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

Su, Bogong; Qu, Jing; Song, Min Suk; Huang, Xiaoyu; Hu, Xiaomeng; Xie, Jian; Zhao, Yong; Ding, Lin‐Can; Shen, Lin; Chen, Jiang; Lin, Lisong; Lin, Xu; Zheng, Dali; Lu, You‐Guang

doi:10.18632/oncotarget.2321

Cited by 54 publications

(47 citation statements)

References 31 publications

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“…The role of NOTCH in carcinogenesis has been explored in a mouse model in which an activated NOTCH4 transgene induces neoplastic transformation of mammary and all three major salivary glands . Overexpression of NOTCH1 in ACC has been recently described and associated with cancer progression . Finally, NOTCH1‐activating mutations recently reported in high‐grade ACC specimens support NOTCH1 as a driver of aggressiveness in ACC.…”

Section: Resultsmentioning

confidence: 60%

“…130 Overexpression of NOTCH1 in ACC has been recently described and associated with cancer progression. 131 Finally, NOTCH1-activating mutations recently reported in highgrade ACC specimens 71,83 support NOTCH1 as a driver of aggressiveness in ACC. Similar activating mutations in NOTCH1-3 occur in basal-like breast cancer, 132,133 for which NOTCH1 activation is also implicated in breast cancer progression, chemotherapy resistance, and stimulation of breast CSCs.…”

Section: Sox10mentioning

confidence: 92%

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Clinical and molecular insights into adenoid cystic carcinoma: Neural crest‐like stemness as a target

Yarbrough

Panaccione

Chang

et al. 2016

Laryngoscope Investig Oto

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ObjectivesThis review surveys trialed therapies and molecular defects in adenoid cystic carcinoma (ACC), with an emphasis on neural crest‐like stemness characteristics of newly discovered cancer stem cells (CSCs) and therapies that may target these CSCs.Data SourcesArticles available on Pubmed or OVID MEDLINE databases and unpublished data.Review MethodsSystematic review of articles pertaining to ACC and neural crest‐like stem cells.ResultsAdenoid cystic carcinoma of the salivary gland is a slowly growing but relentless cancer that is prone to nerve invasion and metastases. A lack of understanding of molecular etiology and absence of targetable drivers has limited therapy for patients with ACC to surgery and radiation. Currently, no curative treatments are available for patients with metastatic disease, which highlights the need for effective new therapies. Research in this area has been inhibited by the lack of validated cell lines and a paucity of clinically useful markers. The ACC research environment has recently improved, thanks to the introduction of novel tools, technologies, approaches, and models. Improved understanding of ACC suggests that neural crest‐like stemness is a major target in this rare tumor. New cell culture techniques and patient‐derived xenografts provide tools for preclinical testing.ConclusionPreclinical research has not identified effective targets in ACC, as confirmed by the large number of failed clinical trials. New molecular data suggest that drivers of neural crest‐like stemness may be required for maintenance of ACC; as such, CSCs are a target for therapy of ACC.

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Section: Resultsmentioning

confidence: 60%

Section: Sox10mentioning

confidence: 92%

Clinical and molecular insights into adenoid cystic carcinoma: Neural crest‐like stemness as a target

Yarbrough

Panaccione

Chang

et al. 2016

Laryngoscope Investig Oto

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“…A number of studies have confirmed that Notch1 is mainly upregulated in the brain (44), gastric cancer (45), colorectal cancer, leukemia, ovarian cancer and HCC (29). In contrast, Notch1 has also been shown to be downregulated in lung (46), breast (47), prostate, kidney cancer and myeloma (48). It has been shown that Notch1 is involved in tumor cell invasion in pancreatic, breast cancer, lingual squamous cell carcinoma and HCC (25)(26)(27)(28).…”

Section: Discussionmentioning

confidence: 99%

Fbxw7 regulates hepatocellular carcinoma migration and invasion via Notch1 signaling pathway

