scholarly journals DIRAS2 Contributes to Radiation Resistance of Renal Cell Carcinoma Via Autophagy Induction and MKK4-JNK1 Pathway Activation

2022 ◽  
Author(s):  
Chengfeng Cai ◽  
Ying He ◽  
Dong Yue ◽  
Jun Tian ◽  
Ning Guo
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Molecular Mechanism ◽  
Radiation Resistance ◽  
Renal Cell ◽  
Clonogenic Survival ◽  
The Cancer Genome Atlas ◽  
Mitogen Activated Protein Kinase ◽  
Definitive Treatment ◽  
Autophagy Induction

Abstract Radiation resistance has been regarded as a main obstacle to improve the definitive treatment of renal cell carcinoma (RCC), of which clear cell RCC (ccRCC) is the most common histological type. However, the molecular mechanism underlying the radiation resistance remains largely unclear. In this study, we investigated the effect of DIRAS2 on the response to ionizing radiation (IR) in human ccRCC cells. Here, we found the expression level of DIRAS2 was significantly upregulated in human ccRCC tissues using the Oncomine platform and the Cancer Genome Atlas (TCGA) database, which was further validated by immunohistochemistry. Overexpression of DIRAS2 promoted radiation resistance of ccRCC cells based on clonogenic survival assay and enhanced the levels of radiation induced-autophagy. Moreover, inhibition of autophagy by chloroquine (CQ) pre-treatment largely eliminated the effect of DIRAS2 overexpression on radiation-resistance. Finally, molecular mechanism investigation showed that overexpression of DIRAS2 upregulated the activity of mitogen-activated protein kinase (MAPK) kinase 4 (MKK4)- c-Jun NH2-terminal kinase 1 (JNK1)-Bcl-2 pathway in response to IR. Taken together, these results indicate that DIRAS2 may confer radiation resistance on human RCC via autophagy induction through MKK4-JNK1-Bcl-2 signaling pathway.

scholarly journals Low intratumor heterogeneity correlates with increased response to PD-1 blockade in renal cell carcinoma

2020 ◽  
Vol 12 ◽  
pp. 175883592097711
Author(s):  
Xia Ran ◽  
Jinyuan Xiao ◽  
Yi Zhang ◽  
Huajing Teng ◽  
Fang Cheng ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Checkpoint Inhibitors ◽  
Simulated Data ◽  
The Cancer Genome Atlas ◽  
Intratumor Heterogeneity ◽  
Cell Renal Cell Carcinoma ◽  
Immune Activity

Background: Intratumor heterogeneity (ITH) has been shown to be inversely associated with immune infiltration in several cancers including clear cell renal cell carcinoma (ccRCC), but it remains unclear whether ITH is associated with response to immunotherapy (e.g. PD-1 blockade) in ccRCC. Methods: We quantified ITH using mutant-allele tumor heterogeneity, investigated the association of ITH with immune parameters in patients with ccRCC ( n = 336) as well as those with papillary RCC (pRCC, n = 280) from The Cancer Genome Atlas, and validations were conducted in patients with ccRCC from an independent cohort ( n = 152). The relationship between ITH and response to anti-PD-1 immunotherapy was explored in patients with metastatic ccRCC from a clinical trial of anti-PD-1 therapy ( n = 35), and validated in three equal-size simulated data sets ( n = 60) generated by random sampling with replacement based on this clinical trial cohort. Results: In ccRCC, low ITH was associated with better survival, more reductions in tumor burden, and clinical benefit of anti-PD-1 immunotherapy through modulating immune activity involving more neoantigens, elevated expression of HLA class I genes, and higher abundance of dendritic cells. Furthermore, we found that the association between the level of ITH and response to PD-1 blockade was independent of the mutation status of PBRM1 and that integrating both factors performed better than the individual predictors in predicting the benefit of anti-PD-1 immunotherapy in ccRCC patients. In pRCC, increased immune activity was also observed in low- versus high-ITH tumors, including higher neoantigen counts, increased abundance of monocytes, and decreased expression of PD-L1 and PD-L2. Conclusions: ITH may be helpful in the identification of patients who could benefit from PD-1 blockade in ccRCC, and even in pRCC where no genomic metrics has been found to correlate with response to immune checkpoint inhibitors.

