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The significance of Notch1 compared with Notch3 in high metastasis and poor overall survival in hepatocellular carcinoma.

Zhou L, Zhang N, Song W, You N, Li Q, Sun W, Zhang Y, Wang D, Dou K - PLoS ONE (2013)

Bottom Line: Kaplan-Meier curves demonstrated that patients with high Notch1 or Notch3 expression were at a significantly increased risk for shortened survival time.In vitro, the down-regulation of Notch1 decreased the migration and invasion capacities of HCC cells by regulating CD44v6, E-cadherin, MMP-2, MMP-9, and uPA via the COX-2 and ERK1/2 pathways.Down-regulation of Notch3 only decreased the invasion capacity of HCC cells by regulating MMP-2 and MMP-9 via the ERK1/2 pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi, People's Republic of China.

ABSTRACT

Background: The prognosis for patients with hepatocellular carcinoma (HCC) is poor, and the mechanisms underlying the development of HCC remain unclear. Notch1 and Notch3 may be involved in malignant transformation, although their roles remain unknown.

Materials and methods: HCC tissues were stained with anti-Notch1 or -Notch3 antibody. The migration and invasion capacities of the cells were measured with transwell cell culture chambers. RT-PCR was used to measure the expression of Notch1 and Notch3 mRNA. Additionally, western blot analysis was used to assess the protein expression of Notch1, Notch3, CD44v6, E-cadherin, matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator (uPA). RNA interference was used to down-regulate the expression of Notch1 and Notch3. Cell viability was assessed using MTT.

Results: Based on immunohistochemistry, high Notch1 expression was correlated with tumor size, tumor grade, metastasis, venous invasion and AJCC TNM stage. High Notch3 expression was only strongly correlated with metastasis, venous invasion and satellite lesions. Kaplan-Meier curves demonstrated that patients with high Notch1 or Notch3 expression were at a significantly increased risk for shortened survival time. In vitro, the down-regulation of Notch1 decreased the migration and invasion capacities of HCC cells by regulating CD44v6, E-cadherin, MMP-2, MMP-9, and uPA via the COX-2 and ERK1/2 pathways. Down-regulation of Notch3 only decreased the invasion capacity of HCC cells by regulating MMP-2 and MMP-9 via the ERK1/2 pathway.

Conclusions: Based on the migration and invasion of HCC, we hypothesize that targeting Notch1 may be more useful than Notch3 for designing novel preventive and therapeutic strategies for HCC in the near future.

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Related in: MedlinePlus

Expression of Notch1 and Notch3 in HCC tissues and Kaplan-Meier statistical analyses of postoperative survival curves according to Notch1 and Notch3 expression.Notch1 expression in HCC tissues (a–d): (a) negative, (b) weakly positive, (b) moderately positive, (d) strongly positive. Notch3 expression in HCC tissues (e-h): (e) negative, (f) weakly positive, (g) moderately positive, (h) strongly positive. (i) Kaplan-Meier statistical analyses of postoperative survival curves according to Notch1 expression; (j) Kaplan-Meier statistical analyses of postoperative survival curves according to Notch3 expression.
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pone-0057382-g001: Expression of Notch1 and Notch3 in HCC tissues and Kaplan-Meier statistical analyses of postoperative survival curves according to Notch1 and Notch3 expression.Notch1 expression in HCC tissues (a–d): (a) negative, (b) weakly positive, (b) moderately positive, (d) strongly positive. Notch3 expression in HCC tissues (e-h): (e) negative, (f) weakly positive, (g) moderately positive, (h) strongly positive. (i) Kaplan-Meier statistical analyses of postoperative survival curves according to Notch1 expression; (j) Kaplan-Meier statistical analyses of postoperative survival curves according to Notch3 expression.

Mentions: Notch1 and Notch3 were mainly localized in the cytoplasm and cell membrane. Neither Notch1 nor Notch3 was significantly expressed in adjacent non-cancerous hepatic tissues, with only weak staining of Notch1 and Notch3 in the cell membrane and cytoplasm. As Fig. 1 (a–h) shows, the expression of Notch1 and Notch3 was different in HCC tissues. Notch1 staining was not detected in 9 samples of HCC. In contrast, weak positive staining of Notch1 was detected in 31 samples of HCC, moderate positive staining was detected in 17 samples, and strong positive staining was detected in 29 samples. Notch3 staining was not detected in 11 samples of HCC. In contrast, weak positive staining of Notch3 was detected in 30 samples of HCC, moderate positive staining was detected in 19 samples, and strong positive staining was detected in 26 samples.


The significance of Notch1 compared with Notch3 in high metastasis and poor overall survival in hepatocellular carcinoma.

