A235: The role of lipocalin 2 regulated by thyroid hormone in liver cancer

I-Hsiao Chung1,Kwang-Huei Lin1

1Chang-Gung University, Taoyuan, Taiwan

Presenting date: Monday 2 November
Presenting time: 12.20-13.10

Background

The thyroid hormone, 3,3',5-triiodo-L-thyronine (T3), regulates cell growth, development and differentiation via interactions with thyroid hormone receptors (TR), but the mechanisms underlying T3-mediated modulation of cancer progression are currently unclear. Lipocalin 2 (LCN2), a tumor-associated protein, is overexpressed in a variety of cancer types. However, the physiological role and pathway of T3-mediated regulation of LCN2 in hepatocellular carcinogenesis remain to be characterized.

Method

Oligonucleotide microarray, coupled with proteomic analysis, has revealed that LCN2 is positively regulated by T3/TR.  To further determine whether LCN2 is directly targeted by TR proteins, the Chromatin immunoprecipitation assay was performed. To determine the function of LCN2, depletion or overexpression of this protein was performed. Statistical analysis was performed using Student's t test and one-way ANOVA.

Results

Upregulation of LCN2 after T3 stimulation was observed in a time- and dose-dependent manner. Additionally, TRE on the LCN2 promoter was identified at positions -1444/-1427. Overexpression of LCN2 enhanced tumor cell migration and invasion, and conversely, its knockdown suppressed migration and invasion, both in vitro and in vivo. LCN2-induced migration occurred through activation of the Met/FAK cascade. LCN2 was overexpressed in clinical hepatocellular carcinoma (HCC) patients, compared with normal subjects, and positively correlated with TR? levels. Both TR? and LCN2 showed similar expression patterns in relation to survival rate, tumor grade, tumor stage and vascular invasion.

Conclusion

Our findings collectively support a potential role of T3/TR in cancer progression through regulation of LCN2 via the Met/FAK cascade. LCN2 may thus be effectively utilized as a novel marker and therapeutic target in HCC.