Differential expression of Notch1 intracellular domain and p21 proteins, and their clinical significance in gastric cancer

Luo, Dinghai; Zhou, Qin; Hu, Sunkuan; Xia, Yiqun; Xu, Chaochao; Lin, Tiesu; Pan, Yuting; Wu, Jiansheng; Jin, Rong

doi:10.3892/ol.2013.1751

Cited by 23 publications

(22 citation statements)

References 29 publications

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“…We found that Notch1 controls HEp-2 cell migration and invasion, although the underlying molecular mechanism remains unclear. Luo et al found that inhibition of NICD decreased tumor invasion in gastric cancer (30). Zhou et al reported that downregulation of Notch1 decreased HCC cell migration and invasion by regulating E-cadherin and CD44v6 (31).…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Functional studies implicate Notch signalling in essentially all of the hallmarks of cancer, being associated with abnormal expression, high mutation rate and poor survival in several cancers such as lung, breast, gastric or lymphoid cancer [7][8][9][10][11]. This oncogenic function of NOTCH in human cancers is related with its capacity to increase cell growth, centered on the ability to induce the expression of Myc [12,13] and to enhance PI3K-Akt signalling [14].…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2

Morrugares

Correa-Sáez

Moreno

et al. 2019

Cell. Mol. Life Sci.

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NOTCH proteins constitute a receptor family with a widely conserved role in cell cycle, growing and development regulation. NOTCH1, the best characterised member of this family, regulates the expression of key genes in cell growth and angiogenesis, playing an essential role in cancer development. These observations provide a relevant rationale to propose the inhibition of the intracellular domain of NOTCH1 (Notch1-IC) as a strategy for treating various types of cancer. Notch1-IC stability is mainly controlled by post-translational modifications. FBXW7 ubiquitin E3 ligase-mediated degradation is considered one of the most relevant, being the previous phosphorylation at Thr-2512 residue required. In the present study, we describe for the first time a new regulation mechanism of the NOTCH1 signalling pathway mediated by DYRK2. We demonstrate that DYRK2 phosphorylates Notch1-IC in response to chemotherapeutic agents and facilitates its proteasomal degradation by FBXW7 ubiquitin ligase through a Thr-2512 phosphorylation-dependent mechanism. We show that DYRK2 regulation by chemotherapeutic agents has a relevant effect on the viability, motility and invasion capacity of cancer cells expressing NOTCH1. In summary, we reveal a novel mechanism of regulation for NOTCH1 which might help us to better understand its role in cancer biology.

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“…Aberrant Notch signalling can often lead to the development of cancer. Our previous work showed that Notch1 intracellular domain (NICD) protein is overexpressed in GC tissues and is associated with overall patient survival, tumour metastasis and an advanced tumour stage [17]. In fact, expression of Notch1 and Hes1 was significantly higher in GC tissues than in normal tissues [18].…”

Section: Introductionmentioning

confidence: 99%

miR‐124 interacts with the Notch1 signalling pathway and has therapeutic potential against gastric cancer

Jiang

Lin

et al. 2015

J Cellular Molecular Medi

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Aberrant Notch signalling plays an important role in cancer progression. However, little is known about the interaction between miRNA and the Notch signalling pathway and its role in gastric cancer (GC). In this study, we found that miR‐124 was down‐regulated in GC compared with adjacent normal tissue. Forced expression of miR‐124 inhibited GC cell growth, migration and invasion, and induced cell cycle arrest. miR‐124 negatively regulated Notch1 signalling by targeting JAG1. miR‐124 levels were also shown to be inversely correlated with JAG1 expression in GC. Furthermore, we found that the overexpression of the intracellular domain of Notch1 repressed miR‐124 expression, promoted GC cell growth, migration and invasion. Conversely, blocking Notch1 using a γ‐secretase inhibitor up‐regulated miR‐124 expression, inhibited GC cell growth, migration and invasion. In conclusion, our data demonstrates a regulatory feedback loop between miR‐124 and Notch1 signalling in GC cells, suggesting that the miR‐124/Notch axis may be a potential therapeutic target against GC.

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Differential expression of Notch1 intracellular domain and p21 proteins, and their clinical significance in gastric cancer

Cited by 23 publications

References 29 publications

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

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

Phosphorylation-dependent regulation of the NOTCH1 intracellular domain by dual-specificity tyrosine-regulated kinase 2

miR‐124 interacts with the Notch1 signalling pathway and has therapeutic potential against gastric cancer

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