scholarly journals circCHST15 is a novel prognostic biomarker that promotes clear cell renal cell carcinoma cell proliferation and metastasis through the miR-125a-5p/EIF4EBP1 axis

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Cheng-Peng Gui ◽  
Bing Liao ◽  
Cheng-Gong Luo ◽  
Yu-Hang Chen ◽  
Lei Tan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Prognostic Biomarker ◽  
Cell Renal Cell Carcinoma ◽  
Proliferation And Metastasis

Abstract Background Circular RNAs (circRNAs) have been indicated as potentially critical mediators in various types of tumor progression, generally acting as microRNA (miRNA) sponges to regulate downstream gene expression. However, the aberrant expression profile and dysfunction of circRNAs in human clear cell renal cell carcinoma (ccRCC) need to be further investigated. This study mined key prognostic circRNAs and elucidates the potential role and molecular mechanism of circRNAs in regulating the proliferation and metastasis of ccRCC. Methods circCHST15 (hsa_circ_0020303) was identified by mining two circRNA microarrays from the Gene Expression Omnibus database and comparing matched tumor versus adjacent normal epithelial tissue pairs or matched primary versus metastatic tumor tissue pairs. These results were validated by quantitative real-time polymerase chain reaction and agarose gel electrophoresis. We demonstrated the biological effect of circCHST15 in ccRCC both in vitro and in vivo. To test the interaction between circCHST15 and miRNAs, we conducted a number of experiments, including RNA pull down assay, dual-luciferase reporter assay and fluorescence in situ hybridization. Results The expression of circCHST15 was higher in ccRCC tissues compared to healthy adjacent kidney tissue and higher in RCC cell lines compared to normal kidney cell lines. The level of circCHST15 was positively correlated with aggressive clinicopathological characteristics, and circCHST15 served as an independent prognostic indicator for overall survival and progression-free survival in patients with ccRCC after surgical resection. Our in vivo and in vitro data indicate that circCHST15 promotes the proliferation, migration, and invasion of ccRCC cells. Mechanistically, we found that circCHST15 directly interacts with miR-125a-5p and acts as a microRNA sponge to regulate EIF4EBP1 expression. Conclusions We found that sponging of miR-125a-5p to promote EIF4EBP1 expression is the underlying mechanism of hsa_circ_0020303-induced ccRCC progression. This prompts further investigation of circCHST15 as a potential prognostic biomarker and therapeutic target for ccRCC.

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.

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.

scholarly journals CENPA promotes clear cell renal cell carcinoma progression and metastasis via Wnt/β-catenin signaling pathway

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Qi Wang ◽  
Jiaju Xu ◽  
Zhiyong Xiong ◽  
Tianbo Xu ◽  
Jingchong Liu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Signaling Pathway ◽  
Renal Cell ◽  
Clear Cell ◽  
Cell Renal Cell Carcinoma ◽  
Promising Direction ◽  
Diagnosis And Prognosis ◽  
Proliferation And Metastasis

AbstractClear cell renal cell carcinoma (ccRCC) is the most common malignant tumor of the kidney. New and reliable biomarkers are in urgent need for ccRCC diagnosis and prognosis. The CENP family is overexpressed in many types of cancers, but its functions in ccRCC have not been fully clarified. In this paper, we found that several CENP family members were highly expressed in ccRCC tissues. Also, CENPA expression level was related to clinicopathological grade and prognosis by weighted gene co-expression network analysis (WGCNA). CENPA served as a representative CENP family member as a ccRCC biomarker. Further in vitro experiments verified that overexpression of CENPA promoted ccRCC proliferation and metastasis by accelerating the cell cycle and activating the Wnt/β-catenin signaling pathway. The elevated β-catenin led by CENPA overexpression translocated to nucleus for downstream effect. Functional recovery experiment confirmed that Wnt/β-catenin pathway was essential for ccRCC progression and metastasis. Developing selective drugs targeting CENPA may be a promising direction for cancer treatment.

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