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Positive feedback loop of IL-1?/Akt/RAR?/Akt signaling mediates oncogenic property of RAR? in gastric carcinoma.

ABSTRACT: Abnormal expression and function of retinoic acid receptor ? (RAR?) have been reported to be associated with various cancers including acute promyelocytic leukemia and hepatocellular carcinoma. However, the role and the mechanism of RAR? in gastric carcinoma (GC) were unknown. Here, the expression of RAR? was frequently elevated in human GC tissues and cell lines, and its overexpression was closely correlated with tumor size, lymph node metastasis and clinical stages in GC patients. Moreover, RAR? overexpression was related with pathological differentiation. Functionally, RAR? knockdown inhibited the proliferation and metastasis of GC cells, as well as enhanced drug susceptibility both in vitro and in vivo. Additionally, RAR? knockdown suppressed GC progression through regulating the expression of cell proliferation, cell cycle, invasion and drug resistance associated proteins, such as PCNA, CyclinB1, CyclinD2, CyclinE, p21, MMP9 and MDR1. Mechanistically, the above oncogenic properties of RAR? in GC were closely associated with Akt signaling activation. Moreover, overexpression of RAR? was induced by IL-1?/Akt signaling activation, which suggested a positive feedback loop of IL-1?/Akt/RAR?/Akt signaling in GC. Taken together, we demonstrated that RAR? was frequently elevated in GC and exerted oncogenic properties. It might be a potential molecular target for GC treatment.

SUBMITTER: Ren HY

PROVIDER: S-EPMC5351665 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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Positive feedback loop of IL-1β/Akt/RARα/Akt signaling mediates oncogenic property of RARα in gastric carcinoma.

Ren Hong-Yue HY Liu Fan F Huang Gui-Li GL Liu Yu Y Shen Jin-Xing JX Zhou Pan P Liu Wen-Ming WM Shen Dong-Yan DY

Oncotarget 20170101 4

Abnormal expression and function of retinoic acid receptor α (RARα) have been reported to be associated with various cancers including acute promyelocytic leukemia and hepatocellular carcinoma. However, the role and the mechanism of RARα in gastric carcinoma (GC) were unknown. Here, the expression of RARα was frequently elevated in human GC tissues and cell lines, and its overexpression was closely correlated with tumor size, lymph node metastasis and clinical stages in GC patients. Moreover, RA ...[more]

PMID: 28035062

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Project description:As novel biomarkers for various cancers, microRNAs negatively regulate genes expression via promoting mRNA degradation and suppressing mRNA translation. miR-589 has been reported to be deregulated in several human cancer types. However, its biological role has not been functionally characterized in gastric cancer. Here, we aim to investigate the biological effect of miR-589 on gastric cancer and to reveal the possible mechanism.Real-time PCR was performed to evaluate the expression of miR-589 in 34 paired normal and stomach tumor specimens, as well as gastric cell lines. Functional assays, such as wound healing, transwell assays and in vivo assays, were used to detect the biological effect of miR-589 and LIFR. We determined the role of miR-589 in gastric cancer tumorigenesis in vivo using xenograft nude models. Dual-luciferase report assays and Chromatin immunoprecipitation (ChIP) assay were performed for target evaluation, and the relationships were confirmed by western blot assay.MiR-589 expression was significantly higher in tumor tissues and gastric cancer cells than those in matched normal tissues and gastric epithelial cells, respectively. Clinically, overexpression of miR-589 is associated with tumor metastasis, invasion and poor prognosis of GC patients. Gain- and loss-of function experiments showed that miR-589 promoted cell migration, metastasis and invasion in vitro and lung metastasis in vivo. Mechanistically, we found that miR-589 directly targeted LIFR to activate PI3K/AKT/c-Jun signaling. Meanwhile, c-Jun bound to the promoter region of miR-589 and activated its transcription. Thus miR-589 regulated its expression in a feedback loop that promoted cell migration, metastasis and invasion.Our study identified miR-589, as an oncogene, markedly induced cell metastasis and invasion via an atypical miR-589-LIFR-PI3K/AKT-c-Jun feedback loop, which suggested miR-589 as a potential biomarker and/or therapeutic target for the gastric cancer management.

Dataset Information

Positive feedback loop of IL-1?/Akt/RAR?/Akt signaling mediates oncogenic property of RAR? in gastric carcinoma.

Publications

Positive feedback loop of IL-1β/Akt/RARα/Akt signaling mediates oncogenic property of RARα in gastric carcinoma.

Similar Datasets

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