Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-β–like signaling pathway
Lihua Ding, … , Cuifen Huang, Qinong Ye
Lihua Ding, … , Cuifen Huang, Qinong Ye
Published January 12, 2009
Citation Information: J Clin Invest. 2009;119(2):349-361. https://doi.org/10.1172/JCI35930.
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Research Article Oncology

Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-β–like signaling pathway

Abstract

The four-and-a-half LIM (FHL) proteins belong to a family of LIM-only proteins that regulate cell proliferation, differentiation, and apoptosis. The exact functions of each FHL protein in cancer development and progression remain unknown. Here we report that FHL1, FHL2, and FHL3 physically and functionally interact with Smad2, Smad3, and Smad4, important regulators of cancer development and progression, in a TGF-β–independent manner. Casein kinase 1δ, but not the TGF-β receptor, was required for the FHL-mediated TGF-β–like responses, including increased phosphorylation of Smad2/3, interaction of Smad2/3 and Smad4, nuclear accumulation of Smad proteins, activation of the tumor suppressor gene p21, and repression of the oncogene c-myc. FHL1–3 inhibited anchorage-dependent and -independent growth of a human hepatoma cell line in vitro and tumor formation in nude mice. Further analysis of clinical samples revealed that FHL proteins are often downregulated in hepatocellular carcinomas and that this correlates with decreased TGF-β–like responses. By establishing a link between FHL proteins and Smad proteins, this study identifies what we believe to be a novel TGF-β–like signaling pathway and indicates that FHL proteins may be useful molecular targets for cancer therapy.

Authors

Lihua Ding, Zhaoyun Wang, Jinghua Yan, Xiao Yang, Aijun Liu, Weiyi Qiu, Jianhua Zhu, Juqiang Han, Hao Zhang, Jing Lin, Long Cheng, Xi Qin, Chang Niu, Bin Yuan, Xiaohui Wang, Cui Zhu, Yan Zhou, Jiezhi Li, Haifeng Song, Cuifen Huang, Qinong Ye

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Figure 8

Expressions of FHL1–3 in human liver tumors and matched nontumor liver tissues and their correlation with TGF-β–like responses.

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Expressions of FHL1–3 in human liver tumors and matched nontumor liver t...
(A) Proteins extracted from the HepG2, Hep3B, L02, and SMMC7721 cells lines were analyzed by Western blot with anti-FHL1, anti-FHL2, and anti-FHL3 (left panel). The densitometric quantitation of FHL1, FHL2, and FHL3 bands normalized to GAPDH from 3 independent experiments is shown (right panel) (mean ± SD). (B and C) Representative immunoblots (B) and immunohistochemical staining (C) of FHL proteins and/or the indicated proteins responsible for FHL-mediated TGF-β–like responses in human cancerous liver tissues (C1–C5) and adjacent normal liver tissues (N1–N5). Original magnification, ×40. (D) Proposed model for FHL1 modulation of TGF-β–like responses. FHL1 phosphorylates cytoplasmic Smad2 and Smad3 through interaction with CK1δ, facilitating formation of Smad2/3 and Smad4 complexes and nuclear accumulation of Smad proteins. In the nucleus, Smad complexes regulate TGF-β–responsive gene transcription through interaction with FHL1.