scholarly journals iPSC-Derived Embryoid Bodies as Models of c-Met-Mutated Hereditary Papillary Renal Cell Carcinoma

2019 ◽  
Vol 20 (19) ◽  
pp. 4867 ◽  
Author(s):  
Jin Wook Hwang ◽  
Christophe Desterke ◽  
Olivier Féraud ◽  
Stephane Richard ◽  
Sophie Ferlicot ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Papillary Renal Cell Carcinoma ◽  
Embryoid Bodies ◽  
Hereditary Cancers ◽  
Nsg Mice ◽  
Progression Markers

Hereditary cancers with cancer-predisposing mutations represent unique models of human oncogenesis, as a driving oncogenic event is present in germline. Currently, there are no satisfactory models to study these malignancies. We report the generation of IPSC from the somatic cells of a patient with hereditary c-met-mutated papillary renal cell carcinoma (PRCC). From these cells we have generated spontaneous aggregates organizing in structures which expressed kidney markers such as PODXL and Six2. These structures expressed PRCC markers both in vitro and in vivo in NSG mice. Gene-expression profiling showed striking molecular similarities with signatures found in a large cohort of PRCC tumor samples. This analysis, applied to primary cancers with and without c-met mutation, showed overexpression of the BHLHE40 and KDM4C only in the c-met-mutated PRCC tumors, as predicted by c-met-mutated embryoid bodies transcriptome. These data therefore represent the first proof of concept of “hereditary renal cancer in a dish” model using c-met-mutated iPSC-derived embryoid bodies, opening new perspectives for discovery of novel predictive progression markers and for drug-screening for future precision-medicine strategies.

scholarly journals Prognostic and Therapeutic Potential of The OIP5 Network in Papillary Renal Cell Carcinoma

2021 ◽  
Author(s):  
Mathilda Chow ◽  
Yan Gu ◽  
Lizhi He ◽  
Xiaozeng Lin ◽  
Ying Dong ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Therapeutic Potential ◽  
Synthetic Lethality ◽  
Papillary Renal Cell Carcinoma ◽  
Mrna Levels ◽  
Rna Seq

Abstract Background: Papillary renal cell carcinoma (pRCC) is an aggressive but minor type of RCC compared to the main RCC type, clear cell RCC. The current understanding and management of pRCC remain poor. OIP5 possesses oncogenic functions; its contributions to pRCC remain unknown.Methods: OIP5 expression in pRCC at both the protein and mRNA levels was determined using tissue microarray and TCGA dataset. OIP5 was ectopically expressed in metastatic ACHN pRCC cells; xenografts were performed with gene expression profiled by RNA-seq. Differentially expressed genes (DEGs) were analyzed for prognostic potential and impact on pRCC. The effect of PLK1, an OIP5-related DEG, on pRCC tumor growth in vivo was examined.Results: OIP5 expression is upregulated in pRCC. The upregulation associates with pRCC adverse features (T1P<T2P<CIMP, Stage1+2<Stage 3<Stage 4, and N0<N1) and effectively stratifies the fatality risk. OIP5 promotes ACHN pRCC cell proliferation and xenograft formation. RNA-seq reveals network alterations related to immune regulation, metabolism, and hypoxia in ACHN OIP5 tumors compared to empty vector tumors. A set of DEGs was derived from ACHN OIP5 xenografts and primary pRCCs (n=282) contingent to OIP5 upregulation; both DEG sets share 66 overlap genes. Overlap66 effectively predicts overall survival (p<2e-16) and relapse (p<2e-16) possibilities. The prediction is associated with a good out-of-sample performance, supporting its clinical applications. High-risk tumors stratified by Overlap66 risk score possess an immune suppressive environment, evident by elevations in Treg cells and PD1 expression in CD8 T cells. Upregulation of PLK1 occurs in both xenografts and primary pRCC tumors with OIP5 elevations. PLK1 displays a synthetic lethality relationship with OIP5; PLK1 inhibitor BI2356 causes G2/M arrest in ACHN OIP5 cells in vitro and significantly inhibits the growth of xenografts formed by ACHN OIP5 cells in vivo. Conclusions: Our research reveals that OIP5 and its network possess robust prognostic and therapeutic potentials; the prognostic value of Overlap66 and the therapeutic potential of PLK1 inhibitors may pave the way for developing personalized medicine for pRCC management.

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.

