scholarly journals Ovatodiolide Targetsβ-Catenin Signaling in Suppressing Tumorigenesis and Overcoming Drug Resistance in Renal Cell Carcinoma

2013 ◽  
Vol 2013 ◽  
pp. 1-16 ◽  
Author(s):  
Jar-Yi Ho ◽  
Ren-Jun Hsu ◽  
Chieh-Lin Wu ◽  
Wen-Liang Chang ◽  
Tai-Lung Cha ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Drug Resistance ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Synergistic Effects ◽  
Biological Effects ◽  
Mouse Xenograft Model ◽  
Signaling Inhibitors

Dysregulatedβ-catenin signaling is intricately involved in renal cell carcinoma (RCC) carcinogenesis and progression. Determining potentialβ-catenin signaling inhibitors would be helpful in ameliorating drug resistance in advanced or metastatic RCC. Screening forβ-catenin signaling inhibitors involvedin silicoinquiry of the PubChem Bioactivity database followed by TCF/LEF reporter assay. The biological effects of ovatodiolide were evaluated in 4 RCC cell linesin vitroand 2 RCC cell lines in a mouse xenograft model. The synergistic effects of ovatodiolide and sorafenib or sunitinib were examined in 2 TKI-resistant RCC cell lines. Ovatodiolide, a pure compound ofAnisomeles indica, inhibitedβ-catenin signaling and reduced RCC cell viability, survival, migration/invasion, andin vitrocell orin vivomouse tumorigenicity. Cytotoxicity was significantly reduced in a normal kidney epithelial cell line with the treatment. Ovatodiolide reduced phosphorylatedβ-catenin (S552) that inhibitedβ-catenin nuclear translocation. Moreover, ovatodiolide decreasedβ-catenin stability and impaired the association ofβ-catenin and transcription factor 4. Ovatodiolide combined with sorafenib or sunitinib overcame drug resistance in TKI-resistant RCC cells. Ovatodiolide may be a potentβ-catenin signaling inhibitor, with synergistic effects with sorafenib or sunitinib, and therefore, a useful candidate for improving RCC therapy.

The role of ZNF395 in renal cell carcinoma proliferation, migration, and invasion.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 592-592 ◽  
Author(s):  
Chen Zhao ◽  
Christopher G. Wood ◽  
Jose A. Karam ◽  
Tapati Maity ◽  
Lei Wang
Keyword(s):  
Renal Cell Carcinoma ◽  
Tumor Growth ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Migration And Invasion ◽  
Mrna Levels

592 Background: Zinc finger protein 395 (ZNF395) is frequently altered in several tumor types. However, the role of ZNF395 remains poorly studied in patients with clear cell renal cell carcinoma (RCC). In this study, we investigated the in vitro and in vivo role of ZNF395 in ccRCC. Methods: cBioPortal For Cancer Genomics was used to correlate the expression of ZNF395 with RCC patient clinical, pathological and molecular profiles. ZNF395 protein and mRNA levels were studied in several RCC cell lines in vitro. Subsequently, ZNF395 knockdown was performed in 786-O and UMRC3 RCC cells and overexpression was done in Caki-1 and 769-P RCC cells. We then evaluated ZNF395 modulation in these cell lines by in vitro MTT, migration and invasion assays. Finally, we studied the effect of ZNF395 knockout and overexpression in vivo using SCID xenograft models. Results: Patients with higher expression of ZNF395 experienced longer disease-free survival and overall survival. Using in vitro models, we confirmed that knockdown of ZNF395 decreased ZNF395 expression, and increased proliferation, migration and invasiveness of 786-O and UMRC3, while overexpression of ZNF395 increased ZNF395 expression, and reduced proliferation, migration and invasiveness of Caki-1 and 769-P. Using in vivo mouse models, knockdown of ZNF395 expression in 786-O promoted tumor growth while its overexpression in Caki-1 resulted in tumor growth inhibition. We are currently performing experiments to understand the process by which ZNF395 regulates ccRCC pathogenesis. Conclusions: Our data support the role of ZNF395 as an important tumor suppressor gene in the pathogenesis of RCC.

