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IL-37 suppresses hepatocellular carcinoma growth by converting pSmad3 signaling
from JNK/pSmad3L/c-Myc oncogenic signaling to pSmad3C/P21 tumor-suppressive
signaling
#MMPMID27835881
Liu R
; Tang C
; Shen A
; Luo H
; Wei X
; Zheng D
; Sun C
; Li Z
; Zhu D
; Li T
; Wu Z
Oncotarget
2016[Dec]; 7
(51
): 85079-85096
PMID27835881
show ga
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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