Thyroid hormone-mediated regulation of lipocalin 2 through the Met/FAK pathway in liver cancer.
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.
Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.
I-Hsiao
IH
Chung
Department of Medical Research, Mackay Memorial Hospital, Taipei, Taiwan.
Cheng-Yi
CY
Chen
Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.
Yang-Hsiang
YH
Lin
Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.
Hsiang-Cheng
HC
Chi
Liver Research Center, Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.
Ya-Hui
YH
Huang
Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.
Pei-Ju
PJ
Tai
Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.
Chia-Jung
CJ
Liao
Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.
Chung-Ying
CY
Tsai
Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.
Syuan-Ling
SL
Lin
Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.
Meng-Han
MH
Wu
Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.
Ching-Ying
CY
Chen
Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.
Kwang-Huei
KH
Lin
D000209:Acute-Phase Proteins / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D051417:Focal Adhesion Kinase 1 / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D000071068:Lipocalin-2; D054834:Lipocalins / Q000235:genetics* / Q000378:metabolism; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics* / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D013963:Thyroid Hormones / Q000378:metabolism* / Q000494:pharmacology; D014183:Transplantation, Heterologous; D014284:Triiodothyronine / Q000378:metabolism / Q000494:pharmacology
D000209:Acute-Phase Proteins; C489506:LCN2 protein, human; D000071068:Lipocalin-2; D054834:Lipocalins; D011518:Proto-Oncogene Proteins; D011988:Receptors, Thyroid Hormone; D013963:Thyroid Hormones; D014284:Triiodothyronine; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human
LCN2; Met/FAK cascade; thyroid hormone receptor