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A novel small-form NEDD4 regulates cell invasiveness and apoptosis to promote tumor metastasis.

Liao CJ, Chi HC, Tsai CY, Chen CD, Wu SM, Tseng YH, Lin YH, Chung IH, Chen CY, Lin SL, Huang SF, Huang YH, Lin KH - Oncotarget (2015)

Bottom Line: A small form of Neural precursor cell-expressed developmentally downregulated 4 (sNEDD4) was identified to be overexpressed in SKM cells, which was confirmed as a novel transcript using liquid chromatography-mass spectrometry.In conclusion, sNEDD4 is a novel metastasis-associated gene, which prevents apoptosis under nutrient restriction conditions.The present findings clearly support the prognostic potential of sNEDD4 for HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Chang-Gung University, Taoyuan, Taiwan 333, Republic of China.

ABSTRACT
Despite numerous investigations on metastasis, the determinants of metastatic processes remain unclear. We aimed to identify the metastasis-associated genes in hepatocellular carcinoma (HCC). Potent metastatic SK-hep-1 (SK) cells, designated 'SKM', were generated using Transwell assay followed by selection in a mouse model. Genes expressed differentially in SKM and SK cells were identified via microarray analyses. A small form of Neural precursor cell-expressed developmentally downregulated 4 (sNEDD4) was identified to be overexpressed in SKM cells, which was confirmed as a novel transcript using liquid chromatography-mass spectrometry. In clinical specimens, sNEDD4 was significantly overexpressed in tumors and serves as a poor prognostic factor for male patients with HCC (P = 0.035). Upon subcutaneous introduction of sNEDD4-overexpressing SK cells into flanks of nude mice, tumors grew faster than those of the control group. Furthermore, sNEDD4-mediated promotion of tumor metastasis was demonstrated in the orthotopic mouse model. Overexpression of sNEDD4 increased the invasive ability of SK cells through upregulation of matrix metalloproteinase 9 and inhibited serum deprivation-induced apoptosis via upregulation of myeloid cell leukemia 1. In conclusion, sNEDD4 is a novel metastasis-associated gene, which prevents apoptosis under nutrient restriction conditions. The present findings clearly support the prognostic potential of sNEDD4 for HCC.

No MeSH data available.


Related in: MedlinePlus

Expression of sNEDD4 in HCCsNEDD4 protein levels were verified in 70 paired adjacent normal and tumor liver tissues. (A) Representative results of Western blot analysis are shown. (B) Quantitative results of Western blot. Survival curves of low- and high- expression sNEDD4 groups of the entire study population (C) and male subgroup (D). N, adjacent normal; T, tumor; **P < 0.01; OS, overall survival.
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Figure 2: Expression of sNEDD4 in HCCsNEDD4 protein levels were verified in 70 paired adjacent normal and tumor liver tissues. (A) Representative results of Western blot analysis are shown. (B) Quantitative results of Western blot. Survival curves of low- and high- expression sNEDD4 groups of the entire study population (C) and male subgroup (D). N, adjacent normal; T, tumor; **P < 0.01; OS, overall survival.

Mentions: In order to investigate whether sNEDD4 is expressing in human livers, expression of sNEDD4 in 70 paired adjacent normal and HCC specimens was determined using Western blot analysis (Figure 2A). The relative intensities of sNEDD4 and NEDD4 were quantified, and statistical analyses performed. Expression levels of sNEDD4 and NEDD4 were significantly higher in tumor tissues than adjacent normal counterparts (Figure 2B and data not shown; P = 0.008 and 0.001, respectively). Tumor-to-normal tissue ratio of sNEDD4 or NEDD4 according to clinical parameters was determined. No significant differences were observed among patients with different ages, tumor sizes, grades, tumor types, vascular invasion status, stage, and cirrhosis status. However, T/N ratios of sNEDD4 were significantly different among patients with different viral status (HBV and HCV vs. NBNC; 1.99 ± 2.1 and 0.7 ± 0.49, respectively; P = 0.015). sNEDD4 T/N ratios of liver tissues were dichotomized according to the media ratio as low- and high-expression groups. Survival of patients with high and low sNEDD4 expression was presented as Kaplan-Meier survival curves (Figure 2C and 2D). In all study populations, patients in the high sNEDD4 expression group displayed a poorer overall survival (OS; Figure 2C) and recurrence-free survival (RFS; data not shown) trends, compared to those in the low expression group. In male populations, OS (but not RFS) of patients with high sNEDD4 expression was significantly poorer than those with low sNEDD4 expression (Figure 2D). However, no significant differences in survival were observed in female populations with different sNEDD4 expression status. Determination of the clinical significances of NEDD4 revealed no significant correlations with clinical parameters or differences in survival of patients with different NEDD4 status (data not shown).


