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NOTCH1 signaling contributes to cell growth, anti-apoptosis and metastasis in salivary adenoid cystic carcinoma.

Su BH, Qu J, Song M, Huang XY, Hu XM, Xie J, Zhao Y, Ding LC, She L, Chen J, Lin LS, Lin X, Zheng DL, Lu YG - Oncotarget (2014)

Bottom Line: We silenced the expression of NOTCH1 and overexpressed activated NOTCH1 to elucidate the effects of NOTCH1 on proliferation, migration and invasion.NOTCH1 target genes were validated by real-time PCR.Overexpression of NOTCH1 in SACC cells promoted cell growth, migration and invasion, and knockdown of NOTCH1 inhibited cell proliferation in vitro and tumorigenicity in vivo by inducing cell apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, Fuzhou, China. These authors contributed equally to this work.

ABSTRACT

Background: Numerous studies have reported both the tumor-suppressive and oncogenic roles of the Notch pathway, indicating that Notch activity regulates tumor biology in a complex, context-dependent manner. The aim of the present study was to identify the role of NOTCH1 in the cell growth and metastasis of SACC.

Methods: We analyzed the expression of NOTCH1 in clinical SACC samples using immunohistochemical staining. We silenced the expression of NOTCH1 and overexpressed activated NOTCH1 to elucidate the effects of NOTCH1 on proliferation, migration and invasion. NOTCH1 target genes were validated by real-time PCR.

Results: Our results showed that NOTCH1 was upregulated in SACC tissues when compared with normal tissues, and this upregulation was further enhanced in SACC tissues with metastasis and recurrence when compared with SACC tissues without metastasis. Overexpression of NOTCH1 in SACC cells promoted cell growth, migration and invasion, and knockdown of NOTCH1 inhibited cell proliferation in vitro and tumorigenicity in vivo by inducing cell apoptosis.

Conclusions: The results of this study suggest that NOTCH1 plays a key role in the cell growth, anti-apoptosis, and metastasis of SACC. NOTCH1 inhibitors might therefore have potential therapeutic applications in treating SACC patients by inhibiting cancer cell growth and metastasis.

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NOTCH1 is upregulated in salivary adenoid cystic carcinomaA-B, Survival of patients with breast cancer (A) or lung cancer (B) relative to different expression levels of NOTCH1 using KM Plotter from publicly available microarray data; C, Representative images for the expression of NOTCH1 by immunohistochemistry in normal salivary gland tissues (a), pleomorphic adenoma samples (b), and adenoid cystic carcinoma without (c) or with metastasis and recurrence (d) (Original magnification 400X).
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Figure 1: NOTCH1 is upregulated in salivary adenoid cystic carcinomaA-B, Survival of patients with breast cancer (A) or lung cancer (B) relative to different expression levels of NOTCH1 using KM Plotter from publicly available microarray data; C, Representative images for the expression of NOTCH1 by immunohistochemistry in normal salivary gland tissues (a), pleomorphic adenoma samples (b), and adenoid cystic carcinoma without (c) or with metastasis and recurrence (d) (Original magnification 400X).

Mentions: Both the overexpression and downregulation of NOTCH1 have been observed in human cancers when compared with normal samples. In this study, we first explored the expression of NOTCH1 in different human cancers in the Oncomine database. According to this public available database, NOTCH1 is mainly overexpressed in brain cancer (Fig S1A-B) [15], gastric cancer (Fig S1A and C) [16], colorectal cancer, leukemia, and ovarian cancer. In contrast, NOTCH1 has also been shown to be downregulated in breast cancer (Fig S1A and D) [17], lung cancer Fig S1A and E) [18], prostate cancer, kidney cancer, and myeloma. Gene expression data for these studies are available through the Oncomine database, as are the studies describing these results (http://www.oncomine.org). We also conducted an unbiased bioinformatic analysis of gene-expression profiles of 3355 patients with breast cancer [19], 1405 with lung cancer [20] and 1171 with ovarian cancer [21] using Kaplan-Meier (KM) Plotter, a meta-analysis-based biomarker assessment tool. This analysis tool utilizes Affymetrix gene-expression profiling data, which involve multiple probe sets for most genes. The results showed that higher expression of NOTCH1 (auto select best cut-off) was associated with poor prognosis and shorter relapse-free survival (RFS; P = 8*10−5, Fig. 1A) in breast cancer but better prognosis and longer overall survival (OS; P=4.4*10−7, Fig. 1B) in lung cancer, with no significant difference in ovarian cancer (data not shown). In our previous study, we found that NOTCH1 was upregulated in the highly metastatic adenoid cystic carcinoma cell line, ACC-M, compared with the low metastatic cell line, ACC-2, suggesting that NOTCH1 contributes to the metastasis of adenoid cystic carcinoma. Next, we investigated the expression of NOTCH1 in salivary adenoid cystic carcinoma using immunohistochemistry. As shown in Fig. 1C and Table 1, NOTCH1 expression was absent or very low in normal salivary gland tissues (except in the ductal cells). Low expression levels were detected in the pleomorphic adenoma samples and adenoid cystic carcinomas without metastasis and recurrence, whereas higher expression levels were observed in the adenoid cystic carcinoma with metastasis and recurrence (P<0.05). This result indicates that NOTCH1 might play an important role in the metastasis of adenoid cystic carcinoma.


NOTCH1 signaling contributes to cell growth, anti-apoptosis and metastasis in salivary adenoid cystic carcinoma.