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 &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 Kinesin Motor Protein KIFC1 Is a Target Protein of miR-338-3p and Is Associated With Poor Prognosis and Progression of Renal Cell Carcinoma

2018 ◽  
Vol 27 (1) ◽  
pp. 125-137 ◽  
Author(s):  
Gang Li ◽  
Tie Chong ◽  
Jie Yang ◽  
Hongliang Li ◽  
Haiwen Chen
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Therapeutic Target ◽  
Renal Cell ◽  
Critical Role ◽  
Survival Prognosis ◽  
Inhibition Of Proliferation ◽  
Invasion And Migration

KIFC1 (kinesin family member C1) plays a critical role in clustering of extra centrosomes in various cancer cells and thus could be considered as a promising therapeutic target. However, whether KIFC1 is involved in the procession of renal cell carcinoma (RCC) still remains unclear. In this study, we found that KIFC1 was upregulated in RCC tissues and is responsible for RCC tumorigenesis (p < 0.001). The high expression of KIFC1 correlates with aggressive clinicopathologic parameters. Kaplan‐Meier analysis suggested that KIFC1 was associated with poor survival prognosis in RCC. Silencing KIFC1 dramatically resulted in inhibition of proliferation, delayed the cell cycle at G2/M phase, and suppressed cell invasion and migration in vitro. The antiproliferative effect of KIFC1 silencing was also observed in xenografted tumors in vivo. miR-338-3p could directly bind to the 3′-untranslated region (3′-UTR) of KIFC1, and ectopic miR-338-3p expression mimicked the inhibitory functions of KIFC1 silencing on RCC cells through inactivation of the PI3K/AKT signaling pathway. Therefore, these results revealed that KIFC1 may be a novel biomarker and an effective therapeutic target for the treatment of RCC.

Synergistic antitumor effect of ionomycin and cisplatin against renal cell carcinoma in vitro and in vivo

Urology ◽  
2001 ◽  
Vol 57 (1) ◽  
pp. 188-192 ◽  
Author(s):  
Masayuki Okamoto ◽  
Isao Hara ◽  
Hideaki Miyake ◽  
Shoji Hara ◽  
Akinobu Gotoh ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Antitumor Effect ◽  
Synergistic Antitumor Effect

scholarly journals Bromodomain-Containing Protein 4 (BRD4) Inhibition Sensitizes Palomid 529-Induced Anti-Renal Cell Carcinoma Cell Activity in Vitro and in Vivo

2018 ◽  
Vol 50 (2) ◽  
pp. 640-653 ◽  
Author(s):  
Zhao-yu Xing ◽  
Yin Wang ◽  
Long Cheng ◽  
Jie Chen ◽  
Xiao-zhou He ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Growth ◽  
Cell Carcinoma ◽  
Cell Apoptosis ◽  
Renal Cell ◽  
Elisa Assay ◽  
Dual Inhibitor ◽  
Brd4 Inhibition

Background/Aims: Mammalian target of rapamycin (mTOR) is a valuable treatment target of renal cell carcinoma (RCC). Palomid 529 is a novel mTORC1/2 dual inhibitor. Methods: RCC cells were treated with different concentrations of Palomid 529. Cell survival was tested by MTT assay and clonogenicity assay. Cell proliferation was tested by BrdU ELISA assay. Cell apoptosis was tested by the Hoechst-33342 nuclei staining assay and Histone DNA ELISA assay. mTOR signaling was tested by Western blotting assay and co-immunoprecipitation (IP) assay. The SCID mouse 786-O xenograft model was established to test RCC cell growth in vivo. Results: Palomid 529 exerted cytotoxic, anti-proliferative and pro-apoptotic activities in 786-O RCC cells. Palomid 529 disassembled mTORC1/2, causing de-phosphorylation of mTORC1/2 substrates. Bromodomain-containing protein 4 (BRD4) is a primary resistant factor of Palomid 529. Palomid 529-induced 786-O cell apoptosis was sensitized by BRD4 inhibitors or BRD4 silencing, but inhibited with BRD4 over-expression. Palomid 529-induced cytotoxicity in the primary human RCC cells was negatively correlated with BRD4 expression level. In vivo, Palomid 529 i.p. administration inhibited 786-O xenograft tumor growth in SCID mice. Its anti-tumor activity was further sensitized by co-administration of the BRD4 inhibitor JQ1. Cconclusion: Palomid 529 inhibits RCC cell growth in vitro and in vivo. BRD4 inhibition could further sensitize Palomid 529 against RCC cells.

Abstract B193: Ibrutinib potentiates the effects of mTOR inhibitors and pazopanib in renal cell carcinoma in vitro and in vivo

2015 ◽  
Author(s):  
Jun Chen ◽  
Jeff Hsu ◽  
Yujun Huang ◽  
Danelle F. James ◽  
Taisei Kinoshita ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Mtor Inhibitors
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