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.

scholarly journals Circular RNA circSDHC serves as a sponge for miR-127-3p to promote the proliferation and metastasis of renal cell carcinoma via the CDKN3/E2F1 axis

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Junjie Cen ◽  
Yanping Liang ◽  
Yong Huang ◽  
Yihui Pan ◽  
Guannan Shu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Target Genes ◽  
Expression Patterns ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Proliferation And Metastasis

Abstract Background There is increasing evidence that circular RNAs (circRNAs) have significant regulatory roles in cancer development and progression; however, the expression patterns and biological functions of circRNAs in renal cell carcinoma (RCC) remain largely elusive. Method Bioinformatics methods were applied to screen for circRNAs differentially expressed in RCC. Analysis of online circRNAs microarray datasets and our own patient cohort indicated that circSDHC (hsa_circ_0015004) had a potential oncogenic role in RCC. Subsequently, circSDHC expression was measured in RCC tissues and cell lines by qPCR assay, and the prognostic value of circSDHC evaluated. Further, a series of functional in vitro and in vivo experiments were conducted to assess the effects of circSDHC on RCC proliferation and metastasis. RNA pull-down assay, luciferase reporter and fluorescent in situ hybridization assays were used to confirm the interactions between circSDHC, miR-127-3p and its target genes. Results Clinically, high circSDHC expression was correlated with advanced TNM stage and poor survival in patients with RCC. Further, circSDHC promoted tumor cell proliferation and invasion, both in vivo and in vitro. Analysis of the mechanism underlying the effects of circSDHC in RCC demonstrated that it binds competitively to miR-127-3p and prevents its suppression of a downstream gene, CDKN3, and the E2F1 pathway, thereby leading to RCC malignant progression. Furthermore, knockdown of circSDHC caused decreased CDKN3 expression and E2F1 pathway inhibition, which could be rescued by treatment with an miR-127-3p inhibitor. Conclusion Our data indicates, for the first time, an essential role for the circSDHC/miR-127-3p/CDKN3/E2F1 axis in RCC progression. Thus, circSDHC has potential to be a new therapeutic target in patients with RCC.

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.

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 Targeting the Proteasome in Advanced Renal Cell Carcinoma: Complexity and Limitations of Patient-Individualized Preclinical Drug Discovery

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 627
Author(s):  
Jielin Li ◽  
Laura Pohl ◽  
Julia Schüler ◽  
Nina Korzeniewski ◽  
Philipp Reimold ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Drug Screening ◽  
Renal Cell ◽  
Treatment Options ◽  
Antitumoral Activity ◽  
In Vitro Drug Screening

Background: Systemic treatment options for metastatic renal cell carcinoma (RCC) have significantly expanded in recent years. However, patients refractory to tyrosine kinase and immune checkpoint inhibitors still have limited treatment options and patient-individualized approaches are largely missing. Patients and Methods: In vitro drug screening of tumor-derived short-term cultures obtained from seven patients with clear cell RCC was performed. For one patient, a patient-derived xenograft (PDX) mouse model was established for in vivo validation experiments. Drug effects were further investigated in established RCC cell lines. Results: The proteasome inhibitor carfilzomib was among the top hits identified in three of four patients in which an in vitro drug screening could be performed successfully. Carfilzomib also showed significant acute and long-term cytotoxicity in established RCC cell lines. The in vivo antitumoral activity of carfilzomib was confirmed in a same-patient PDX model. The cytotoxicity of carfilzomib was found to correlate with the level of accumulation of ubiquitinated proteins. Conclusions: In this proof-of-concept study, we show that patient-individualized in vitro drug screening and preclinical validation is feasible. However, the fact that carfilzomib failed to deliver a clinical benefit in RCC patients in a recent phase II trial unrelated to the present study underscores the complexities and limitations of this strategy.

scholarly journals Histone Methyltransferase G9a Promotes the Development of Renal Cancer through Epigenetic Silencing of Tumor Suppressor Gene SPINK5

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Ren-Gui Li ◽  
Huan Deng ◽  
Xiu-Heng Liu ◽  
Zhi-yuan Chen ◽  
Shan-shan Wan ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Kidney Cancer ◽  
Renal Cancer ◽  
Renal Cell ◽  
Target Genes ◽  
Migration And Invasion ◽  
Downstream Target