Su BH, Qu J, Song M, Huang XY, Hu XM, Xie J, Zhao Y, Ding LC, She L, Chen J, Lin LS, Lin X, Zheng DL, Lu YG - Oncotarget (2014)

NOTCH1 is upregulated in salivary adenoid cystic carcinomaA-B, Survival of patients with breast cancer (A) or lung cancer (B) relative to different expression levels of NOTCH1 using KM Plotter from publicly available microarray data; C, Representative images for the expression of NOTCH1 by immunohistochemistry in normal salivary gland tissues (a), pleomorphic adenoma samples (b), and adenoid cystic carcinoma without (c) or with metastasis and recurrence (d) (Original magnification 400X).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196170&req=5

Figure 1: NOTCH1 is upregulated in salivary adenoid cystic carcinomaA-B, Survival of patients with breast cancer (A) or lung cancer (B) relative to different expression levels of NOTCH1 using KM Plotter from publicly available microarray data; C, Representative images for the expression of NOTCH1 by immunohistochemistry in normal salivary gland tissues (a), pleomorphic adenoma samples (b), and adenoid cystic carcinoma without (c) or with metastasis and recurrence (d) (Original magnification 400X).
Mentions: Both the overexpression and downregulation of NOTCH1 have been observed in human cancers when compared with normal samples. In this study, we first explored the expression of NOTCH1 in different human cancers in the Oncomine database. According to this public available database, NOTCH1 is mainly overexpressed in brain cancer (Fig S1A-B) [15], gastric cancer (Fig S1A and C) [16], colorectal cancer, leukemia, and ovarian cancer. In contrast, NOTCH1 has also been shown to be downregulated in breast cancer (Fig S1A and D) [17], lung cancer Fig S1A and E) [18], prostate cancer, kidney cancer, and myeloma. Gene expression data for these studies are available through the Oncomine database, as are the studies describing these results (http://www.oncomine.org). We also conducted an unbiased bioinformatic analysis of gene-expression profiles of 3355 patients with breast cancer [19], 1405 with lung cancer [20] and 1171 with ovarian cancer [21] using Kaplan-Meier (KM) Plotter, a meta-analysis-based biomarker assessment tool. This analysis tool utilizes Affymetrix gene-expression profiling data, which involve multiple probe sets for most genes. The results showed that higher expression of NOTCH1 (auto select best cut-off) was associated with poor prognosis and shorter relapse-free survival (RFS; P = 8*10−5, Fig. 1A) in breast cancer but better prognosis and longer overall survival (OS; P=4.4*10−7, Fig. 1B) in lung cancer, with no significant difference in ovarian cancer (data not shown). In our previous study, we found that NOTCH1 was upregulated in the highly metastatic adenoid cystic carcinoma cell line, ACC-M, compared with the low metastatic cell line, ACC-2, suggesting that NOTCH1 contributes to the metastasis of adenoid cystic carcinoma. Next, we investigated the expression of NOTCH1 in salivary adenoid cystic carcinoma using immunohistochemistry. As shown in Fig. 1C and Table 1, NOTCH1 expression was absent or very low in normal salivary gland tissues (except in the ductal cells). Low expression levels were detected in the pleomorphic adenoma samples and adenoid cystic carcinomas without metastasis and recurrence, whereas higher expression levels were observed in the adenoid cystic carcinoma with metastasis and recurrence (P<0.05). This result indicates that NOTCH1 might play an important role in the metastasis of adenoid cystic carcinoma.

Bottom Line: We silenced the expression of NOTCH1 and overexpressed activated NOTCH1 to elucidate the effects of NOTCH1 on proliferation, migration and invasion.NOTCH1 target genes were validated by real-time PCR.Overexpression of NOTCH1 in SACC cells promoted cell growth, migration and invasion, and knockdown of NOTCH1 inhibited cell proliferation in vitro and tumorigenicity in vivo by inducing cell apoptosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Preventive Dentistry, Affiliated Stomatological Hospital, Fujian Medical University, Fuzhou, China. These authors contributed equally to this work.

ABSTRACT

Background: Numerous studies have reported both the tumor-suppressive and oncogenic roles of the Notch pathway, indicating that Notch activity regulates tumor biology in a complex, context-dependent manner. The aim of the present study was to identify the role of NOTCH1 in the cell growth and metastasis of SACC.

Methods: We analyzed the expression of NOTCH1 in clinical SACC samples using immunohistochemical staining. We silenced the expression of NOTCH1 and overexpressed activated NOTCH1 to elucidate the effects of NOTCH1 on proliferation, migration and invasion. NOTCH1 target genes were validated by real-time PCR.

Results: Our results showed that NOTCH1 was upregulated in SACC tissues when compared with normal tissues, and this upregulation was further enhanced in SACC tissues with metastasis and recurrence when compared with SACC tissues without metastasis. Overexpression of NOTCH1 in SACC cells promoted cell growth, migration and invasion, and knockdown of NOTCH1 inhibited cell proliferation in vitro and tumorigenicity in vivo by inducing cell apoptosis.

Conclusions: The results of this study suggest that NOTCH1 plays a key role in the cell growth, anti-apoptosis, and metastasis of SACC. NOTCH1 inhibitors might therefore have potential therapeutic applications in treating SACC patients by inhibiting cancer cell growth and metastasis.

Show MeSH
Related in: MedlinePlus