scholarly journals Inhibition of the CDK4/6-Cyclin D-Rb Pathway by Ribociclib Augments Chemotherapy and Immunotherapy in Renal Cell Carcinoma

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Dehong Chen ◽  
Xiaosong Sun ◽  
Xuejun Zhang ◽  
Jun Cao
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Target Genes ◽  
Standard Of Care ◽  
Cyclin D ◽  
Rb Pathway

Renal cell carcinoma (RCC) is the most aggressive type of genitourinary cancer and is resistant to current therapies. Identifying drugs that enhance the efficacy of RCC standard-of-care drugs at sublethal concentrations is an alternative therapeutic strategy. Ribociclib is an orally available cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor that is approved for the treatment of breast cancer. In this work, we demonstrate that ribociclib at clinically achievable concentrations inhibits proliferation of 7 out of 9 tested RCC cell lines, with IC50 range from 76 to 280 nM. In addition, ribociclib induces apoptosis of RCC cells, but with less potency compared to its antiproliferative activity. The combination of ribociclib with chemotherapeutic or immunotherapeutic agents is synergistic in RCC cell lines. Of note, ribociclib demonstrates selective anti-RCC activity by sparing normal kidney cells and fibroblast cells. Consistent with the in vitro findings, ribociclib inhibits RCC growth at the dosage that does not lead to toxicity in mice and enhances the in vivo efficacy of RCC standard-of-care drugs. Mechanistically, we show that ribociclib remarkably inhibits phosphorylation of retinoblastoma protein (Rb) at various sites, leading to the suppression of transcription of E2F target genes in RCC cells. Our findings clearly demonstrate the potency and selectivity of ribociclib in RCC preclinical models, via inhibition of the CDK4/6-cyclin D/Rb pathway. Our findings support a clinical trial for the combination of ribociclib with chemo/immunotherapy in RCC.

Long Noncoding RNA LINC00460 Facilitates the Proliferation and Metastasis of Renal Cell Carcinoma via PI3K/AKT Signaling Pathway

2021 ◽  
Author(s):  
Feng-Juan Zhou ◽  
Sen Meng ◽  
Hongmei Yong ◽  
Ping-Fu Hou ◽  
Min-Le Li ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Noncoding Rna ◽  
Underlying Mechanism ◽  
The Cancer Genome Atlas ◽  
Akt Pathway

Abstract Renal cell carcinoma (RCC) is one of the most prevalent cancers. Long noncoding RNAs (LncRNAs) have been indicated as a mediator acted in tumorigenesis of RCC. However, the mechanism of LINC00460 on RCC is yet to be investigated. This study aimed to investigate the potential function of LINC00460 and underlying mechanism of RCC. We detected LINC00460 expression in RCC tissues and the prognosis in RCC patients using Gene Expression Profiling Interactive Analysis (GEPIA) website and The Cancer Genome Atlas (TCGA) database. LINC00460 level in normal renal cell line and RCC cell lines were detected by quantitative real-time polymerase chain reaction (qRT-PCR). We study the effects of LINC00460 on proliferation, migration, invasion, apoptosis in RCC cells lines using a series of in vivo and in vitro experiments. RNA sequencing (RNA-seq) analysis for the whole transcriptome was applied to searching potential LINC00460 related signal pathway in RCC. We identified the significant up-regulated expression level of LINC00460 in RCC tissues and cell lines. Elevated LINC00460 was correlated with shorter survival of RCC patients. Overexpression of LINC00460 promoted cell viability, proliferation, invasion and migration, while down-regulation of LINC00460 exerted inhibitory effect on these activities. We crucially identified that LNC00460 promotes development of RCC by influencing the PI3K/AKT pathway. Knockdown of LNC00460 decreased the phosphorylation of AKT and mTOR. The key finding of our study provided a new evidence suggesting that LINC00460 functions as an oncogene in RCC pathogenesis by mediating the PI3K/AKT pathway, which may provide a new target for the treatment of RCC.

