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Sorafenib inhibits caspase-1 expression through suppressing TLR4/stat3/SUMO1 pathway in hepatocellular carcinoma.

ABSTRACT: Sorafenib has been demonstrated to be a beneficial treatment for advanced hepatocellular carcinoma (HCC). Emerging evidence indicates that caspase-1 activation plays a crucial role in HCC progression. However, the relationship between caspase-1 and sorafenib has rarely been reported. In this study, we showed that caspase-1 was essential for lipopolysaccharide (LPS)-induced epithelial-mesenchymal transition (EMT). Moreover, sorafenib treatment could inhibit LPS-stimulated caspase-1 overexpression through restricting the nuclear transport of p65, which contributed to inactivation of NF-κB. Co-immunoprecipitation (Co-IP) experiments and immunoblot analysis indicated that sorafenib treatment decreased the SUMOylation of p65 via inhibiting TLR4/stat3/SUMO1 signaling cascades. In conclusion, the results of this study suggest that sorafenib inhibits caspase-1 expression through suppressing the nuclear translocation of p65 and provide new insights into the mechanisms of sorafenib treatment in HCC.

SUBMITTER: Li J

PROVIDER: S-EPMC6301813 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Sorafenib inhibits caspase-1 expression through suppressing TLR4/stat3/SUMO1 pathway in hepatocellular carcinoma.

Li Jun J Zhou Yuan Y Liu Yang Y Dai Bo B Zhang Yu-Hen YH Zhang Peng-Fei PF Shi Xiao-Lei XL

Cancer biology & therapy 20181002 11

Sorafenib has been demonstrated to be a beneficial treatment for advanced hepatocellular carcinoma (HCC). Emerging evidence indicates that caspase-1 activation plays a crucial role in HCC progression. However, the relationship between caspase-1 and sorafenib has rarely been reported. In this study, we showed that caspase-1 was essential for lipopolysaccharide (LPS)-induced epithelial-mesenchymal transition (EMT). Moreover, sorafenib treatment could inhibit LPS-stimulated caspase-1 overexpression ...[more]

PMID: 30277836

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Project description:BackgroundHepatocellular carcinoma (HCC) is still the most common cause of tumor-related death worldwide and accumulating studies report that long non-coding RNAs (LncRNAs) are closely related with HCC development, metastasis and prognosis. Cisplatinum, a well-known chemotherapeutic drug, has been widely used for treatment of numerous human cancers including HCC. This study aimed to investigate the differential expressions of LncRNAs in HCC cells treated with cisplatinum and its underlying mechanism.MethodsThe differential expressions of LncRNAs in HCC cells treated with cisplatinum were determined by RNA-seq. The roles of TPTEP1 in HCC development by applying gene function gain and loss analysis in MHCC97H and QYG-7703 cell lines were detected by quantitative real-time polymerase chain reaction (qRT-PCR), cell proliferation, colony formation, cell invasion and flow cytometry assays. The underlying mechanism of TPTEP1 sensitizing hepatocellular carcinoma cells to cisplatinum was examined by RNA-pull down, western blotting, subcellular fractionation, RNA immunoprecipitation and dual luciferase reporter assays. The effect of TPTEP1 on tumorigenesis in vivo was performed with a subcutaneous xenograft mouse model of HCC. In addition, TPTEP1 expression was detected in clinical tumor tissue samples by qRT-PCR.ResultsLncRNA TPTEP1 was highly expressed in cisplatinum-treated HCC cells, which sensitizes hepatocellular carcinoma cell to cisplatinum-induced apoptosis. TPTEP1 overexpression inhibited, while TPTEP1 knockdown promoted HCC cell proliferation, tumorigenicity and invasion. Furthermore, TPTEP1 exerted its tumor suppressing activities by interacting with signal transducer and activator of transcription 3 (STAT3) to inhibit its phosphorylation, homodimerization, nuclear translocation and down-stream genes transcription. Moreover, TPTEP1 overexpression obviously inhibits tumor masses in vivo in a subcutaneous xenograft mouse model of HCC and TPTEP1 is frequently downregulated in HCC tissues, compared to its corresponding pre-tumor tissues.ConclusionLncRNA TPTEP1 inhibits hepatocellular carcinoma cells progression by affecting IL-6/STAT3 signaling. Taken together, our findings suggest a tumor suppressing role of TPTEP1 in HCC progression and provide a novel understanding of TPTEP1 during the chemotherapy for HCC.

Dataset Information

Sorafenib inhibits caspase-1 expression through suppressing TLR4/stat3/SUMO1 pathway in hepatocellular carcinoma.

Publications

Sorafenib inhibits caspase-1 expression through suppressing TLR4/stat3/SUMO1 pathway in hepatocellular carcinoma.

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