scholarly journals Identification of Six Potentially Long Noncoding RNAs as Biomarkers Involved Competitive Endogenous RNA in Clear Cell Renal Cell Carcinoma

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Kang Yang ◽  
Xiao-fan Lu ◽  
Peng-cheng Luo ◽  
Jie Zhang
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Expression Profiles ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma ◽  
Cerna Network

Background. Clear cell renal cell carcinoma (ccRCC), the most common subtype of renal cell carcinoma (RCC), usually is representative of metastatic heterogeneous neoplasm that links with poor prognosis, but the pathogenesis of ccRCC remains unclear. Currently, numerous evidences prove that long noncoding RNAs (lncRNAs) are considered as competing endogenous RNA (ceRNA) to participate in cellular processes of tumors. Therefore, to investigate the underlying mechanisms of ccRCC, the expression profiles of lncRNAs, miRNAs, and mRNAs were downloaded from the Cancer Genome Atlas (TCGA) database. A total of 1526 differentially expressed lncRNAs (DElncRNAs), 54 DEmiRNAs, and 2352 DEmRNAs were identified. To determine the connection of them, all DElncRNAs were input to the miRcode database. The results indicated that 85 DElncRNAs could connect with 9 DEmiRNAs in relation to our study. Then, databases of TargetScan and miRDB were used to search for targeted genes with reference to DEmiRNAs. The results showed that 203 out of 2352 targeted genes were identified in our TCGA set. Subsequently, ceRNA network was constructed according to Cytoscape and the targeted genes were functionally analyzed to elucidate the mechanisms of DEmRNAs. The results of survival analysis and regression analysis indicated that 6 DElncRNAs named COL18A1-AS1, WT1-AS, LINC00443, TCL6, AL356356.1, and SLC25A5-AS1 were significantly correlative with the clinical traits of ccRCC patients and could be served as predictors for ccRCC. Finally, these findings were validated by quantitative RT-PCR (qRT-PCR). Based on these discoveries, we believe that this identified ceRNA network will provide a novel perspective to elucidate ccRCC pathogenesis.

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

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Qianwei Xing ◽  
Tengyue Zeng ◽  
Shouyong Liu ◽  
Hong Cheng ◽  
Limin Ma ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Overall Survival ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Cox Regression ◽  
Clear Cell ◽  
Low Risk ◽  
The Cancer Genome Atlas ◽  
Regression Analyses ◽  
Cell Renal Cell Carcinoma

Abstract Background The role of glycolysis in tumorigenesis has received increasing attention and multiple glycolysis-related genes (GRGs) have been proven to be associated with tumor metastasis. Hence, we aimed to construct a prognostic signature based on GRGs for clear cell renal cell carcinoma (ccRCC) and to explore its relationships with immune infiltration. Methods Clinical information and RNA-sequencing data of ccRCC were obtained from The Cancer Genome Atlas (TCGA) and ArrayExpress datasets. Key GRGs were finally selected through univariate COX, LASSO and multivariate COX regression analyses. External and internal verifications were further carried out to verify our established signature. Results Finally, 10 GRGs including ANKZF1, CD44, CHST6, HS6ST2, IDUA, KIF20A, NDST3, PLOD2, VCAN, FBP1 were selected out and utilized to establish a novel signature. Compared with the low-risk group, ccRCC patients in high-risk groups showed a lower overall survival (OS) rate (P = 5.548Ee-13) and its AUCs based on our established signature were all above 0.70. Univariate/multivariate Cox regression analyses further proved that this signature could serve as an independent prognostic factor (all P < 0.05). Moreover, prognostic nomograms were also created to find out the associations between the established signature, clinical factors and OS for ccRCC in both the TCGA and ArrayExpress cohorts. All results remained consistent after external and internal verification. Besides, nine out of 21 tumor-infiltrating immune cells (TIICs) were highly related to high- and low- risk ccRCC patients stratified by our established signature. Conclusions A novel signature based on 10 prognostic GRGs was successfully established and verified externally and internally for predicting OS of ccRCC, helping clinicians better and more intuitively predict patients’ survival.

