scholarly journals Mutational Analysis of PBRM1 and Significance of PBRM1 Mutation in Anti-PD-1 Immunotherapy of Clear Cell Renal Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Abudureyimujiang Aili ◽  
Jie Wen ◽  
Lixiang Xue ◽  
Junjie Wang
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Mutational Analysis ◽  
Cell Renal Cell Carcinoma ◽  
Expression Levels ◽  
Tumor Microenvironments ◽  
Tumor Tissues ◽  
Human And Mouse

Renal cell carcinoma is a common solid tumor. PBRM1 is one of the most mutation-prone genes in clear cell renal cell carcinoma (ccRCC) with the occurrence of mutation in 40% of ccRCC patients. Mutations in PBRM1 have been correlated with the efficacy of immunotherapy. However, the mutation types of PBRM1 are not well characterized. The effects of PBRM1 expression levels in the tumor microenvironment are not well studied. In addition, the mechanism and effect of anti-PD-1 immunotherapy in ccRCC tumor microenvironments are not well clarified. In this study, using bioinformatics methods we analyzed the alternation frequency and expression levels of PBRM1 in various tumors. Next, we experimentally validated their expression levels in ccRCC tissues from human and mouse models. We attempted to clarify the mechanisms of anti-PD-1 immunotherapy in ccRCC with various PBRM1 expression levels. Our results showed that deficiency of PBRM1 protein is correlated with CD4 T cell reduction in human and mouse ccRCC tissues. We also showed that anti-PD-1 Immunotherapy can increase the infiltration of T cells in both PBRM1 high and PBRM1 low tumors but to different degrees. Our study indicates that the reduction of CD4 cells in tumor tissues with low expression of PBRM1 may explain the compromised efficacy of anti-PD-1 immunotherapy in patients with PBRM1 mutated ccRCC. Our study sheds light on the potential of PBRM1 as a therapeutic target in ccRCC.

scholarly journals Combination of expression levels of miR-21 and miR-126 is associated with cancer-specific survival in clear-cell renal cell carcinoma

BMC Cancer ◽  
2014 ◽  
Vol 14 (1) ◽  
Author(s):  
Daniel Vergho ◽  
Susanne Kneitz ◽  
Andreas Rosenwald ◽  
Charlotte Scherer ◽  
Martin Spahn ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Cancer Specific Survival ◽  
Expression Levels

Tumor-infiltrating regulatory T lymphocytes orchestrate oncogenic PAK1-conferred immune evasion in clear-cell renal cell carcinoma

2019 ◽  
Author(s):  
Yang Qu ◽  
Jiajun Wang ◽  
Qi Bai ◽  
Yangyang Qi ◽  
Yifan Chen ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
T Lymphocytes ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Regulatory T Lymphocytes ◽  
Tumor Tissues ◽  
Pak1 Expression

Abstract Background: Little is known about the associations between PAK1 and anti-tumor immunity in clear-cell renal cell carcinoma (ccRCC). This study aims to explore the prognostic value of PAK1 in ccRCC patients and investigated the molecular immune mechanism for its oncogenic role. Methods: We retrospectively enrolled 282 ccRCC patients undergoing nephrectomy between 2005 and 2007 in Zhongshan hospital. Immunohistochemistry evaluated PAK1, CCL22, FOXP3 and CD8 expression in clinical specimens. Fresh tumor tissues, para-tumor tissues and peripheral blood samples for RT-PCR, ELISA, flow cytometry analyses were collected from patients who underwent nephrectomy in Zhongshan Hospital from September 2017 to April 2018. We compared clinical outcomes by Kaplan-Meier survival analysis and Cox regression model. Bioinformatics analysis performed in TCGA KIRC cohort. Results: High PAK1 expression indicated poorer overall survival (OS) and recurrence free survival (RFS) (both p<0.001) in ccRCC patients. Multivariate analyses indicated PAK1 as an independent prognostic factor. In clinical samples, PAK1 clearly correlated with immunosuppressive microenvironment in ccRCC tissues. Significantly, PAK1 positively correlated with Tumor-infiltrating regulatory T lymphocytes (Tregs). Furthermore, IL-10+ and TGF-β+ tumor-infiltrating Tregs both increased in PAK1 high tumors. Additionally, CCL22 was highly secreted in PAK1 high tumors. After treated by IPA-3 (an PAK1 inhibitor), CCL22 secretion was clearly inhibited (p<0.001). Finally, we built a nomogram to predict overall survival for ccRCC patients with higher predictive accuracy. Conclusions: Increased PAK1 expression predicted dismal prognosis in ccRCC patients by inducing tumor immune escape. IL-10+ and TGF-β+ tumor-infiltrating Tregs recruited by CCL22 play dominant immunosuppressive roles in PAK1 high tumors.