Background. Renal cell carcinoma (RCC) accounts for approximately 2–3% of malignant tumors in adults, while clear cell renal cell carcinoma accounts for 70–85% of kidney cancer cases, with an increasing incidence worldwide. G9a is the second histone methyltransferase found in mammals, catalyzing lysine and histone methylation. It regulates gene transcription by catalyzing histone methylation and interacting with transcription factors to alter the tightness of histone-DNA binding. The main purpose of this study is to explore the role and mechanism of G9a in renal cell carcinoma. Methods. Firstly, we investigated the expression of G9a in 80 clinical tissues and four cell lines. Then, we explored the effect of G9a-specific inhibitor UNC0638 on proliferation, apoptosis, migration, and invasion of two renal cancer cell lines (786-O, SN12C). In order to study the specific mechanism, G9a knocking down renal cancer cell line was constructed by lentivirus. Finally, we identified the downstream target genes of G9a using ChIP experiments and rescue experiments. Results. The results showed that the specific G9a inhibitor UNC0638 significantly inhibited the proliferation, migration, and invasion of kidney cancer in vivo and in vitro; similar results were obtained after knocking down G9a. Meanwhile, we demonstrated that SPINK5 was one of the downstream target genes of G9a through ChIP assay and proved that G9a downregulate the expression of SPINK5 by methylation of H3K9me2. Therefore, targeting G9a might be a new approach to the treatment of kidney cancer. Conclusion. G9a was upregulated in renal cancer and could promote the development of renal cancer in vitro and in vivo. Furthermore, we identified SPINK5 as one of the downstream target genes of G9a. Therefore, targeting G9a might be a new treatment for kidney cancer.

Identification of an appropriate cell line for the renal cell carcinoma model

2020 ◽  
Author(s):  
In Youb Chang ◽  
Takbum Ohn ◽  
Daeun Moon ◽  
Young Hee Maeng ◽  
Bo Gun Jang ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Cell Line ◽  
Cell Lines ◽  
Renal Cell ◽  
Tissue Microarrays ◽  
Future Research ◽  
Proximal Tubule Cells

Abstract Background Although renal cell carcinoma (RCC) is known to be susceptible to ferroptosis, we found primary RCC cells showed resistance to ferroptosis and aimed to investigate a feasible candidate for an appropriate cell line for the RCC model. Methods Glutathione peroxidase 4 (GPX4) immunostaining was adopted in the RCC tissue microarrays. Normal human proximal tubule cells (HK-2) and RCC cell lines were used for the MTT assay, Western blotting, sphere-forming assay, and orthotopic injection of athymic Balb/c-nude mice. Results GPX4 immunostaining showed low intensity compared to the normal kidney, which coincided with the ferroptosis-susceptibility of RCC. Primary RCC cell lines (Caki-2, SNU-333, SNU-349, and SNU-1272) showed resistance to 5-fluorouracil and a GPX4 inhibitor compared to the HK-2 cells and to metastatic RCC cells (Caki-1). The Caki-2 cells showed increased GPX4 and xCT, and the SNU-333 cells showed increased ferritin heavy chain (FTH1) compared to the other RCC cells. The Caki-2 cells showed increased aSMA, fibronectin, vimentin, and SNAIL, and the SNU-333 cells showed increased aSMA, E-cadherin, and EpCAM. The Caki-2 cells showed increased Sox-2 and CD105, and the SNU-333 cells showed increased c-Myc and Lgr5. The Caki-1 and SNU-333 cells formed spheres in vitro and orthotopic RCC masses in vivo. The injected SNU-333 tumor only showed high intensities of CD10 and PAX8, consistent with the diagnostic criteria for RCC. Conclusions The primary RCC cell lines used in this study were more resistant to ferroptosis and 5-fluorouracil, and the SNU-333 cells showed tumor-initiating capacities in vitro and in vivo. These results suggest that SNU-333 might be suitable as a orthotopic RCC model for future research.

scholarly journals MicroRNA-373 promotes tumorigenesis of renal cell carcinoma in vitro and in vivo

2017 ◽  
Vol 16 (5) ◽  
pp. 7048-7055 ◽  
Author(s):  
Yanli Li ◽  
Da Zhang ◽  
Jiaxiang Wang
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell

GV1001 Induces Apoptosis by Reducing Angiogenesis in Renal Cell Carcinoma Cells Both In Vitro and In Vivo

Urology ◽  
2018 ◽  
Vol 113 ◽  
pp. 129-137 ◽  
Author(s):  
Ga Eun Kim ◽  
Ae Ryang Jung ◽  
Mee Young Kim ◽  
Joseph Bada Lee ◽  
Ji Houn Im ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Carcinoma Cells

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 < 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 < 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 < 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.

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