IL-37 suppresses hepatocellular carcinoma growth by converting pSmad3 signaling from JNK/pSmad3L/c-Myc oncogenic signaling to pSmad3C/P21 tumor-suppressive signaling.
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.
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Rui
R
Liu
Department of Clinical Pharmacology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Chengyong
C
Tang
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.|Department of Hepatobiliary Surgery, Chongqing Cancer Institute, Chongqing 400030, China.
Ai
A
Shen
Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Huating
H
Luo
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Xufu
X
Wei
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Daofeng
D
Zheng
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Chao
C
Sun
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Zhongtang
Z
Li
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Di
D
Zhu
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Tingting
T
Li
Department of Hepatobiliary Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Zhongjun
Z
Wu
D000818:Animals; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D059447:Cell Cycle Checkpoints; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D007375:Interleukin-1 / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D011379:Prognosis; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism*; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D020741:rho GTP-Binding Proteins / Q000378:metabolism
C508587:IL37 protein, human; D007375:Interleukin-1; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D051900:Smad3 Protein; D025521:Tumor Suppressor Proteins; D048670:MAP Kinase Kinase 4; D020741:rho GTP-Binding Proteins
IL-37; JNK/pSmad3L/c-Myc; TGF-β; hepatocellular carcinoma; pSmad3C/p21