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Background: Nephrectomy, whether in the era of cytokine therapy or targeted therapy, has an important role in the treatment of metastatic renal cell carcinoma. With the advent of immunotherapy, immunotherapy combined with targeted therapy has become the mainstream of systemic therapy, but the role of nephrectomy in metastatic renal cell carcinoma is unclear. In this study, we retrospectively analyzed the impact of nephrectomy on survival in patients with metastatic renal cell carcinoma who received immune-targeted therapy., Methods: Patients with metastatic renal cell carcinoma who received immune-targeted therapy at three centers between May 17, 2019 and August 1, 2022 were collected, who were divided into two groups based on whether nephrectomy was performed or not. Survival, response rate and adverse event were compared between the two groups. The primary end point was progression free survival, Subgroup analysis and univariate and multivariable prognostic analyses were also assessed., Results: With a median follow-up time of 29.3 months (95% CI 28.5-30.2), 165 patients were recruited and divided into two groups based on whether they underwent nephrectomy or not. There were 68 patients in the non-nephrectomy group, 97 in the nephrectomy group. Compared to patients treated with immune-targeted therapy, patients treated with immune-targeted therapy plus nephrectomy were able to achieve survival benefits, with a median PFS of 10.8 months (95% CI 8.3-13.3) and 14.4 months (95% CI 12.6-16.2), respectively, as well as an HR of 0.476 (95% CI 0.323-0.701, p = 0.0002). The 12-month and 18-month PFS rates were 30.9% versus 60.8% and 7.4% versus 25.8%, respectively. The objective response rate (ORR) was 52.9% and 60.8%, respectively, in the non-nephrectomy and nephrectomy groups (p = 0.313), and the disease control rate (DCR) was 75% and 83.5%, respectively (p = 0.179). The most common adverse events related to treatment were hypothyroidism, immune-related pneumonitis and rash. Multivariate analysis showed that primary tumor nephrectomy prior to immune-targeted therapy, clear cell renal carcinoma and oligo metastasis were independent prognostic factors., Conclusions: Nephrectomy may provide PFS benefit with tolerable safety for patients with metastatic renal cell carcinoma who receive immune-targeted therapy. In multivariate analysis, nephrectomy, clear cell carcinoma, and oligo-organ metastasis were found to be favorable independent prognostic factors., (© 2023. BioMed Central Ltd., part of Springer Nature.)

PDZK1 downregulation was reported to independently predict poor prognosis of clear cell renal cell carcinoma (ccRCC) patients and induce ccRCC development and progression. However, the underlying mechanism of PDZK1 downregulation remains unknown. Competing endogenous RNA (ceRNA) networks are emerging as new players in gene regulation and are associated with cancer development. ceRNAs regulate other RNA transcripts by competing for shared miRNAs. To investigate the role and mechanism of ceRNAs in PDZK1 downregulation and the development of ccRCC, we searched databases for miRNAs and lncRNAs that regulate PDZK1 expression in ccRCC tissues and assessed their effects in ccRCC. We found that miR-15b was expressed at higher levels in ccRCC tissues, and its upregulation was clinically associated with lower PDZK1 level, larger tumor size and shorter survival time of ccRCC patients. Conversely, a novel lncRNA (lncPENG) was expressed at a lower level in ccRCC tissues, and its downregulation was associated with the same effects as upregulation of miR-15b. Downregulation of miR-15b and upregulation of lncPENG resulted in a significant increase in PDZK1 level and inhibition of proliferation in vitro and in vivo. Mechanistically, lncPENG directly bound to miR-15b and effectively functioned as a sponge for miR-15b to modulate the expression of PDZK1. Thus, lncPENG may function as a ceRNA to attenuate miR-15b-dependent PDZK1 downregulation and inhibit cell proliferation, suggesting that it may be clinically valuable as a therapeutic target and a prognostic biomarker of ccRCC.

