SPC2968—A novel Hif-1α antagonist for treatment of clear cell renal cell carcinoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14581-14581 ◽  
Author(s):  
M. Westergaard ◽  
H. F. Hansen ◽  
C. A. Thrue ◽  
J. B. Hansen ◽  
L. S. Kjaerulff ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Endothelial Cells ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Locked Nucleic Acid ◽  
Mrna Levels ◽  
Kidney Liver

14581 Background: SPC2968 is a short (16-mer), oligonucleotide antagonist of Hif-1α mRNA in which potency has been enhanced through incorporation of Locked Nucleic Acid. Over-expression of Hif-1α has been correlated with increased vascularisation, metastatic potential and poor clinical outcome in a variety of malignancies, including Renal Cell Carcinoma (RCC) of clear cell aetiology, where Hif-1α dysregulation, brought about by mutations in the von Hippel Lindau gene, appears to play a major pathogenic role. Methods: In vitro, human cancer and endothelial cells grown under hypoxic conditions were used to evaluate the effect of SPC2968 on mRNA and protein to Hif-1α as well as phenotypic effects, measured by quantitative polymerase chain reaction (QPCR), Western blotting and biochemical/cellular assays. QPCR was also used to measure mRNA levels in SPC2968-treated mice, while the effects of the drug on tumour growth and vascularisation were evaluated in xenografts. To assess biodistribution in vivo, tritium-labelled SPC2968 was injected intravenously. Results: In vitro, SPC2968 at 1nM reduced both mRNA and protein levels of Hif-1α in cancer cell lines and downregulated two downstream targets of Hif-1, VEGF and MMP-2.Treatment also induced apoptosis in tumour cells and prevented tube formation by endothelial cells in vitro. Parenteral administration of SPC2968 in mice yielded potent inhibition of Hif-1α and VEGF mRNA in several tissues, including kidney, liver, and colon. Radioactively labelled SPC2968 distributed to kidney, liver, colon, bone marrow, lymph nodes and skin. Preclinical studies investigating acute and sub-acute toxicity and safety pharmacology of SPC2968 are completed, and SPC2968 was well tolerated. Conclusions: SPC2968 is an effective suppressor of Hif-1α mRNA and Hif-1α-regulated genes in vitro and in vivo and has shown good tissue biostability and biodistribution in rodents. Preclinical safety studies have been completed, and SPC2968 is ready for clinical testing. A phase I/II, dose-escalating study of SPC2968 in clear cell RCC in the US and the EU is planned to be submitted by mid 2006. [Table: see text]

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.

scholarly journals Targeting β2-Adrenergic Receptors Shows Therapeutical Benefits in Clear Cell Renal Cell Carcinoma from Von Hippel–Lindau Disease

2020 ◽  
Vol 9 (9) ◽  
pp. 2740
Author(s):  
Virginia Albiñana ◽  
Eunate Gallardo-Vara ◽  
Isabel de Rojas-P ◽  
Lucia Recio-Poveda ◽  
Tania Aguado ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Von Hippel Lindau ◽  
Gene And Protein Expression ◽  
Ici 118,551

Von Hippel–Lindau (VHL), is a rare autosomal dominant inherited cancer in which the lack of VHL protein triggers the development of multisystemic tumors such us retinal hemangioblastomas (HB), CNS-HB, and clear cell renal cell carcinoma (ccRCC). ccRCC ranks third in terms of incidence and first in cause of death. Standard systemic therapies for VHL-ccRCC have shown limited response, with recurrent surgeries being the only effective treatment. Targeting of β2-adrenergic receptor (ADRB) has shown therapeutic antitumor benefits on VHL-retinal HB (clinical trial) and VHL-CNS HB (in vitro). Therefore, the in vitro and in vivo antitumor benefits of propranolol (ADRB-1,2 antagonist) and ICI-118,551 (ADRB-2 antagonist) on VHL−/− ccRCC primary cultures and 786-O tumor cell lines have been addressed. Propranolol and ICI-118,551 activated apoptosis inhibited gene and protein expression of HIF-2α, CAIX, and VEGF, and impaired partially the nuclear internalization of HIF-2α and NFĸB/p65. Moreover, propranolol and ICI-118,551 reduced tumor growth on two in vivo xenografts. Finally, ccRCC patients receiving propranolol as off-label treatment have shown a positive therapeutic response for two years on average. In summary, propranolol and ICI-118,551 have shown antitumor benefits in VHL-derived ccRCC, and since ccRCCs comprise 63% of the total RCCs, targeting ADRB2 becomes a promising drug for VHL and other non-VHL tumors.

scholarly journals LncRNA-LET inhibits cell growth of clear cell renal cell carcinoma by regulating miR-373-3p

