Dataset Information

The long noncoding RNA CRAL reverses cisplatin resistance via the miR-505/CYLD/AKT axis in human gastric cancer cells.

ABSTRACT: Emerging evidence has suggested that long noncoding RNAs (lncRNAs) play an essential role in the tumorigenesis of multiple types of cancer including gastric cancer (GC). However, the potential biological roles and regulatory mechanisms of lncRNA in response to cisplatin, which may be involved in cisplatin resistance, have not been fully elucidated. In this study, we identified a novel lncRNA, cisplatin resistance-associated lncRNA (CRAL), that was downregulated in cisplatin-resistant GC cells, impaired cisplatin-induced DNA damage and cell apoptosis and thus contributed to cisplatin resistance in GC cells. Furthermore, the results indicated that CRAL mainly resided in the cytoplasm and could sponge endogenous miR-505 to upregulate cylindromatosis (CYLD) expression, which further suppressed AKT activation and led to an increase in the sensitivity of gastric cancer cells to cisplatin in vitro and in preclinical models. Moreover, a specific small molecule inhibitor of AKT activation, MK2206, effectively reversed the cisplatin resistance in GC caused by CRAL deficiency. In conclusion, we provide the first evidence that a novel lncRNA, CRAL, could function as a competing endogenous RNA (ceRNA) to reverse GC cisplatin resistance via the miR-505/CYLD/AKT axis, which suggests that CRAL could be considered a potential predictive biomarker and therapeutic target for cisplatin resistance in gastric cancer.

SUBMITTER: Wang Z

PROVIDER: S-EPMC7567514 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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The long noncoding RNA CRAL reverses cisplatin resistance via the miR-505/CYLD/AKT axis in human gastric cancer cells.

Wang Zhangding Z Wang Qiang Q Xu Guifang G Meng Na N Huang Xinli X Jiang Zerun Z Chen Chen C Zhang Yan Y Chen Junjie J Li Aiping A Li Nan N Zou Xiaoping X Zhou Jianwei J Ding Qingqing Q Wang Shouyu S

RNA biology 20200107 11

Emerging evidence has suggested that long noncoding RNAs (lncRNAs) play an essential role in the tumorigenesis of multiple types of cancer including gastric cancer (GC). However, the potential biological roles and regulatory mechanisms of lncRNA in response to cisplatin, which may be involved in cisplatin resistance, have not been fully elucidated. In this study, we identified a novel lncRNA, cisplatin resistance-associated lncRNA (CRAL), that was downregulated in cisplatin-resistant GC cells, i ...[more]

PMID: 31885317

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Project description:Platinum-based cytotoxic chemotherapy is considered the standard treatment for advanced gastric cancer (GC). However, cisplatin chemoresistance often occurs with the mechanisms being not well clarified, which results in the cancer recurrence and poor survival. Ginsenoside Rg3, isolated from the Chinese Herb Panax Ginseng, is recognized as an anti-cancer agent. Herein, we aimed to reveal whether Ginsenoside Rg3 alleviates cisplatin resistance and sensitizes GC cells to cisplatin-induced apoptosis, and draw out the underlying molecular mechanism in cisplatin-resistant GC cells. The lower expression of miR-429 was found in AGSR-CDDP cells; it was also in association with cisplatin-resistance in GC cells and expression of which was restored following Ginsenoside Rg3 treatment. We also demonstrated that miR-429 made a contribution toward chemosensitivity in GC cells partly through SOX2 regulation. SOX2 was found to contribute to developing platinum resistance and was an authentic target for miR-429 in AGSR-CDDP cells. Importantly, enforced expression of SOX2 with a pcDNA3-SOX2 construct lacking the 3'-UTR miRNA binding site diminished the cytotoxic effects of miR-429 in AGSR-CDDP cells. We demonstrated that Ginsenoside Rg3 enhanced chemosensitivity in AGSR-CDDP GC cells, at least in part, through up-regulating miR-429, thereby targeting SOX2 and modulating downstream PI3K/AKT/mTOR signaling. Ginsenoside Rg3 was also found to regulate apoptosis-related genes via miR-429 in cisplatin-resistant GC cells. Ginsenoside Rg3 treatment significantly suppressed the migration rate of AGSR-CDDP GC cells, while following transfection with anti-miR-429, the anti-migratory effects of Ginsenoside Rg3 was partially abolished. This data suggested that Ginsenoside Rg3 may impede the chemoresistance and migration of GC cells mainly mediated through miR-429. We concluded that miR-429-regulated SOX2 expression was one of the main mechanisms by which Ginsenoside Rg3 dramatically promoted its anticancer effects on cisplatin-resistant GC cells. We also underscored a supporting model in which miR-429 adjusted PI3K/AKT/mTOR signaling by regulating SOX2 in cisplatin-resistant GC cells.

Dataset Information

The long noncoding RNA CRAL reverses cisplatin resistance via the miR-505/CYLD/AKT axis in human gastric cancer cells.

Publications

The long noncoding RNA CRAL reverses cisplatin resistance via the miR-505/CYLD/AKT axis in human gastric cancer cells.

Similar Datasets

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