 Regulates the Immunosuppressive Microenvironment of Renal Cell Carcinoma.

Interferon-gamma (IFN-γ) has a complex role in modulating the tumor microenvironment (TME) during renal cell carcinoma (RCC) development. To define the role of IFN-γ response genes in RCC progression, we characterized the differential gene expression, prognostic implications, and DNA variation profiles of selected IFN-γ response signatures, which exhibited a significant hazard ratio for the overall survival (OS) and progression-free survival (PFS) of papillary, chromophobia, and clear cell RCC (ccRCC) patients (n = 944). Prognostic nomograms were constructed to predict the outcomes for ccRCC patients, highlighting the prognostic implications of RANBP2-type and C3HC4-type zinc finger containing 1 (RBCK1). Interestingly, large-scale pan-cancer samples (n = 12,521) and three single-cell RNA datasets revealed that RBCK1 showed markedly differential expression between cancer and normal tissues and significantly correlated with tumor-infiltrating immune cells, tumor purity, and immune checkpoint molecules, such as PD-L1, CTLA-4, LAG-3, and TIGIT in pan-cancer samples. Notably, the TIDE score was significantly higher in the RBCK1high group compared with the RBCK1low group in both ccRCC and RCC cohorts. Besides, immunohistochemistry staining showed significantly elevated RBCK1 expression in tumors (n = 50) compared with kidney samples (n = 40) from a real-world cohort, Fudan University Shanghai Cancer Center (FUSCC, Shanghai). After RBCK1 expression was confirmed in ccRCC, we found a significantly decreased number of infiltrating CD4+ T cells, CD4+ FOXP3+ Treg cells, M1 macrophages, and CD56bight/dim NK cells in the immune-cold RBCK1high group. In addition to the distinct heterogeneous immune microenvironment, the increased expression of RBCK1 predicted a prominently worse prognosis than the RBCK1low group for 232 ccRCC patients in the FUSCC proteomic cohort. Furthermore, after transfected with siRNA in human ccRCC cells, extraordinarily decreased cell proliferation, migration capacities, and prominently elevated apoptosis tumor cell proportion were found in the siRNA groups compared with the negative control group. In conclusion, this study identified IFN-γ response clusters, which might be used to improve the prognostic accuracy of immune contexture in the ccRCC microenvironment. Immune-cold RBCK1high patients have pro-tumorigenic immune infiltration and significantly worse outcomes than RBCK1low patients based on results from multi-omics to real-world data. Our discovery of novel independent prognostic indicators for RCC highlights the association between tumor alterations and immune phenotype.

Xu W ，Tao J ，Zhu W ，Liu W ，Anwaier A ，Tian X ，Su J ，Shi G ，Huang H ，Wei G ，Li C ，Qu Y ，Zhang H ，Ye D ... -  《Frontiers in Immunology》

A novel prognostic model based on immunogenomics for clear cell renal cell carcinoma.

Immune cell infiltration into tumor tissue is closely related to the clinical outcomes of patients with clear cell renal cell carcinoma (ccRCC). This study aimed to screen out potential immune genes associated with ccRCC, analyze their relationships with clinical outcomes, and construct a signature to predict ccRCC. The transcriptome RNA-sequencing data in 539 ccRCC and 72 adjacent normal tissues were obtained from TCGA database. Biomedical computational algorithms were conducted to identify immune-related differential expressed genes (IRDGs) and enriched pathways. Then, LASSO Cox and multivariate Cox analyses were performed to screen out genes that were then used to construct the prognostic model. A total of 116 down-regulated and 565 up-regulated IRDGs were identified. Pathway enrichment analysis suggested that IRDGs was mainly enriched in the pathway of "cytokines and cytokine receptors". The entire data of ccRCC were randomly divided into the training set and the test set with a ratio of 1:1. A 4-gene signature was then constructed using LASSO Cox analysis and multivariate Cox analysis in the training set. This prognostic signature could stratify patients into high- and low-risk groups successfully, and serve as an independent predictor when adjusted with clinical factors by univariate and multivariate Cox regression analysis. These results were verified in the test set and the entire set. Besides, the abundance of CD4 + T cells and dendritic cells increased in the high-risk group. Finally, we built a nomogram incorporating risk score and clinical factors to predict the overall survival of ccRCC patients. These findings may contribute to the research of ccRCC in immunization part.

Wu Z ，Shen Y ，Fan D ，Liu J ，Chen D ，Wang K ，Xu X ... -  《-》

HJURP is a prognostic biomarker for clear cell renal cell carcinoma and is linked to immune infiltration.

Clear cell renal cell carcinoma (ccRCC) is the most prevalent and highly malignant pathological type of kidney cancer. Finding more precise biomarkers is critical for enhancing the prognosis of patients with ccRCC. Multiple studies have suggested that Holliday junction recognition protein (HJURP) promotes tumor progression and predicts poor prognosis in a variety of cancers. However, the role of HJURP in ccRCC remains unclear. The ccRCC dataset was obtained from The Cancer Genome Atlas (TCGA), and the relationship between HJURP expression and ccRCC clinical features was investigated using R software. The effect of HJURP expression on survival was assessed using survival probabilities and Cox regression. Gene set enrichment analysis (GSEA) was used to identify HJURP-related signaling pathways in ccRCC. Finally, Tumor IMmune Estimation Resource (TIMER) and Gene Expression Profiling Interactive Analysis (GEPIA)were used to analyzethe correlation between HJURP expression and immunocyte infiltrates in ccRCC. HJURP expression was upregulated in ccRCC. Increased HJURP expression was associated with poor pathological features and correlated with poor prognosis in patients with ccRCC. Cox regression further found that HJURP expression was a high-risk factor for ccRCC patients. GSEA revealed that HJURP was closely linked to multiple immune-related signaling pathways. In ccRCC, HJURP expression was closely correlated with infiltration of various immune cells and expression of a wide range of immunocyte gene markers. HJURP is a potential independent prognostic marker in ccRCC that plays an essential role in the tumor microenvironment by regulating immunocyte infiltration.

Zhang F ，Yuan D ，Song J ，Chen W ，Wang W ，Zhu G ，Hu B ，Chen X ，Zhu J ... -  《-》

A novel 10 glycolysis-related genes signature could predict overall survival for clear cell renal cell carcinoma.

Xing Q ，Zeng T ，Liu S ，Cheng H ，Ma L ，Wang Y ... -  《BMC CANCER》