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Zhuo Ye ◽  
Jiachen Duan ◽  
Lihui Wang ◽  
Yanli Ji ◽  
Baoping Qiao
Keyword(s):  
Cell Cycle ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Luciferase Reporter ◽  
Cell Renal Cell Carcinoma

Abstract Background Clear cell renal cell carcinoma (ccRCC) is the most common renal cell carcinoma subtype with a poor prognosis. LncRNA-LET is a long non-coding RNA (lncRNA) that is down-regulated in ccRCC tissues. However, its role in ccRCC development and progress is unclear. Methods LncRNA-LET expression was detected in ccRCC tissues and ccRCC cells using quantitative real-time PCR. The overexpression and knockdown experiments were performed in ccRCC cells and xenograft mouse model to evaluate role of lncRNA-LET. Cell cycle, apoptosis and JC-1 assays were conducted via flow cytometer. The protein levels were measured through western blot analysis and the interaction between lncRNA-LET and miR-373-3p was identified via luciferase reporter assay. Results LncRNA-LET expression was lower in ccRCC tissues than that in the matched adjacent non-tumor tissues (n = 16). In vitro, lncRNA-LET overexpression induced cell cycle arrest, promoted apoptosis and impaired mitochondrial membrane potential, whereas its knockdown exerted opposite effects. Moreover, we noted that lncRNA-LET may act as a target for oncomiR miR-373-3p. In contrast to lncRNA-LET, miR-373-3p expression was higher in ccRCC tissues. The binding between lncRNA-LET and miR-373-3p was validated. Two downstream targets of miR-373-3p, Dickkopf-1 (DKK1) and tissue inhibitor of metalloproteinase-2 (TIMP2), were positively regulated by lncRNA-LET in ccRCC cells. MiR-373-3p mimics reduced lncRNA-LET-induced up-regulation of DKK1 and TIMP2 levels, and attenuated lncRNA-LET-mediated anti-tumor effects in ccRCC cells. In vivo, lncRNA-LET suppressed the growth of ccRCC xenograft tumors. Conclusion These findings indicate that lncRNA-LET plays a tumor suppressive role in ccRCC by regulating miR-373-3p.

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 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 VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma

Science ◽  
2018 ◽  
Vol 361 (6399) ◽  
pp. 290-295 ◽  
Author(s):  
Jing Zhang ◽  
Tao Wu ◽  
Jeremy Simon ◽  
Mamoru Takada ◽  
Ryoichi Saito ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Nuclear Factor Κb ◽  
Loss Of Function ◽  
Cell Renal Cell Carcinoma ◽  
A Genome

Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.

scholarly journals FMNL1 Exhibits Pro-Metastatic Activity via CXCR2 in Clear Cell Renal Cell Carcinoma

2020 ◽  
Vol 10 ◽  
Author(s):  
Mei-Fang Zhang ◽  
Qiu-Li Li ◽  
Yu-Feng Yang ◽  
Yun Cao ◽  
Chris Zhiyi Zhang
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Tumor Metastasis ◽  
Clear Cell ◽  
Luciferase Reporter ◽  
Cell Renal Cell Carcinoma ◽  
Metastatic Activity

Formin-like (FMNL) proteins are responsible for cytoskeletal remodeling and have been implicated in the progression and spread of human cancers. Yet the clinical significance and biological function of FMNL1 in clear cell renal cell carcinoma (ccRCC) remain unclear. In this study, the expression of FMNL1 in ccRCC and its clinical value were determined by tissue microarray-based IHC and statistical analyses. The role of FMNL1 in ccRCC metastasis and the underlying mechanism were investigated via in vitro and in vivo models using gene regulation detection, ChIP, Luciferase reporter assays, and rescue experiments. We show that FMNL1 is upregulated in ccRCC and exhibits pro-metastatic activity via induction of CXCR2. High expression of FMNL1 is significantly correlated with advanced tumor stage, higher pathological tumor grade, tumor metastasis, and unfavorable prognosis in two independent cohorts containing over 800 patients with ccRCC. The upregulation of FMNL1 in ccRCC is mediated by the loss of GATA3. Ectopic expression of FMNL1 promotes, whereas FMNL1 depletion inhibits cell migration in vitro and tumor metastasis in vivo. The FMNL1-enhanced cell mobility is markedly attenuated by the knockdown of CXCR2. Further studies demonstrate that FMNL1 increases the expression of CXCR2 via HDAC1. In clinical samples, FMNL1 expression is positively associated with CXCR2, and is negatively connected to GATA3 expression. Collectively, our data suggest FMNL1 serve as a potential prognostic factor and function as an oncogene. The axis of GATA3/FMNL1/CXCR2 may present a promising therapeutic target for tumor metastasis in ccRCC.

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