scholarly journals Expression and clinical significance of PTPN12 in clear cell renal cell carcinoma

2020 ◽  
Vol 48 (12) ◽  
pp. 030006052093604
Author(s):  
Yi Jin ◽  
Tian-xi Wang ◽  
Hao Li ◽  
Peng Guo ◽  
Qing-qing Wang
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Mrna Expression ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Expression Levels ◽  
Relative Expression ◽  
Normal Tissues ◽  
Mrna Expression Levels

Background Clear cell renal cell carcinoma (ccRCC) is a common urological disease. Expression of the protein tyrosine phosphatase 12 gene ( PTPN12) is decreased in many cancers; however, the relationship between PTPN12 gene function and renal cancer remains unclear. Methods We detected PTPN12 protein expression in ccRCC and corresponding normal tissues from 64 patients with ccRCC by immunohistochemistry, and relative PTPN12 mRNA levels by real-time quantitative polymerase chain reaction. The relationships between the relative expression levels of PTPN12 mRNA and the patients’ clinical data were analyzed. Results PTPN12 protein and mRNA expression levels were significantly lower in ccRCC compared with the corresponding normal tissues. The mRNA expression levels in the ccRCC and corresponding normal tissues from the 64 patients with ccRCC were 0.459±0.445 and 1.001±0.128, respectively, compared with the control (glyceraldehyde 3-phosphate dehydrogenase). There was a significant correlation between relative expression of PTPN12 mRNA in ccRCC tissues and tumor diameter and clinical stage. Conclusion The expression levels of PTPN12 protein and mRNA were significantly lower in ccRCC tissues compared with normal tissues. The role of PTPN12 may provide new insights and evidence to aid the diagnosis and targeted therapy of ccRCC.

Decreased prolyl hydroxylase 3 mRNA expression in oncocytomas compared with clear cell renal cell carcinoma

2020 ◽  
Vol 35 (4) ◽  
pp. 80-86
Author(s):  
Spyridon Kampantais ◽  
Ilias Kounatidis ◽  
Vasiliki Kotoula ◽  
Ioannis Vakalopoulos ◽  
Konstantinos Gkagkalidis ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Mrna Expression ◽  
Renal Cell ◽  
Clear Cell ◽  
Prolyl Hydroxylase ◽  
Renal Tumors ◽  
Cell Renal Cell Carcinoma ◽  
Expression Levels ◽  
Fresh Frozen

Introduction: Hypoxia inducible factors (HIF) and prolyl hydroxylase domain (PHD) enzymes play a central role in tumor progression in clear cell renal cell carcinoma (ccRCC). However, there are currently no data regarding the behavior of this pathway (HIF/PHD) in a large number of benign renal tumors, the oncocytomas. The aim of the present study was to compare the expression levels of these factors between ccRCC and oncocytoma tumors. Material and methods: A total of 56 fresh frozen specimens from patients with ccRCC and 14 oncocytoma specimens were analyzed via reverse transcription-quantitative polymerase chain reaction in order to assess the expression levels of HIF-1α, HIF-2α, PHD1, PHD2, and PHD3. The analysis involved both fresh frozen tumor samples as well as adjacent normal kidney tissues. Results: In ccRCC, HIF-1α and HIF-2α levels were upregulated in 65.5% and 71.4% of cases, respectively. PHD3 was downregulated only in 15.4% of the ccRCC cases, in contrast with oncocytoma cases, which exhibited low expression levels in the majority. The upregulation of PHD3 messenger RNA (mRNA) levels in ccRCC when compared with oncocytoma was statistically significant ( P<0.001). No other comparisons (HIF-1α, HIF-2α, PHD1, and PHD2) were significantly different. HIF-2α and PHD3 mRNA expression levels were negatively correlated with Fuhrman Grade ( P=0.029 and P=0.026, respectively) in ccRCC. Conclusion: To the best of our knowledge, this is the first time that the HIF/PHD pathway was compared between ccRCC and a common benign tumor, identifying the upregulation of PHD3 as the possible underlying factor guiding the difference in the behavior of ccRCC.

