Dataset Information

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

ACCESS DATA

Publications

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

Similar Datasets

Project description:BackgroundAs 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.MethodsReal-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.ResultMiR-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.ConclusionOur 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.

Project description:Ventoclax-based combinations are a new standard of care for patients with acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy, but not all patients respond to these treatments, and those who do may relapse. MDM2 inhibitors are promising therapeutics for treating TP53 wild-type tumors, including most de novo AML cases, but clinical trials have shown modest and variable clinical activity. Functional genomic data suggest that venetoclax and the MDM2 inhibitor, idasanutlin, may be ineffective against monocytic leukemia (FAB M4/M5) or leukemia cells with a high immune signature. We hypothesize upregulated myeloid transcription factors and enrichment of certain environmental cues that confer intrinsic and extrinsic drug resistance to these cells. We show that monocytic leukemia cells express a high level of CEBPB and CEBPB overexpression confers drug resistance to a broad range of BH3 mimetics, venetoclax combinations, and MDM2 inhibitors by downregulating CASP3, CASP6, BCL2, and p53 pathway targets, while upregulating MCL1, BCL2A1, and the NFKB/IL1/TNFA pathway. Moreover, leukemia monocytes can extrinsically protect leukemia blasts from venetoclax and MDM2 inhibition by secreting elevated IL1 and TNFA, which drive myelo/monocytic differentiation and upregulate inflammatory cytokines and receptors, including IL1/TNFA pathway in an autoregulatory loop. Remarkably, IL1A/IL1B and TNFA uniquely upregulate CEBPB expression in M4/M5 cells and protect them from apoptosis induced by venetoclax and MDM2 inhibitors. Conversely, TNFA treatment enhances extrinsic apoptosis in M0/M1 leukemia cells. Inhibitors of IRAK or MAPK14 (p38), which block IL1/TNFA signaling, showed synergistic cytotoxicity in M4/M5 AML when combined with venetoclax and idasanutlin. In summary, we described a targetable, positive feedback loop between CEBPB and IL1/TNFA in monocytic leukemia that drives intrinsic and extrinsic drug resistance to BCL2 and MDM2 inhibitors, offering promising therapeutic strategies to enhance treatment efficacy for monocytic leukemia.

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

OmicsDI is part of the ELIXIR infrastructure

Tweets