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, Tzu-Bi Shih, Po Huang Lee

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Article numberbgr219
Pages (from-to)1815-1823
Number of pages9
JournalCarcinogenesis
Volume32
Issue number12
DOIs
Publication statusPublished - Dec 2011

Fingerprint

alpha-Fetoproteins
Down-Regulation
Hepatocellular Carcinoma
Hep G2 Cells
Liver
Neoplasms
Homeobox Genes
Computer Simulation
Carcinogenesis
Western Blotting
Immunohistochemistry
Binding Sites
Phenotype
Growth

ASJC Scopus subject areas

  • Cancer Research

Cite this

Hung, T. M., Hu, R. H., Ho, C. M., Chiu, Y. L., Lee, J. L., Jeng, Y. M., ... Lee, P. H. (2011). Downregulation of alpha-fetoprotein expression by LHX4: A critical role in hepatocarcinogenesis. Carcinogenesis, 32(12), 1815-1823. [bgr219]. https://doi.org/10.1093/carcin/bgr219

Downregulation of alpha-fetoprotein expression by LHX4 : A critical role in hepatocarcinogenesis. / Hung, Tzu Min; Hu, Rey Heng; Ho, Cheng Maw; Chiu, Ya Lun; Lee, Jia Ling; Jeng, Yung Ming; Shih, Tzu-Bi; Lee, Po Huang.

In: Carcinogenesis, Vol. 32, No. 12, bgr219, 12.2011, p. 1815-1823.

Research output: Contribution to journalArticle

Hung, TM, Hu, RH, Ho, CM, Chiu, YL, Lee, JL, Jeng, YM, Shih, T-B & Lee, PH 2011, 'Downregulation of alpha-fetoprotein expression by LHX4: A critical role in hepatocarcinogenesis', Carcinogenesis, vol. 32, no. 12, bgr219, pp. 1815-1823. https://doi.org/10.1093/carcin/bgr219
Hung, Tzu Min ; Hu, Rey Heng ; Ho, Cheng Maw ; Chiu, Ya Lun ; Lee, Jia Ling ; Jeng, Yung Ming ; Shih, Tzu-Bi ; Lee, Po Huang. / Downregulation of alpha-fetoprotein expression by LHX4 : A critical role in hepatocarcinogenesis. In: Carcinogenesis. 2011 ; Vol. 32, No. 12. pp. 1815-1823.
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