Thyroid hormone-mediated regulation of lipocalin 2 through the Met/FAK pathway in liver cancer
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I-Hsiao Chung1, Cheng-Yi Chen2, Yang-Hsiang Lin1, Hsiang-Cheng Chi1, Ya-Hui Huang3, Pei-Ju Tai1, Chia-Jung Liao1, Chung-Ying Tsai1, Syuan-Ling Lin1, Meng-Han Wu1, Ching-Ying Chen1, Kwang-Huei Lin1
1Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan
2Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan
3Liver Research Center, Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, Linkou, Taoyuan, Taiwan
Kwang-Huei Lin, e-mail: [email protected]
Keywords: thyroid hormone receptor, LCN2, Met/FAK cascade
Received: December 02, 2014 Accepted: March 25, 2015 Published: April 10, 2015
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. Oligonucleotide microarray, coupled with proteomic analysis, has revealed that LCN2 is positively regulated by T3/TR. However, the physiological role and pathway of T3-mediated regulation of LCN2 in hepatocellular carcinogenesis remain to be characterized. 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 TRα levels. Both TRα and LCN2 showed similar expression patterns in relation to survival rate, tumor grade, tumor stage and vascular invasion. 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.
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