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

Chung IH, Chen CY, Lin YH, Chi HC, Huang YH, Tai PJ, Liao CJ, Tsai CY, Lin SL, Wu MH, Chen CY, Lin KH - Oncotarget (2015)

Bottom Line: 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.LCN2 may thus be effectively utilized as a novel marker and therapeutic target in HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.

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.

No MeSH data available.


Related in: MedlinePlus

LCN2 and TR expression in clinical specimensTR, LCN2, p-Met and p-FAK protein levels determined via Western blot in 18 representative HCC tumor tissues A. and B. IHC in 2 paired patient sections.
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Figure 7: LCN2 and TR expression in clinical specimensTR, LCN2, p-Met and p-FAK protein levels determined via Western blot in 18 representative HCC tumor tissues A. and B. IHC in 2 paired patient sections.

Mentions: The clinicopathologic significance of LCN2 in HCC and its correlation with TR were evaluated. LCN2 levels were analyzed in 80 consecutive HCC patients using qRT-PCR. Among the 80 HCC sample pairs, LCN2 was overexpressed in 71.3% (57 of 80) cancerous tissues, compared with matched noncancerous tissues, and TRα levels elevated by about 76.3% (61 of 80) in cancerous tissues. High TRα and LCN2 levels were commonly observed in patients with poor survival rates (Fig. 6A, left and middle panels). Linear regression analysis further revealed a significant positive correlation between LCN2 and TRα1 levels, based on the T/N ratio (Spearman correlation coefficient = 0.3399, P = 0.002) (Fig. 6A, right panel). In contrast, no significant correlation between LCN2 and TRβ1 levels was evident (data not shown). We examined LCN2 and TRα1 expression in relation to several parameters. Both LCN2 and TRα displayed similar expression patterns relative to tumor grade (Fig. 6B), TNM stage (Figure 6C), and vascular invasion grade (Fig. 6D). Increased LCN2 expression and concomitantly elevated TRα, p-Met, and p-FAK levels in HCC tissues of 18 representative paired specimens are presented in Fig. 7A and 7B. Similar expression patterns of LCN2 and TRα were consistently observed in public Oncomine microarray datasets (Fig. S2). In conclusion, T3/TR-regulated LCN2 promotes cell migration and invasion via activation of the Met/FAK cascade and E-cadherin suppression. Our collective in vitro and in vivo findings support the potential utility of LCN2 as an effective therapeutic target for HCC treatment.


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

Chung IH, Chen CY, Lin YH, Chi HC, Huang YH, Tai PJ, Liao CJ, Tsai CY, Lin SL, Wu MH, Chen CY, Lin KH - Oncotarget (2015)

LCN2 and TR expression in clinical specimensTR, LCN2, p-Met and p-FAK protein levels determined via Western blot in 18 representative HCC tumor tissues A. and B. IHC in 2 paired patient sections.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4558135&req=5

Figure 7: LCN2 and TR expression in clinical specimensTR, LCN2, p-Met and p-FAK protein levels determined via Western blot in 18 representative HCC tumor tissues A. and B. IHC in 2 paired patient sections.
Mentions: The clinicopathologic significance of LCN2 in HCC and its correlation with TR were evaluated. LCN2 levels were analyzed in 80 consecutive HCC patients using qRT-PCR. Among the 80 HCC sample pairs, LCN2 was overexpressed in 71.3% (57 of 80) cancerous tissues, compared with matched noncancerous tissues, and TRα levels elevated by about 76.3% (61 of 80) in cancerous tissues. High TRα and LCN2 levels were commonly observed in patients with poor survival rates (Fig. 6A, left and middle panels). Linear regression analysis further revealed a significant positive correlation between LCN2 and TRα1 levels, based on the T/N ratio (Spearman correlation coefficient = 0.3399, P = 0.002) (Fig. 6A, right panel). In contrast, no significant correlation between LCN2 and TRβ1 levels was evident (data not shown). We examined LCN2 and TRα1 expression in relation to several parameters. Both LCN2 and TRα displayed similar expression patterns relative to tumor grade (Fig. 6B), TNM stage (Figure 6C), and vascular invasion grade (Fig. 6D). Increased LCN2 expression and concomitantly elevated TRα, p-Met, and p-FAK levels in HCC tissues of 18 representative paired specimens are presented in Fig. 7A and 7B. Similar expression patterns of LCN2 and TRα were consistently observed in public Oncomine microarray datasets (Fig. S2). In conclusion, T3/TR-regulated LCN2 promotes cell migration and invasion via activation of the Met/FAK cascade and E-cadherin suppression. Our collective in vitro and in vivo findings support the potential utility of LCN2 as an effective therapeutic target for HCC treatment.

Bottom Line: 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.LCN2 may thus be effectively utilized as a novel marker and therapeutic target in HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, School of Medicine, Chang-Gung University, Taoyuan, Taiwan.

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.

No MeSH data available.


Related in: MedlinePlus