scholarly journals Anti-tumor effect of ribavirin in combination with interferon-α on renal cell carcinoma cell lines in vitro

2014 ◽  
Vol 14 (1) ◽  
pp. 63 ◽  
Author(s):  
Lichen Teng ◽  
Dexin Ding ◽  
Yongsheng Chen ◽  
Hongshuang Dai ◽  
Guobin Liu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Carcinoma Cell ◽  
Interferon Α ◽  
Renal Cell Carcinoma Cell ◽  
Carcinoma Cell Lines

scholarly journals Leptin Is Associated with Poor Clinical Outcomes and Promotes Clear Cell Renal Cell Carcinoma Progression

Biomolecules ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 431
Author(s):  
Wen-Lang Fan ◽  
Yuan-Ming Yeh ◽  
Tsung-Ta Liu ◽  
Wei-Ming Lin ◽  
Tse-Yen Yang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Migration ◽  
Cell Carcinoma ◽  
Clinical Outcomes ◽  
Cell Lines ◽  
Renal Cell ◽  
Biological Effects ◽  
Prognostic Impact ◽  
Jnk Signaling ◽  
Transcriptomic Data

Emerging evidence has shown the oncogenic roles of leptin in modulating cancer progression in addition to its original roles. Analyses of transcriptomic data and patients’ clinical information have revealed leptin’s prognostic significance in renal cell carcinoma (RCC). However, its biological effects on RCC progression have not yet been explored. Clinical and transcriptomic data of a RCC cohort of 603 patients were retrieved from The Cancer Genome Atlas (TCGA) and analyzed to reveal the correlation of leptin with clinical outcomes and the hierarchical clustering of gene signatures based on leptin levels. In addition, cox univariate and multivariate regression analyses, cell migration upon leptin treatment, identification of putative leptin-regulated canonical pathways via ingenuity pathway analysis (IPA), and the investigation of induction of Wnt5a, ROR2, and Jun N-terminal Kinases (JNK) phosphorylation activation were performed. We first observed a correlation of high leptin levels and poor outcomes in RCC patients. Knowledge-based analysis by IPA indicated the induction of cancer cell migration by leptin, which was manifested via direct leptin treatment in the RCC cell lines. In RCC patients with high leptin levels, the planar cell polarity (PCP)/JNK signaling pathway was shown to be activated, and genes in the axis, including CTHRC1, FZD2, FZD10, ROR2, WNT2, WNT4, WNT10B, WNT5A, WNT5B, and WNT7B, were upregulated. All of these genes were associated with unfavorable clinical outcomes. WNT5A and ROR2 are pivotal upstream regulators of PCP/JNK signaling, and their correlations with leptin expression levels were displayed by a Pearson correlation analysis. The inhibition of signal transduction by SP600125 reversed leptin-mediated cell migration properties in RCC cell lines. The results indicate the prognostic impact of leptin on RCC patients and uncover its ability to promote cell migration via PCP/JNK signaling.

scholarly journals Blocking Exosomal miR-19b-3p from Renal Cell Carcinoma Cells Enhances Sunitinib Mediated Anti-Tumor Activity via Promoting TGFBR2/KLF10 Expression

2021 ◽  
Author(s):  
Dong Lv ◽  
Taimin Shen ◽  
Juncheng Yao ◽  
Qi Yang ◽  
Ying Xiang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Proliferation ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Resistant Cell ◽  
Cell Counting ◽  
Induced Apoptosis ◽  
Related Proteins