A novel small-form NEDD4 regulates cell invasiveness and apoptosis to promote tumor metastasis.

Liao CJ, Chi HC, Tsai CY, Chen CD, Wu SM, Tseng YH, Lin YH, Chung IH, Chen CY, Lin SL, Huang SF, Huang YH, Lin KH - Oncotarget (2015)

Expression of sNEDD4 in HCCsNEDD4 protein levels were verified in 70 paired adjacent normal and tumor liver tissues. (A) Representative results of Western blot analysis are shown. (B) Quantitative results of Western blot. Survival curves of low- and high- expression sNEDD4 groups of the entire study population (C) and male subgroup (D). N, adjacent normal; T, tumor; **P < 0.01; OS, overall survival.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496221&req=5

Figure 2: Expression of sNEDD4 in HCCsNEDD4 protein levels were verified in 70 paired adjacent normal and tumor liver tissues. (A) Representative results of Western blot analysis are shown. (B) Quantitative results of Western blot. Survival curves of low- and high- expression sNEDD4 groups of the entire study population (C) and male subgroup (D). N, adjacent normal; T, tumor; **P < 0.01; OS, overall survival.
Mentions: In order to investigate whether sNEDD4 is expressing in human livers, expression of sNEDD4 in 70 paired adjacent normal and HCC specimens was determined using Western blot analysis (Figure 2A). The relative intensities of sNEDD4 and NEDD4 were quantified, and statistical analyses performed. Expression levels of sNEDD4 and NEDD4 were significantly higher in tumor tissues than adjacent normal counterparts (Figure 2B and data not shown; P = 0.008 and 0.001, respectively). Tumor-to-normal tissue ratio of sNEDD4 or NEDD4 according to clinical parameters was determined. No significant differences were observed among patients with different ages, tumor sizes, grades, tumor types, vascular invasion status, stage, and cirrhosis status. However, T/N ratios of sNEDD4 were significantly different among patients with different viral status (HBV and HCV vs. NBNC; 1.99 ± 2.1 and 0.7 ± 0.49, respectively; P = 0.015). sNEDD4 T/N ratios of liver tissues were dichotomized according to the media ratio as low- and high-expression groups. Survival of patients with high and low sNEDD4 expression was presented as Kaplan-Meier survival curves (Figure 2C and 2D). In all study populations, patients in the high sNEDD4 expression group displayed a poorer overall survival (OS; Figure 2C) and recurrence-free survival (RFS; data not shown) trends, compared to those in the low expression group. In male populations, OS (but not RFS) of patients with high sNEDD4 expression was significantly poorer than those with low sNEDD4 expression (Figure 2D). However, no significant differences in survival were observed in female populations with different sNEDD4 expression status. Determination of the clinical significances of NEDD4 revealed no significant correlations with clinical parameters or differences in survival of patients with different NEDD4 status (data not shown).

Bottom Line: A small form of Neural precursor cell-expressed developmentally downregulated 4 (sNEDD4) was identified to be overexpressed in SKM cells, which was confirmed as a novel transcript using liquid chromatography-mass spectrometry.In conclusion, sNEDD4 is a novel metastasis-associated gene, which prevents apoptosis under nutrient restriction conditions.The present findings clearly support the prognostic potential of sNEDD4 for HCC.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, Chang-Gung University, Taoyuan, Taiwan 333, Republic of China.

ABSTRACT
Despite numerous investigations on metastasis, the determinants of metastatic processes remain unclear. We aimed to identify the metastasis-associated genes in hepatocellular carcinoma (HCC). Potent metastatic SK-hep-1 (SK) cells, designated 'SKM', were generated using Transwell assay followed by selection in a mouse model. Genes expressed differentially in SKM and SK cells were identified via microarray analyses. A small form of Neural precursor cell-expressed developmentally downregulated 4 (sNEDD4) was identified to be overexpressed in SKM cells, which was confirmed as a novel transcript using liquid chromatography-mass spectrometry. In clinical specimens, sNEDD4 was significantly overexpressed in tumors and serves as a poor prognostic factor for male patients with HCC (P = 0.035). Upon subcutaneous introduction of sNEDD4-overexpressing SK cells into flanks of nude mice, tumors grew faster than those of the control group. Furthermore, sNEDD4-mediated promotion of tumor metastasis was demonstrated in the orthotopic mouse model. Overexpression of sNEDD4 increased the invasive ability of SK cells through upregulation of matrix metalloproteinase 9 and inhibited serum deprivation-induced apoptosis via upregulation of myeloid cell leukemia 1. In conclusion, sNEDD4 is a novel metastasis-associated gene, which prevents apoptosis under nutrient restriction conditions. The present findings clearly support the prognostic potential of sNEDD4 for HCC.

No MeSH data available.


Related in: MedlinePlus