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GAS5 functions as a ceRNA to regulate hZIP1 expression by sponging miR-223 in clear cell renal cell carcinoma.

ABSTRACT: Several studies have shown that low expression of hZIP1 is closely associated with many human cancers, including clear cell renal cell carcinoma (ccRCC). In this study, we aimed to explore the potential mechanism responsible for hZIP1 silencing and revealed a novel regulatory pathway in the pathogenesis of ccRCC. Here, miR-223 was predicted and experimentally validated to be a regulator of hZIP1, and its expression was negatively correlated with the mRNA levels of hZIP1 in primary tumors. Upregulation of hZIP1 inhibited cell proliferation, cell cycle progression, and invasion and induced apoptosis, while inhibition of miR-223 showed the opposite effect on cellular processes. Moreover, GAS5 interacted with miR-223 and was markedly downregulated in tumors. Knockdown of GAS5 partially reversed the effect of the miR-223 inhibitor on cell proliferation, cell cycle distribution, apoptosis and invasion. In addition, GAS5 acted as a molecular sponge to positively regulate the mRNA and protein levels of hZIP1 via regulating miR-223. The tumorigenicity of ccRCC cells was enhanced by silencing GAS5 but diminished by overexpression of hZIP1 in vivo. Clinically, the low expression of hZIP1 was significantly correlated with advanced clinical stage and Fuhrman stage. Downregulation of GAS5 indicated tumor progression and recurrence and was independently associated with disease-free survival of patients. Taken together, our results suggest that GAS5 may act as a competing endogenous RNA (ceRNA) to regulate hZIP1 by sponging miR-223 in the progression of ccRCC and that targeting the GAS5/miR-223/hZIP1 axis may serve as a therapeutic strategy for patients.

SUBMITTER: Dong X

PROVIDER: S-EPMC6129482 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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GAS5 functions as a ceRNA to regulate hZIP1 expression by sponging miR-223 in clear cell renal cell carcinoma.

Dong Xiao X Kong Chuize C Liu Xiankui X Bi Jianbin J Li Zhenhua Z Li Zeliang Z Zhu Yuyan Y Zhang Zhe Z

American journal of cancer research 20180801 8

Several studies have shown that low expression of hZIP1 is closely associated with many human cancers, including clear cell renal cell carcinoma (ccRCC). In this study, we aimed to explore the potential mechanism responsible for hZIP1 silencing and revealed a novel regulatory pathway in the pathogenesis of ccRCC. Here, miR-223 was predicted and experimentally validated to be a regulator of hZIP1, and its expression was negatively correlated with the mRNA levels of hZIP1 in primary tumors. Upregu ...[more]

PMID: 30210913

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Project description:Chronic obstructive pulmonary disease (COPD) is characterized by irreversible and progressive airflow limitation and encompasses a spectrum of diseases, including chronic obstructive bronchitis and emphysema. Pyroptosis is a unique form of inflammatory cell death mediated by the activation of caspase‑1 and inflammasomes. The long non‑coding RNA (lncRNA) growth arrest‑specific 5 (GAS5) is a well‑documented tumor suppressor, which is associated with cell proliferation and death in various diseases. The aim of the present study was to evaluate whether lncRNA GAS5 is associated with the pyroptosis in COPD. To create a COPD cell model, MRC‑5 cells were treated with 10 µg/ml lipopolysaccharide (LPS) for 48 h. Then the level of pro‑caspase 1, caspase 1, IL‑1β, IL‑18, NLRP3 and cleaved gasdermin D (GSDMD) was examined by western blotting. GAS5 mRNA level was detected by qualitative PCR following LPS treatment in MRC‑5 cells. Subsequently, IL‑2, IL‑6, IL‑10 and TNF‑α in MRC‑5 cells was measured by ELISA. Then the proliferation ability of MRC‑5 cells was detected by CCK‑8. Cell death was detected by TUNEL assay. LDH release was measured using an LDH Cytotoxicity Assay kit. The Magna RIP kit was used to validate the interaction between GAS5 and miR‑223‑3p. The present study revealed that increased expression levels of caspase‑1, IL‑1β, IL‑18 and cleaved GSDMD were observed in LPS‑treated MRC‑5 cells, indicating that pyroptosis is involved in COPD progression. Additionally, LPS induced the increase in GAS5 mRNA expression levels and the release of inflammatory factors (IL‑2, IL‑6, IL‑10 and TNF‑α), suggesting that GAS5 is implicated in pyroptosis in COPD. Furthermore, upregulation of GAS5 promoted cell death and inhibited proliferation in the MRC‑5 cell line. Additionally, increased GAS5 expression significantly promoted the production of caspase‑1, IL‑1β, IL‑18, cleaved GSDMD and NLR pyrin domain containing protein 3 (NLRP3). A dual‑luciferase assay demonstrated that GAS5 could directly bind to microRNA‑223‑3p (miR‑223‑3p), and NLRP3 is a direct target of miR‑223‑3p. Furthermore, GAS5 reduced the expression levels of miR‑223‑3p, while it increased the expression levels of NLRP3. The present study concluded that lncRNA GAS5 promoted pyroptosis in COPD by targeting the miR‑223‑3p/NLRP3 axis, implying that GAS5 could be a potential target for COPD.

Dataset Information

GAS5 functions as a ceRNA to regulate hZIP1 expression by sponging miR-223 in clear cell renal cell carcinoma.

Publications

GAS5 functions as a ceRNA to regulate hZIP1 expression by sponging miR-223 in clear cell renal cell carcinoma.

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