IL-37 suppresses hepatocellular carcinoma growth by converting pSmad3 signaling from JNK/pSmad3L/c-Myc oncogenic signaling to pSmad3C/P21 tumor-suppressive signaling
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Rui Liu1, Chengyong Tang2, Ai Shen1,3, Huating Luo4, Xufu Wei1, Daofeng Zheng1, Chao Sun1, Zhongtang Li1, Di Zhu1, Tingting Li1, Zhongjun Wu1
1Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
2Department of Clinical Pharmacology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
3Department of Hepatobiliary Surgery, Chongqing Cancer Institute, Chongqing 400030, China
4Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
Zhongjun Wu, email: [email protected]
Keywords: hepatocellular carcinoma, IL-37, TGF-β, JNK/pSmad3L/c-Myc, pSmad3C/p21
Received: April 01, 2016 Accepted: October 26, 2016 Published: November 08, 2016
IL-37 has been characterized as a fundamental inhibitor of innate immunity and a tumor suppressor in several cancers. However, the molecular mechanism of IL-37 in hepatocellular carcinoma (HCC) is largely unclear. In this study we found IL-37 expression was down-regulated in human HCC tissues and cell lines, and was negatively correlated with tumor size, vascular invasion, as well as overall-survial and disease-free survival (OS and DFS) of HCC. Multivariate Cox analysis revealed that IL-37 was an independent prognostic indicator for OS and DFS in HCC. Functional studies further showed that IL-37 overexpression significantly suppressed tumor growth by confining HCC to G2/M cell cycle arrest in vitro and in vivo. Mechanistically, we determined that IL-37 promoted Smad3 phospho-isoform signaling conversion from JNK/pSmad3L/c-Myc oncogenic signaling to pSmad3C/p21 tumor-suppressive signaling. Consistently, we detected a significant negative correlation between IL-37 expression and pSmad3L levels in a cohort of HCC biopsies; and the expression of pSmad3L predicted poorer outcome. These data highlight the importance of IL-37 in the cell proliferation and progression of HCC, and suggests that IL-37 may be a valuable biomarker for HCC prognosis.
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