scholarly journals Expression levels of immune control points genes in renal cell carcinoma

2020 ◽  
pp. 64-65
Author(s):  
Н.В. Апанович ◽  
А.А. Алимов ◽  
П.В. Апанович ◽  
А.Ю. Кузеванова ◽  
Д.Ж. Мансорунов ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
New Drugs ◽  
Control Points ◽  
Immune Control ◽  
Cell Renal Cell Carcinoma ◽  
Expression Levels ◽  
Further Development

Внедрение в терапию рака новых препаратов на основе ингибирования иммунных контрольных точек (ИКТ) существенно улучшило прогноз для больных. Тем не менее, такая терапия не всегда эффективна. Для вскрытия возможных причин этого мы изучили уровни экспрессии PD-L1 и других генов ИКТ - IDO1, CEACAM1, PVR, TDO2, CD276, GAL9 и ADAM17 в образцах светлоклеточного почечно-клеточного рака. В результате анализа выявили наиболее часто экспрессирующиеся совместно с PD-L1 гены - IDO1, TDO2, CD276, GAL9 и ADAM17. Значимую корреляцию с экспрессией PD-L1 имела экспрессия генов ADAM17, PVR и CD276. Полученные данные могут иметь значение для дальнейшего развития терапии на основе блокирования ИКТ, включая PD-L1. The introduction of new drugs based on the inhibition of immune control points (ICР) into cancer therapy has significantly improved the prognosis for patients. However, such therapy is not always effective. To reveal the possible reasons for this, we studied the expression levels of PD-L1 and other ICР genes - IDO1, CEACAM1, PVR, TDO2, CD276, GAL9 and ADAM17 in samples of clear cell renal cell carcinoma. The analysis revealed the genes most often expressed together with PD-L1 - IDO1, TDO2, CD276, GAL9 and ADAM17. Significant correlation with the expression of PD-L1 was found for the expression of ADAM17, PVR, and CD276 genes. The data obtained may be important for the further development of therapy based on blocking ICP, including PD-L1.

scholarly journals Identification of ACSL4 as a biomarker and contributor of ferroptosis in clear cell renal cell carcinoma

2020 ◽  
Author(s):  
na guo
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Gene Transfection ◽  
Prognostic Significance ◽  
Expression Level ◽  
Cell Renal Cell Carcinoma ◽  
Expression Levels ◽  
Protein Ubiquitination

Abstract Background ACSL4 has been reported to be related to tumor genesis and involved in the processes of ferroptosis. However, the expression levels and prognostic value of ACSL4 in clear cell renal cell carcinoma (ccRCC) remain unclear. Methods The Oncomine and TCGA databases were used to predict the expression of ACSL4 mRNA in ccRCC and its association with ccRCC prognosis. The expression levels of ACSL4 were determined in human RCC tissues by real-time PCR. Kaplan-Meier curves were used to analyze the diagnostic and prognostic significance of ACSL4 in ccRCC. A ferroptosis inducer (erastin) was used to investigate the effects of ACSL4 on ferroptosis in ccRCC cell lines. Results The expression level of ACSL4 was significantly down-regulated in ccRCC tissues (P < 0.001), which was consistent with the analysis of the Oncomine and TCGA database. Then, immunohistochemical results demonstrated that the ACSL4 was weak or not detected in ccRCC tissues than that in normal tissues. ACSL4 differential expression level was significantly related to gender, ccRCC subtypes, nodal invasion, tumor grade and cancer stages (all P < 0.001). Survival analysis revealed that overall survival was favorable in ccRCC patients with ACSL4 high expression (P = 0.014). Overexpression of ACSL4 by gene transfection restores ferroptosis sensitization in cancer cells, whereas suppression of ACSL4 expression by RNAi increases ferroptosis resistance. Mechanically, protein ubiquitination may be involved in ACSL4-mediated ferroptosis. Conclusions As a monitor and contributor of ferroptosis, ACSL4 was decreased in ccRCC and served as a useful diagnostic and prognostic biomarker, which will be a new potential therapeutic target for ccRCC.