scholarly journals Long Non-Coding RNA LINC02747 Promotes the Proliferation of Clear Cell Renal Cell Carcinoma by Inhibiting miR-608 and Activating TFE3

2020 ◽  
Vol 10 ◽  
Author(s):  
Xiang Ju ◽  
Yangyang Sun ◽  
Feng Zhang ◽  
Xiaohui Wei ◽  
Zhenguo Wang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Histological Grade ◽  
Rapid Development ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma

With the rapid development of biotechnology, long noncoding RNAs (lncRNAs) have exhibited good application prospects in the treatment of cancer, and they may become new treatment targets for cancer. This study aimed to explore lncRNAs in clear cell renal cell carcinoma (ccRCC). Differentially expressed lncRNAs in 54 pairs of ccRCC tissues and para-carcinoma tissues were analyzed in The Cancer Genome Atlas (TCGA), and the most significant lncRNAs were selected and verified in ccRCC tissues. We found that lncRNA LINC02747 was highly expressed in ccRCC (P &lt; 0.001) and was closely related to high TNM stage (P = 0.006) and histological grade (P = 0.004) and poor prognosis of patients (P &lt; 0.001). In vivo and in vitro experiments confirmed that LINC02747 could promote the proliferation of ccRCC cells. We also found that LINC02747 regulated the proliferation of RCC cells by adsorbing miR-608. Subsequent mechanistic research showed that miR-608 is downregulated in ccRCC (P &lt; 0.001), and overexpression of miR-608 inbibited the proliferation of RCC cells. Moreover, we found that TFE3 is a direct target gene of miR-608. MiR-608 regulated the proliferation of RCC cells by inhibiting TFE3. In conclusion, LINC02747 upregulates the expression of TFE3 by adsorbing miR-608, ultimately promoting the proliferation of ccRCC cells. The above findings indicate that LINC02747 acts as an oncogene in ccRCC and may be developed as a molecular marker for the diagnosis and prognosis of ccRCC. The LINC02747/miR-608/TFE3 pathway may become a new therapeutic target for ccRCC.

scholarly journals miR-142-3p as a novel biomarker for predicting poor prognosis in renal cell carcinoma patients after surgery

2019 ◽  
Vol 34 (3) ◽  
pp. 302-308 ◽  
Author(s):  
Xiqi Peng ◽  
Xiang Pan ◽  
Kaihao Liu ◽  
Chunduo Zhang ◽  
Liwen Zhao ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Receiver Operating Characteristic ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Poor Prognosis ◽  
Operating Characteristic ◽  
Characteristic Curve ◽  
Area Under The Curve ◽  
The Cancer Genome Atlas ◽  
Receiver Operating

Background: miR-142-3p has proved to be involved in tumorigenesis and the development of renal cell carcinoma. The present study aimed to explore the prognostic value of miR-142-3p. Methods: Total RNA was extracted from renal cell carcinoma specimens and the expression level of miR-142-3p was measured. Pearson Chi-square test, Kaplan–Meier analysis, as well as univariate and multivariate regression analysis were performed to determine the correlation between miR-142-3p and the prognosis of renal cell carcinoma patients. Receiver operating characteristic curves were constructed to evaluate the predictive efficiency of miR-142-3p for the prognosis of renal cell carcinoma patients. Data from The Cancer Genome Atlas (TCGA) were utilized to validate our findings. Results: Our results demonstrated that upregulation of miR-142-3p was correlated with shorter overall survival (P=0.002) and was, in the meantime, an independent prognostic factor for renal cell carcinoma patients (P=0.002). The receiver operating characteristic curve combining miR-142-3p expression with tumor stage showed an area under the curve of 0.633 (95% confidence interval 0.563, 0.702). The result of TCGA data was consistent with our findings. Conclusions: Our results suggest miR-142-3p expression is correlated with poor prognosis of renal cell carcinoma patients and may serve as a prognostic biomarker in the future.

