Mammalian SIRT4 is a tumor suppressor of clear cell renal cell carcinoma by inhibiting cancer proliferation, migration and invasion

2020 ◽  
Vol 29 (4) ◽  
pp. 453-462 ◽  
Author(s):  
Changming Wang ◽  
Chiyuan Piao ◽  
Junlong Liu ◽  
Zhe Zhang ◽  
Yuyan Zhu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Suppressor ◽  
Cell Carcinoma ◽  
Survival Data ◽  
Renal Cell ◽  
Clear Cell ◽  
Expression Level ◽  
Migration And Invasion ◽  
Advanced Tumor Stage ◽  
Cell Renal Cell Carcinoma

OBJECTIVE: Sirtuins family are defined as class III histone deacetylases (HDACs). Recently, mammalian silent information regulator two 4 (SIRT4) has been reported to be a tumor suppressor gene in multiple cancers. The objective of the present study was to explore the potential role of SIRT4 in clear cell renal cell carcinoma (ccRCC). METHODS: We estimated SIRT4 expression levels in ccRCC and its adjacent non-neoplastic tissue by Western blotting (WB), quantitative real-time polymerase chain reaction (qRT-PCR) and bioinformatics data, the clinical and survival data were also collected and analyzed. In vitro study, ccRCC cell lines were transfected with SIRT4-siRNA or lentivirus to downregulate or overexpress the expression level of SIRT4. Then, the proliferation capacity of tumor cell was assessed by 5-Ethynyl-2’-deoxyuridine (EDU) assay, cell migration and invasion capacity were assessed by Transwell assays. RESULTS: Our results indicated that the expression level of SIRT4 in ccRCC was significantly lower than the corresponding normal tissues (P< 0.001). Meanwhile, bioinformatics data and the result of WB showed that low SIRT4 expression level was obviously involved with poor overall survival and advanced tumor stage in ccRCC patients. Biological experiments demonstrated that overexpression of SIRT4 significantly reduced the proliferation, migration and invasion ability of ccRCC cells. Conversely, downregulation of SIRT4 enhanced the proliferation, migration and invasion ability of ccRCC cells. CONCLUSIONS: These findings support that SIRT4 acts as a tumor suppressor in ccRCC and might be a novel biomarker and new therapeutic target for ccRCC.

scholarly journals KDF1, a Novel Tumor Suppressor in Clear Cell Renal Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Jing-min Zheng ◽  
Mei-fu Gan ◽  
Hong-yuan Yu ◽  
Lu-xia Ye ◽  
Qing-xin Yu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Suppressor ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Tumor Tissue ◽  
Clear Cell ◽  
Expression Level ◽  
Disease Specific Survival ◽  
Cell Renal Cell Carcinoma ◽  
Disease Specific

KDF1 has been identified as a key regulator of epidermal proliferation and differentiation, but it is unknown whether KDF1 is involved in the pathogenesis of malignancy. No study has reported the expression and function of KDF1 in renal cancer. To explore the pathologic significance of KDF1 in clear cell renal cell carcinoma (ccRCC), the expression level of KDF1 protein in the tumor tissue of ccRCC patients was examined by immunohistochemistry and Western blot while the expression level of KDF1 mRNA was analyzed by using the data from TCGA database. In vitro cell experiments and allogeneic tumor transplantation tests were performed to determine the effects of altered KDF1 expression on the phenotype of ccRCC cells. Both the KDF1 mRNA and protein were found to be decreasingly expressed in the tumor tissue of ccRCC patients when compared with the adjacent non-tumor control tissue. The expression level of KDF1 in the tumor tissue was found to correlate negatively with the tumor grade. Patients with higher KDF1 in the tumor tissue were found to have longer overall survival and disease-specific survival time. KDF1 was shown to be an independent factor influencing the disease-specific survival of the ccRCC patients. Overexpression of KDF1 was found to inhibit the proliferation, migration and invasion of ccRCC cells, which could be reversed by decreasing the expression of KDF1 again. ccRCC cells with KDF1 overexpression were found to produce smaller transgrafted tumors. These results support the idea that KDF1 is involved in ccRCC and may function as a tumor suppressor.