Zhou L, Zhang N, Song W, You N, Li Q, Sun W, Zhang Y, Wang D, Dou K - PLoS ONE (2013)

Expression of Notch1 and Notch3 in HCC tissues and Kaplan-Meier statistical analyses of postoperative survival curves according to Notch1 and Notch3 expression.Notch1 expression in HCC tissues (a–d): (a) negative, (b) weakly positive, (b) moderately positive, (d) strongly positive. Notch3 expression in HCC tissues (e-h): (e) negative, (f) weakly positive, (g) moderately positive, (h) strongly positive. (i) Kaplan-Meier statistical analyses of postoperative survival curves according to Notch1 expression; (j) Kaplan-Meier statistical analyses of postoperative survival curves according to Notch3 expression.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3585338&req=5

pone-0057382-g001: Expression of Notch1 and Notch3 in HCC tissues and Kaplan-Meier statistical analyses of postoperative survival curves according to Notch1 and Notch3 expression.Notch1 expression in HCC tissues (a–d): (a) negative, (b) weakly positive, (b) moderately positive, (d) strongly positive. Notch3 expression in HCC tissues (e-h): (e) negative, (f) weakly positive, (g) moderately positive, (h) strongly positive. (i) Kaplan-Meier statistical analyses of postoperative survival curves according to Notch1 expression; (j) Kaplan-Meier statistical analyses of postoperative survival curves according to Notch3 expression.
Mentions: Notch1 and Notch3 were mainly localized in the cytoplasm and cell membrane. Neither Notch1 nor Notch3 was significantly expressed in adjacent non-cancerous hepatic tissues, with only weak staining of Notch1 and Notch3 in the cell membrane and cytoplasm. As Fig. 1 (a–h) shows, the expression of Notch1 and Notch3 was different in HCC tissues. Notch1 staining was not detected in 9 samples of HCC. In contrast, weak positive staining of Notch1 was detected in 31 samples of HCC, moderate positive staining was detected in 17 samples, and strong positive staining was detected in 29 samples. Notch3 staining was not detected in 11 samples of HCC. In contrast, weak positive staining of Notch3 was detected in 30 samples of HCC, moderate positive staining was detected in 19 samples, and strong positive staining was detected in 26 samples.

Bottom Line: Kaplan-Meier curves demonstrated that patients with high Notch1 or Notch3 expression were at a significantly increased risk for shortened survival time.In vitro, the down-regulation of Notch1 decreased the migration and invasion capacities of HCC cells by regulating CD44v6, E-cadherin, MMP-2, MMP-9, and uPA via the COX-2 and ERK1/2 pathways.Down-regulation of Notch3 only decreased the invasion capacity of HCC cells by regulating MMP-2 and MMP-9 via the ERK1/2 pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi, People's Republic of China.

ABSTRACT

Background: The prognosis for patients with hepatocellular carcinoma (HCC) is poor, and the mechanisms underlying the development of HCC remain unclear. Notch1 and Notch3 may be involved in malignant transformation, although their roles remain unknown.

Materials and methods: HCC tissues were stained with anti-Notch1 or -Notch3 antibody. The migration and invasion capacities of the cells were measured with transwell cell culture chambers. RT-PCR was used to measure the expression of Notch1 and Notch3 mRNA. Additionally, western blot analysis was used to assess the protein expression of Notch1, Notch3, CD44v6, E-cadherin, matrix metalloproteinase-2 (MMP-2), MMP-9, and urokinase-type plasminogen activator (uPA). RNA interference was used to down-regulate the expression of Notch1 and Notch3. Cell viability was assessed using MTT.

Results: Based on immunohistochemistry, high Notch1 expression was correlated with tumor size, tumor grade, metastasis, venous invasion and AJCC TNM stage. High Notch3 expression was only strongly correlated with metastasis, venous invasion and satellite lesions. Kaplan-Meier curves demonstrated that patients with high Notch1 or Notch3 expression were at a significantly increased risk for shortened survival time. In vitro, the down-regulation of Notch1 decreased the migration and invasion capacities of HCC cells by regulating CD44v6, E-cadherin, MMP-2, MMP-9, and uPA via the COX-2 and ERK1/2 pathways. Down-regulation of Notch3 only decreased the invasion capacity of HCC cells by regulating MMP-2 and MMP-9 via the ERK1/2 pathway.

Conclusions: Based on the migration and invasion of HCC, we hypothesize that targeting Notch1 may be more useful than Notch3 for designing novel preventive and therapeutic strategies for HCC in the near future.

Show MeSH
Related in: MedlinePlus