TY - JOUR
T1 - Thyroid hormone-mediated regulation of lipocalin 2 through the Met/FAK pathway in liver cancer
AU - Chung, I. Hsiao
AU - Chen, Cheng Yi
AU - Lin, Yang-Hsiang
AU - Chi, Hsiang-Cheng
AU - Huang, Ya-Hui
AU - Tai, Pei Ju
AU - Liao, Chia Jung
AU - Tsai, Chung Ying
AU - Lin, Syuan Ling
AU - Wu, Meng Han
AU - Chen, Ching Ying
AU - Lin, Kwang Huei
PY - 2015
Y1 - 2015
N2 - 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 TRa levels. Both TRa 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.
AB - 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 TRa levels. Both TRa 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.
KW - LCN2
KW - Met/FAK cascade
KW - Thyroid hormone receptor
UR - http://www.scopus.com/inward/record.url?scp=84934343426&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.3670
DO - 10.18632/oncotarget.3670
M3 - 文章
C2 - 25940797
AN - SCOPUS:84934343426
SN - 1949-2553
VL - 6
SP - 15050
EP - 15064
JO - Oncotarget
JF - Oncotarget
IS - 17
ER -