scholarly journals Low Expression Levels of SLC22A12 Indicates a Poor Prognosis and Progresses Clear Cell Renal Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Jiaju Xu ◽  
Yuenan Liu ◽  
Jingchong Liu ◽  
Yi Shou ◽  
Zhiyong Xiong ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Survival Data ◽  
Renal Cell ◽  
Clear Cell ◽  
Gene Set Enrichment Analysis ◽  
Migration And Invasion ◽  
Cell Renal Cell Carcinoma ◽  
Expression Levels ◽  
Low Expression

Clear cell renal cell carcinoma (ccRCC) accounts for approximately 4/5 of all kidney cancers. Accumulation of minor changes in the cellular homeostasis may be one cause of ccRCC. Therefore, we downloaded the RNA sequencing and survival data of the kidney renal cell carcinoma (KIRC) cohort from the Cancer Genome Atlas (TCGA) database. After the univariate and multivariate Cox regression analyses, 19 kidney-specific differentially expressed genes (DEGs) were found. Solute Carrier Family 22 Member 12 (SLC22A12) resulted in an independent prognostic predictor for both overall survival (OS) and disease-free survival (DFS). SLC22A12 expression was lower in tumoral tissue compared to normal tissue. Moreover, patients in the SLC22A12 low expression group had a higher pathological stage and worse survival than the high expression group. Additionally, qRT-PCR assay, immunoblotting test (IBT), and immunohistochemical (IHC) analyses of cancer tissues/cells and the corresponding normal controls verified that SLC22A12 is downregulated in ccRCC. Receiver operator characteristic (ROC) curves showed that the low expression level of SLC22A12 could be a good diagnostic marker for ccRCC (AUC=0.7258; p &lt;0.0001). Gene set enrichment analysis (GSEA) showed that SLC22A12 expression levels are related to metabolism, cell cycle, and tumor-related signaling pathways. GO and KEGG analyses revealed that SLC22A12 transports multiple organic compounds, ions, and hormones and participates in the extracellular structure organization. Furthermore, SLC22A12 over-expression in vitro inhibited the proliferation, migration, and invasion of renal cancer cells by regulating PI3K/Akt pathways. Such effects were reversed when knocking out SLC22A12. In summary, as a transporter for many vital metabolites, SLC22A12 may affect tumor cell survival through its impacts on the mentioned metabolites. In conclusion, this study uncovered that SLC22A12 is a promising prognostic and diagnostic biomarker for ccRCC.

scholarly journals Long noncoding RNA lnc-DILC stabilizes PTEN and suppresses clear cell renal cell carcinoma progression

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Han Zhang ◽  
Pengtao Wei ◽  
Wenwei Lv ◽  
Xingtao Han ◽  
Jinhui Yang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Liver Cancer ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Migration And Invasion ◽  
Cell Renal Cell Carcinoma ◽  
Mechanistic Investigation

Abstract Background Increasing evidence has indicated that long noncoding RNAs (lncRNAs) are crucial regulators affecting the progression of human cancers. Recently, lncRNA downregulated in liver cancer stem cells (lnc-DILC) was identified to function as a tumor suppressor inhibiting the tumorigenesis and metastasis in liver cancer and colorectal cancer. However, to date, little is known about the functional roles of lnc-DILC in modulating malignant phenotypes of clear cell renal cell carcinoma (ccRCC) cells. Methods lnc-DILC expression in human ccRCC tissues was detected by qRT-PCR. Overexpression and knockdown experiments were carried out to determine the effects of lnc-DILC on ccRCC cell proliferation, migration and invasion. To reveal the underlying mechanisms of lnc-DILC functions in ccRCC cells. RNA immunoprecipitation, RNA pull-down, in vivo ubiquitination, co-immunoprecipitation and western blot assays were performed. Results Here, we identified that lnc-DILC levels were dramatically downregulated in ccRCC tissues. Loss of lnc-DILC expression was correlated with larger tumor size, advanced tumor grade and lymph node metastasis, and also predicted worse prognosis in patients with ccRCC. Functionally, knockdown and overexpression experiments demonstrated that lnc-DILC inhibited cell proliferation, migration and invasion in ccRCC cells. Mechanistic investigation revealed that lnc-DILC bound to tumor suppressor PTEN and suppressed its degradation. lnc-DILC repressed the PTEN ubiquitination through blocking the interaction between PTEN and E3 ubiquitin ligase WWP2 and recruiting the deubiquitinase USP11 to PTEN. Moreover, we demonstrated that PTEN–AKT signaling was crucial for lnc-DILC-mediated suppressive effects. Conclusions In summary, our research revealed a novel mechanism by which lnc-DILC regulates PTEN stability via WWP2 and USP11, and shed light on potential therapeutic strategies by the restoration of lnc-DILC expression in patients with ccRCC.

