Thyroid hormone-mediated regulation of lipocalin 2 through the Met/FAK pathway in liver cancer

Abstract

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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“…38,39 Abrogation of FAK with multiple modalities, including small interfering RNA, AdFAK-CD, and small molecule inhibitors, has been shown to decrease tumor migration and to increase survival. 44,45 Integrins bind to the β subunits of FAK and lead to FAK phosphorylation. Chen et al 43 demonstrated that the expression of FAK correlated with tumor stage and vascular invasion of HCC.…”

Molecular functions and clinical impact of thyroid hormone-triggered autophagy in liver-related diseases

“…For instance, administration of TH not only reduces the size of preneoplastic lesions in the livers of rats suffering with HCC, but suppresses the aberrant cellular growth via control the expression of cell cycle regulators, such as CDK2, Cyclin E, UHRF1, STMN1 mir-214 and BC200 lncRNA [7,[171][172][173][174]. Our recent studies further support the preventive effect of TH on hepatocarcinogenesis via activating autophagy [16,17], whereas TH/THR is reported to promote metastasis and chemoresistance through control the expressions of BSSP4, TRAIL, BCL2L11, LCN2, mir-21, and mir-130b [7,173,[175][176][177][178][179][180]. This characteristic of THs supports the double-edged sword effect of autophagy in cancer progression.…”

“…Significant links between the regulation of selective autophagy and liver complications associated with NAFLD and HCC have been reported, supporting the manipulation of this process as a potential therapeutic strategy for liver-related diseases. Apoptosis regulator TRAIL [175] Metastatic regulator BSSP4 [178] LCN2 [180] mir-130b [177] mir-21 [179] Autophagy in liver-related diseases…”

Lasp1 promotes malignant phenotype of non-small-cell lung cancer via inducing phosphorylation of FAK-AKT pathway

“…As it is known to us all, FAK was served as an upstream factor of AKT signaling [ 33 , 34 ], our finding may provide a new sight to Lasp1 function. Since the activation of FAK signaling is shown to be regulated by c-Met signaling [ 35 – 37 ], we also evaluated the phosphorylation of c-Met and Gab1 after either overexpressing or depleting Lasp1. No significant changes were observed ( Supplementary Figure 2 ).…”