Abstract Background Multiple studies have found that microRNAs contribute to the malignant progression and chemoresistance of renal cell carcinoma (RCC). This study intends to probe the effect of miR-19b-3p shuttled by exosomes derived from RCC cells on RCC development and its resistance to Sunitinib. Methods Sunitinib-resistant cell lines (OSRC-2R and Caki-1R) were constructed from OSRC-2 and Caki-1 RCC cells. Exosomes in the RCC cell supernatant were isolated, and the miR-19b-3p profile in cells and exosomes was measured by reverse transcription-polymerase chain reaction (RT-PCR). Subsequently, the TGFβR2/SMAD2/3 pathway was activated by TGFβ, and the KLF10 overexpression and miR-19b-3p overexpression/knockdown models were constructed. The cell counting kit-8 (CCK-8) assay, colony formation assay and flow cytometry were implemented to verify RCC cell proliferation, Sunitinib chemosensitivity, and apoptosis. The expression of apoptosis-related proteins and the TGFβR2-SMAD2/3-KLF10 pathway was monitored by Western blot. MiR-19b-3p was overexpressed in sunitinib-resistant RCC cell lines (OSRC-2R and Caki-1R) and their exosomes (vs. normal OSRC-2 and Caki-1 cell lines). Results In-vitro experiments showed that knocking down cellular and exosomal miR-19b-3p levels reduced the proliferation and colony-forming ability of OSRC-2 and Caki-1 cells and strengthened their apoptosis and sensitivity to Sunitinib. Bioinformatics analysis illustrated that miR-19b-3p targeted TGFβR2 and inhibited TGFβR2/SMAD2/3. Activation of the TGFβR2-SMAD2/3 pathway via TGFβ dampened ORSC-2 and Caki-1 cell proliferation, induced apoptosis, and enhanced their chemosensitivity to Sunitinib. Conclusion Moreover, TGFβ heightened KLF10 expression, and overexpressing KLF10 attenuated miR-19b-3p-mediated carcinogenic effects and resistance to Sunitinib by increasing SMAD2/3 phosphorylation. RCC cell-derived exosomal miR-19b-3p enhances RCC progression and Sunitinib chemoresistance by inactivating TGFβR2-SMAD2/3-KLF10.

scholarly journals Trim24 prompts tumor progression via inducing EMT in renal cell carcinoma

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 1153-1162
Author(s):  
Tao Jiang ◽  
Houping Mao ◽  
Qin Chen ◽  
Linsheng Cao ◽  
Yanfeng He ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Migration And Invasion ◽  
Tubular Epithelial Cells ◽  
Tripartite Motif ◽  
Clinicopathological Significance ◽  
Renal Tubular

AbstractRenal cell carcinoma (RCC) is a malignant tumor originating from renal tubular epithelial cells with poor prognosis and high metastatic rate. Tripartite motif-containing 24 (Trim24) is a member of the tripartite motif (Trim) family and also a valuable oncogene, but its role in RCC remains unclear. We constructed the overexpression and knockdown of Trim24 cell lines to investigate its roles in RCC progression. CCK8, wound healing, and transwell assay were performed to determine the proliferation, migration, and invasion of RCC cell lines, respectively. Moreover, the expression of Trim24 and its clinicopathological significance were evaluated in a human RCC tissue microarray. From our results, Trim24 promoted the proliferation, migration, and invasion of RCC cells in vitro. Importantly, overexpression of Trim24 led to a significant increase in the expression levels of MMP-2, MMP-9, fibronectin, snail, vimentin, N-cadherin, and β-catenin, inducing the EMT process in turn, while the expression of these proteins was significantly downregulated when Trim24 was knocked down in ACHN cells. In addition, Trim24 was significantly upregulated in RCC, and its high expression was negatively associated with the tumor size. Trim24 might operate as an oncogene in RCC progression by inducing the EMT process, suggesting that Trim24 was a potential target for human RCC.

scholarly journals Prediction of in vitro response to interferon-? in renal cell carcinoma cell lines

2007 ◽  
Vol 98 (4) ◽  
pp. 529-534 ◽  
Author(s):  
Toru Shimazui ◽  
Yoshihiro Ami ◽  
Kazuhiro Yoshikawa ◽  
Kazuhiko Uchida ◽  
Takahiro Kojima ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Renal Cell ◽  
Carcinoma Cell ◽  
Renal Cell Carcinoma Cell ◽  
Carcinoma Cell Lines ◽  
In Vitro Response
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