scholarly journals Long Noncoding RNA HOTTIP Serves as an Independent Predictive Biomarker for the Prognosis of Patients with Clear Cell Renal Cell Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-13
Author(s):  
Zhanxin Liu ◽  
Zichun Wang ◽  
Xiaoxiong Wang ◽  
Meisong Lu ◽  
Guang Chen
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Noncoding Rna ◽  
Clear Cell ◽  
Clinical Stage ◽  
Predictive Biomarker ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma ◽  
Advanced Clinical Stage

Several studies have indicated that HOXA transcript at the distal tip (HOTTIP) play important roles in the tumorigenesis and development of various cancers. We aim to investigate the expression and prognostic value of HOTTIP in clear cell renal cell carcinoma (ccRCC). A systematic review of PubMed, Embase, Medline, and Web of Science databases was performed to select eligible literatures relevant to the correlation between HOTTIP expression and clinical outcome of different cancers. The association between the HOTTIP level and overall survival (OS), lymph node metastasis (LNM), or clinical stage was subsequently analyzed. Survival analyses were performed in a large cohort of more than 500 patients with ccRCC from The Cancer Genome Atlas (TCGA) using bioinformatic methods. Seventeen studies with a total of 1594 patients with thirteen kinds of carcinomas were included in this analysis. The result showed that high HOTTIP expression could predict worse outcome in cancer patients, with the pooled hazard ratio (HR) of 2.34 (95% confidence interval (CI) 1.96–2.79, p<0.0001). The result also showed that elevated HOTTIP expression was correlated with more LNM (OR=2.61, 95% CI 1.91-3.58, p<0.0001) and advanced clinical stage (OR=3.57, 95% CI 2.58-4.93, p<0.0001). We further validated that ccRCC patients with higher HOTTIP expression tend to have unsatisfactory outcomes both in the entire TCGA dataset and different clinical stratums, like age, grade, and stage. The tumor of those patients was associated with a larger size, easier to metastasis, advanced clinical stage, and a higher pathological grade. These findings suggested that increased HOTTIP expression might act as a novel prognostic marker for ccRCC patients.

scholarly journals 8q24 clear cell renal cell carcinoma germline variant is associated with VHL mutation status and clinical aggressiveness

BMC Urology ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Jeanette E. Eckel-Passow ◽  
Huihuang Yan ◽  
Matthew L. Kosel ◽  
Daniel Serie ◽  
Paul A. Decker ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Target Genes ◽  
Clear Cell ◽  
The Cancer Genome Atlas ◽  
Cell Renal Cell Carcinoma ◽  
Mutation Status ◽  
Germline Variants ◽  
Tumor Genetics

Abstract Background The four most commonly-mutated genes in clear cell renal cell carcinoma (ccRCC) tumors are BAP1, PBRM1, SETD2 and VHL. And, there are currently 14 known RCC germline variants that have been reproducibly shown to be associated with RCC risk. However, the association of germline genetics with tumor genetics and clinical aggressiveness are unknown. Methods We analyzed 420 ccRCC patients from The Cancer Genome Atlas. Molecular subtype was determined based on acquired mutations in BAP1, PBRM1, SETD2 and VHL. Aggressive subtype was defined clinically using Mayo SSIGN score and molecularly using the ccA/ccB gene expression subtype. Publically-available Hi-C data were used to link germline risk variants with candidate target genes. Results The 8q24 variant rs35252396 was significantly associated with VHL mutation status (OR = 1.6, p = 0.0037) and SSIGN score (OR = 1.9, p = 0.00094), after adjusting for multiple comparisons. We observed that, while some germline variants have interactions with nearby genes, some variants demonstrate long-range interactions with target genes. Conclusions These data further demonstrate the link between rs35252396, HIF pathway and ccRCC clinical aggressiveness, providing a more comprehensive picture of how germline genetics and tumor genetics interact with respect to tumor development and progression.

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