scholarly journals Downregulation of lncRNA ZNF582-AS1 due to DNA hypermethylation promotes clear cell renal cell carcinoma growth and metastasis by regulating the N(6)-methyladenosine modification of MT-RNR1

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Wuping Yang ◽  
Kenan Zhang ◽  
Lei Li ◽  
Yawei Xu ◽  
Kaifang Ma ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Renal Cell Carcinoma ◽  
Protein Expression ◽  
Cell Carcinoma ◽  
Clinical Significance ◽  
Renal Cell ◽  
Clear Cell ◽  
Expression Level ◽  
Cell Renal Cell Carcinoma ◽  
Qrt Pcr

Abstract Background Emerging evidence confirms that lncRNAs (long non-coding RNAs) are potential biomarkers that play vital roles in tumors. ZNF582-AS1 is a novel lncRNA that serves as a potential prognostic marker of cancers. However, the specific clinical significance and molecular mechanism of ZNF582-AS1 in ccRCC (clear cell renal cell carcinoma) are unclear. Methods Expression level and clinical significance of ZNF582-AS1 were determined by TCGA-KIRC data and qRT-PCR results of 62 ccRCCs. DNA methylation status of ZNF582-AS1 promoter was examined by MSP, MassARRAY methylation and demethylation analysis. Gain-of-function experiments were conducted to investigate the biological roles of ZNF582-AS1 in the phenotype of ccRCC. The subcellular localization of ZNF582-AS1 was detected by RNA FISH. iTRAQ, RNA pull-down and RIP-qRT-PCR were used to identify the downstream targets of ZNF582-AS1. rRNA MeRIP-seq and MeRIP-qRT-PCR were utilized to examine the N(6)-methyladenosine modification status. Western blot and immunohistochemistry assays were used to determine the protein expression level. Results ZNF582-AS1 was downregulated in ccRCC, and decreased ZNF582-AS1 expression was significantly correlated with advanced tumor stage, higher pathological stage, distant metastasis and poor prognosis. Decreased ZNF582-AS1 expression was caused by DNA methylation at the CpG islands within its promoter. ZNF582-AS1 overexpression inhibited cell proliferative, migratory and invasive ability, and increased cell apoptotic rate in vitro and in vivo. Mechanistically, we found that ZNF582-AS1 overexpression suppressed the N(6)-methyladenosine modification of MT-RNR1 by reducing rRNA adenine N(6)-methyltransferase A8K0B9 protein level, resulting in the decrease of MT-RNR1 expression, followed by the inhibition of MT-CO2 protein expression. Furthermore, MT-RNR1 overexpression reversed the decreased MT-CO2 expression and phenotype inhibition of ccRCC induced by increased ZNF582-AS1 expression. Conclusions This study demonstrates for the first time that ZNF582-AS1 functions as a tumor suppressor gene in ccRCC and ZNF582-AS1 may serve as a potential biomarker and therapeutic target of ccRCC.

scholarly journals Positive feedback regulation of lncRNA PVT1 and HIF2α contributes to clear cell renal cell carcinoma tumorigenesis and metastasis

Oncogene ◽  
2021 ◽  
Author(s):  
Ming-xiao Zhang ◽  
Li-zhen Zhang ◽  
Liang-min Fu ◽  
Hao-hua Yao ◽  
Lei Tan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Positive Feedback ◽  
Renal Cell ◽  
Clear Cell ◽  
Biological Significance ◽  
Specific Inhibitor ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Cell Renal Cell Carcinoma