Differentially expressed (DE) microRNAs (miRNAs) in clear cell renal cell carcinoma (ccRCC) tissues from pooled samples were reported to affect the tumorigenesis and progression of ccRCC. However, systematic studies on the miRNA-mRNA regulatory networks involved in various pathways in all four stages of the disease are lacking. In this study, we applied microarray technology to perform an integrated analysis of the miRNome and transcriptome in ccRCC tissues from patients at different stages of ccRCC. A total of 604 DEmiRNAs and 6892 DEgenes (DEGs) were identified by comparison with corresponding adjacent normal tissues. The pairing of miRNAs with DEGs were searched using validated miRWalk module, and the pairs were confirmed by comparing with DEmiRNAs in our study. Our results demonstrated that different stages of ccRCC had distinct miRNA/mRNA profiles. However, four common pathways (the complement and coagulation cascades, the pathway for the metabolism of xenobiotics by cytochrome P450, the PPAR signaling pathway, and the pathway for aldosterone-regulated sodium reabsorption) were enriched by targets of DEmiRNAs at all stages of ccRCC. We carried out an extensive analysis of data on miR-16, which had the most target genes, and found that its differential expression was validated in The Cancer Genome Atlas dataset. We also verified the correlation between miR-16 expression and target pathways by gene set enrichment analysis and in vitro experiments. High miR-16 level was also associated with shorter survival time in ccRCC. Our work presents a systematic profiling of miRNA, mRNA and pathways regulated by miRNAs in different stages of ccRCC. Our cross-omics results also identify four common pathways that function aberrantly in all stages of the disease. These pathways are likely to be critical in occurrence and progression of ccRCC. These common dysfunctional pathways have the potential to serve as therapeutic targets and diagnostic biomarkers, whereas miRNAs (miR-20, 484, 497) differentially expressed in only stage I tissues and in blood could be used to diagnose early-stage ccRCC patients., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Precision therapy for clear cell renal cell carcinoma (ccRCC) requires molecular biomarkers ascertaining disease prognosis. In this study, we performed integrated proteomic and transcriptomic screening in all four tumour-node-metastasis stages of ccRCC and adjacent normal tissues (n = 18) to investigate differentially expressed genes. Most identified differentially expressed genes revealed a strong association with transforming growth factor-β level and the epithelial-to-mesenchymal transition process. Of them, Serpin peptidase inhibitor clade H member 1 (SERPINH1) revealed the strongest association with poor prognosis and regulation on the expression levels of epithelial-to-mesenchymal transition markers. Subsequently, two independent sets (n = 532 and 105) verified the high level of SERPINH1 in ccRCC tissues and its association with reduced overall survival and disease-free survival in all tumour-node-metastasis stages and patients with von Hippel-Lindau wild-type (VHL-WT). SERPINH1 was an independent predictor of poor overall survival (hazard ratio 0.696 for all patients) and disease-free survival (hazard ratio 0.433 for all patients and 0.362 for patients with VHL-WT) in ccRCC. We have thus shown for the first time that SERPINH1 is an independent precision predictor for unfavourable prognosis in ccRCC. This could assist in identifying patients who need early aggressive management and deepen our understanding of the pathogenesis of VHL-WT ccRCC., (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

Clear cell renal cell carcinoma (ccRCC) is the most lethal neoplasm of the urologic system. Clinical therapeutic effect varies greatly between individual ccRCC patients, so there is an urgent need to develop prognostic molecular biomarkers to help clinicians identify patients in need of early aggressive management. In this study, samples from primary ccRCC tumor and their corresponding nontumor adjacent tissues (n=18) were analyzed by quantitative proteomic assay. Proteins downregulated in tumors were studied by GO and KEGG pathways enrichment analyses. Six proteins were found both downregulated and annotated with cell proliferation in ccRCC patients. Of these proteins, PDZK1 and FABP1 were also involved in the lipid metabolism pathway. The downregulation of PDZK1 was further validated in TCGA_KIRC dataset (n=532) and independent set (n=202). PDZK1 could discriminate recurrence, metastasis and prognosis between ccRCC patients. Low level of PDZK1 in both mRNA and protein was associated with reduced overall survival (OS) and disease-free survival (DFS) in two independent sets. In univariate and multivariate analyses, PDZK1 was defined as an independent prognostic factor for both OS and DFS. These findings indicated that low level of PDZK1 could predict poor clinical outcome in patients with ccRCC., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

MicroRNAs (miRNAs) were reported to be involved in the development of clear cell renal cell carcinoma (ccRCC). However, the study on miRNAs in ccRCC is far from complete. The present study identified miRNAs which could act as potential novel prognostic markers for ccRCC, and analyzed its possible mechanism. We found that miR-19a correlated with poor prognosis of ccRCC patients via promoting cell proliferation and suppressing PTEN/SMAD4 expression. Both the microarray screening result and TCGA KIRC dataset analysis showed that miR-19a was significantly upregulated in ccRCC tissues, and further analysis of TCGA data revealed that the upregulated level of miR-19a was strongly associated with advanced T stage and poor prognosis of ccRCC patients. Consistent with clinical observations, miR-19a overexpression significantly promoted ccRCC cell proliferation in vitro. To further explore the mechanism by which miR-19a correlated with cell proliferation and poor prognosis of ccRCC, we performed gene set enrichment analysis (GSEA) for target genes of miR-19a in ccRCC patients. Result indicated that the key target genes of miR-19a included SMAD4 and PTEN. In ccRCC tissues, expression levels of SMAD4 and PTEN were negatively correlated with expression level of miR-19a, revealing that miR-19a suppressed the expression of SMAD4 and PTEN in ccRCC patients. miR-19a overexpression significantly suppressed the expression of SMAD4 and PTEN in vitro, further verifying that SMAD4 and PTEN were the target genes of miR-19a in ccRCC cells. Our results elucidated the tumor promoting role of miR-19a and established miR-19a as a potential novel prognostic marker for ccRCC.