scholarly journals Similarities and Differences between Clear Cell Tubulo-Papillary and Conventional Clear Cell Renal Cell Carcinoma: A Comparative Phenotypical and Mutational Analysis

Diagnostics ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. 123
Author(s):  
Francesca Giunchi ◽  
Tania Franceschini ◽  
Elisa Gruppioni ◽  
Annalisa Altimari ◽  
Elisa Capizzi ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Differential Diagnosis ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Mutational Analysis ◽  
Papillary Renal Cell Carcinoma ◽  
Tumor Type ◽  
Wild Type ◽  
Cell Renal Cell Carcinoma

Background: Clear cell tubulo-papillary renal cell carcinoma (cctpRCC) is characterized by clear cell morphology, but differs from conventional clear cell carcinoma (ccRCC) for its indolent clinical behavior and genetic background. The differential diagnosis between the two is based on histology and immunohistochemistry (IHC). Methods: We performed a comparative case-control histological, IHC, and genetic analysis by next generation sequencing (NGS), to point out the differences in 10 cases of cctpRCC, and six controls of ccRCC with low stage and grade. Results: All 16 cases showed the IHC profile with cytokeratin 7, racemase, and carbonic anhydrase IX expected for the histological features of each tumor type. By contrast, the NGS mutation analysis that covered 207 amplicons of 50 oncogenes or tumor suppressor genes provided conflicting results. Among the 10 cctpRCC cases, eight (80%) were wild type for all of the genes in the panel, while two (20%) harbored VHL mutations typical of ccRCC. Three of the six (50%) ccRCC control cases showed expected VHL mutations; two (33%) harbored pathogenic mutations in the p53 or the CKIT genes; and one (16%) was wild type. Conclusion: We can assume that histology and ICH are not sufficient for a definitive diagnosis of cctpRCC or ccRCC. Although with a panel covering 50 genes, we found that 80% of cctpRCC were genetically silent; thus, suggesting an indolent biology of these tumors. The differential diagnosis between ccptRCC and ccRCC for the choice of the best therapeutic strategy likely requires the comprehensive evaluation of histology, IHC, and at least VHL mutations.

Pathological significance of C3aR signaling in the tumor cells of clear cell renal cell carcinoma: a clinical observation

2020 ◽  
Author(s):  
Jing-Min Zheng ◽  
Xiong Tian ◽  
Mei-Fu Gan ◽  
Hong-Yuan Yu ◽  
Li-Cai Mo
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Survival Time ◽  
Tumor Cells ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Ki 67 ◽  
Tumor Tissues

Abstract Background Increasing evidences suggest that anaphylotoxin-induced signaling is involved in tumor pathogenesis, but the exact role of C3a/C3aR signaling in clear cell renal cell carcinoma (ccRCC) still remains to be investigated. The aim of the study was to investigate the pathological significance of C3a/C3aR signaling in ccRCC. Methods The expression of C3aR and C3 mRNA in the tumor tissues of ccRCC patients were analyzed by using the data from TCGA database. The expression of C3aR and C3c protein in the tumor tissues of another 129 ccRCC patients were examined by immunohistochemistry. Results Compared with the normal controls, both C3aR and C3 mRNA increased in the tumor tissues. Patients with higher C3 mRNA had shorter survival time. Immunostaining for C3aR and C3c also increased in the tumor tissues when compared with the adjacent normal renal tissues. Higher level of C3aR in the tumor cells and C3c in the tumor tissues were found to be associated with indices reflecting poor prognosis including higher tumor grade, the presence of necrosis in tumor tissues and shorter survival time. Besides, the level of C3aR in the tumor cells and C3c in the tumor tissues were found to correlate with the level of Vimentin, E-Cadherin and the ratio of Ki-67 positive tumor cells. Conclusions These results support the idea that C3aR signaling is over-activated in the tumor cells and may contribute to the progression of ccRCC. Inducing EMT and promoting the proliferation of tumor cells might be among the mechanisms underlying the role of C3aR signaling in ccRCC.

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