Journal Article

Downregulation of alpha-fetoprotein expression by LHX4: a critical role in hepatocarcinogenesis

Tzu-Min Hung, Rey-Heng Hu, Cheng-Maw Ho, Ya-Lun Chiu, Jia-Ling Lee, Yung-Ming Jeng, Daniel Tzu-Bi Shih and Po-Huang Lee

in Carcinogenesis

Volume 32, issue 12, pages 1815-1823
Published in print December 2011 | ISSN: 0143-3334
Published online September 2011 | e-ISSN: 1460-2180 | DOI:
Downregulation of alpha-fetoprotein expression by LHX4: a critical role in hepatocarcinogenesis

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LHX4 is a member of the LIM-homeobox family and plays a critical role in pituitary development and differentiation. Several lines of evidences have reported their aberrant expression in cancers. However, the exact roles of LHX4 in carcinogenesis remain unclear. In this study, LHX4 expression was analyzed in tumor and paired non-tumor tissues obtained from patients with hepatocellular carcinoma (HCC) using western blotting and immunohistochemistry. LHX4 was found to be downregulated in tumor tissues and negatively correlated with differentiation grade and alpha-fetoprotein (AFP) levels in 66 HCC patients. To clarify the biological functions of LHX4, transient or stable transfectants overexpressing LHX4 were generated in human hepatoma cells (Huh7 and HepG2). LHX4 overexpression in Huh7 and HepG2 cells induced a more differentiated phenotype by reducing AFP expression. Using in silico analysis, the evolutionary conserved region within the AFP promoter containing LHX4-binding site was identified, implying that AFP is a putative target for LHX4. Moreover, ectopic LHX4 overexpression attenuated Huh7 and HepG2 proliferation. Importantly, the growth-inhibitory effect of LHX4 was reversed by replenishing AFP to the LHX4-overexpressing cells, providing a functional relevance between LHX4 and AFP. Finally, we analyzed expressions of LHX4 and AFP during normal liver development. Hepatic LHX4 expression increased in adult liver in a manner that parallel AFP repression. In conclusion, these data indicate that LHX4 may act as a potential tumor suppressor in hepatocarcinogenesis, suggesting that targeting LHX4 to downregulate AFP might have therapeutic implications.

Journal Article.  5527 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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