AbstractLong noncoding RNAs (lncRNAs) have been reported to exert important roles in tumors, including clear cell renal cell carcinoma (ccRCC). PVT1 is an important oncogenic lncRNA which has critical effects on onset and development of various cancers, however, the underlying mechanism of PVT1 functioning in ccRCC remains largely unknown. VHL deficiency-induced HIF2α accumulation is one of the major factors for ccRCC. Here, we identified the potential molecular mechanism of PVT1 in promoting ccRCC development by stabilizing HIF2α. PVT1 was significantly upregulated in ccRCC tissues and high PVT1 expression was associated with poor prognosis of ccRCC patients. Both gain-of-function and loss-of function experiments revealed that PVT1 enhanced ccRCC cells proliferation, migration, and invasion and induced tumor angiogenesis in vitro and in vivo. Mechanistically, PVT1 interacted with HIF2α protein and enhanced its stability by protecting it from ubiquitination-dependent degradation, thereby exerting its biological significance. Meanwhile, HIF2α bound to the enhancer of PVT1 to transactivate its expression. Furthermore, HIF2α specific inhibitor could repress PVT1 expression and its oncogenic functions. Therefore, our study demonstrates that the PVT1/ HIF2α positive feedback loop involves in tumorigenesis and progression of ccRCC, which may be exploited for anticancer therapy.

scholarly journals Analysis of various potential prognostic markers and survival data in clear cell renal cell carcinoma

2017 ◽  
Vol 43 (3) ◽  
pp. 440-454 ◽  
Author(s):  
Tastekin Ebru ◽  
Oz Puyan Fulya ◽  
Akdere Hakan ◽  
Yurut-Caloglu Vuslat ◽  
Sut Necdet ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Survival Data ◽  
Renal Cell ◽  
Prognostic Markers ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma

scholarly journals IgG is involved in the migration and invasion of clear cell renal cell carcinoma

2015 ◽  
Vol 69 (6) ◽  
pp. 497-504 ◽  
Author(s):  
Zhengzuo Sheng ◽  
Yang Liu ◽  
Caipeng Qin ◽  
Zhenhua Liu ◽  
Yeqing Yuan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Western Blot ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Clear Cell ◽  
Migration And Invasion ◽  
Cancer Therapies ◽  
Normal Kidney ◽  
Cell Renal Cell Carcinoma

OBJECTIVE:To investigate if IgG can be expressed in clear cell renal cell carcinoma (cRCC) , and the expression of IgG is involved in the cancer progression. If IgG expression can serve as a potential target in cancer therapies and be used for judging the prognosis.MATERIALS AND METHODS:By immunohistochemistry, we detected IgG in cRCC tissues(75 cRCC tissues and75 adjacent normal kidney tissues). Immunofluorescence and Western blot was used to detect the IgG in cRCC cell lines (786-0, ACHN and CAKI-I). By RT-PCR, the functional transcript of IgG heavy chain was detected. Knockdown of IgG was to analyze the proliferation, migration and invasion ability by CCK8, Transwell and Matrigel and apoptosis in cRCC cell lines.RESULTS:By immunohistochemistry, we found strong staining of IgG in 66 cases of 75 cRCC tissues and 63 cases of 75 adjacent normal kidney tissues. Immunofluorescence and Western blot was found IgG in cRCC cell lines. Knock-down IgG in cRCC cell lines resulted in significant inhibition of cell proliferation, migration and invasion, and the induction of apoptosis of the 786-0 cells. The immunohistochemistry analysis showed that high IgG expression significantly correlated with the poor differentiation and advanced stage of cRCC.CONCLUSION:IgG was over expressed in cRCC and was involved in the proliferation, migration and invasion of cancer cells. IgG expression may serve as a potential target in cancer therapies and could be used for judging the prognosis.

scholarly journals RhoB Acts as a Tumor Suppressor That Inhibits Malignancy of Clear Cell Renal Cell Carcinoma

PLoS ONE ◽  
2016 ◽  
Vol 11 (7) ◽  
pp. e0157599 ◽  
Author(s):  
Weihao Chen ◽  
Shaoxi Niu ◽  
Xin Ma ◽  
Peng Zhang ◽  
Yu Gao ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Suppressor ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma
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