Wang

Zhang²,

Zhou³

et al. 2015

International Journal of Oncology

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Abstract. Hepatocellular carcinoma (HCC) is one of the most common human malignancies and also the leading cause of cancer-related death in the world. The mechanisms underlying the progression and metastasis of HCC remain unclear. The E3 ubiquitin ligase F-box and WD repeat domain-containing 7 (Fbxw7) is broadly considered as a tumor suppressor gene. However, the role of Fbxw7 in HCC is not clear. To investigate the expression and biological functions of Fbxw7 in HCC, we examined Fbxw7 expression level using HCC tissue microarray and immunohistochemistry. Our data showed that Fbxw7 expression is significantly reduced in HCC compared with non-cancerous tissues (P<0.05). Fbxw7 levels were significantly associated with tumor differentiation (P= 0.013), the incidence of portal or hepatic venous invasion (P=0.031), metastasis (P= 0.027) and AJCC cancer stage (P= 0.047). Then, we observed a strong correlation between low Fbxw7 expression and a worse 5-year survival of HCC patients (P<0.001). Furthermore, multivariate Cox regression analyses demonstrated that the Fbxw7 expression (P<0.001) was an independent factor for the prediction of the overall survival of HCC patients. We also found that both Fbxw7 mRNA and protein levels were significantly reduced in HCC cell lines compared with human liver non-tumor cell line. Moreover, our in vitro experiments showed a remarkable increase of cell migration and invasion in Fbxw7-knockdown cells and a decrease in Fbxw7-overexpress cells. In addition, the present study demonstrated that Fbxw7 is involved in the migration and invasion of HCC cells via regulating Notch1 and the downstream molecules of Notch1. Taken together, our findings indicate that Fbxw7 can be used as a prognostic marker; it has an important role in HCC progression and inhibits HCC cell migration and invasion through the Notch1 signaling pathway.

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“…Therefore, Notch receptor-ligand interaction occurs between two adjacent cells. Notch proteins are synthesized as precursors in the endoplasmic reticulum, and then the Notch intracellular domain (NICD) is released, translocating to the nucleus, driving the expression of HEY1, HES1, Myc, CCND1, Bcl-2 and other cellular process-regulating genes involved in proliferation, differentiation, stem cell maintenance and apoptosis (5).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of Notch1 induces apoptosis and inhibits cell proliferation and metastasis in laryngeal squamous cell carcinoma

et al. 2015

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Notch signaling plays a key role in a wide variety of human tumors; it can be an oncogene or a tumor-suppressor gene depending on the tissue context. The functions of Notch1 in laryngeal squamous cell carcinoma (LSCC) are largely unknown. We investigated the role of Notch1 in LSCC cell growth, apoptosis and metastasis. We analyzed Notch1 expression in clinical LSCC samples using quantum dot immunohistochemistry (QD-IHC) and conventional IHC. Human laryngeal carcinoma HEp-2 cells were transfected with Notch1-specific short hairpin RNA (shRNA), and cell proliferation, apoptosis, and migration and invasion were evaluated using the cell counting assay, flow cytometry and wound healing and Transwell assays, respectively; western blotting was used to validate the expression of Notch1 target genes. Compared with normal tissues, Notch1 was upregulated in LSCC tissues; compared with LSCC tissues without metastasis, Notch1 upregulation was enhanced in LSCC tissues with metastasis (P<0.05). Transfection downregulated Notch1 mRNA and protein expression levels in the Notch1 shRNA group. There was a significantly greater decrease in cell proliferation in the Notch1 shRNA group than cell proliferation in the non-transfected (P<0.05) and negative shRNA groups (P<0.05). Furthermore, Notch1 knockdown induced apoptosis in the HEp-2 cells. Additionally, the number of migrated and invasive cells in the Notch1 shRNA group was decreased (P<0.05). Notch1 knockdown in the HEp-2 cells greatly inhibited phosphorylated extracellular signal-related kinase (p-ERK), phosphorylated protein kinase B (p-AKT), c-Myc, Bcl-2, p21, cyclin D1, cyclin-dependent kinase 4 (CDK4) and cyclin E expression levels and increased Bax expression. Altogether, our findings indicate that Notch1 expression is increased in human LSCC and correlates with tumorigenesis and metastasis, while in HEp-2 cells, Notch1 knockdown inhibited cell growth, induced apoptosis and inhibited migration and invasion by regulating Notch1 target genes, suggesting it may be a potential therapeutic target for treating LSCC.

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

Cited by 54 publications

References 31 publications

Clinical and molecular insights into adenoid cystic carcinoma: Neural crest‐like stemness as a target

Clinical and molecular insights into adenoid cystic carcinoma: Neural crest‐like stemness as a target

Fbxw7 regulates hepatocellular carcinoma migration and invasion via Notch1 signaling pathway

Downregulation of Notch1 induces apoptosis and inhibits cell proliferation and metastasis in laryngeal squamous cell carcinoma

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