Notch1 regulates invasion and metastasis of head and neck squamous cell carcinoma by inducing EMT through c-Myc

Inamura, Naoya; Kimura, Taichi; Wang, Lei; Yanagi, Hiroko; Tsuda, Masumi; Tanino, Mishie; Nishihara, Hiroshi; Fukuda, Satoshi; Tanaka, Shinya

doi:10.1016/j.anl.2016.08.003

Cited by 26 publications

(22 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…39,40,43 c-Myc is a key oncogene participating in the modulation of cell cycle and EMT signals. [44][45][46] In this study, we found that c-Myc expression was reduced in miR-296-3p-overexpressing NPC cells. Furthermore, we also observed that increased miR-296-3p expression obviously decreased nuclear c-Myc expression and induced c-Myc cytoplasm translocation.…”

Section: Discussionmentioning

confidence: 48%

miR-296-3p Negatively Regulated by Nicotine Stimulates Cytoplasmic Translocation of c-Myc via MK2 to Suppress Chemotherapy Resistance

Deng

Liu

et al. 2018

Molecular Therapy

View full text Add to dashboard Cite

This study aimed to identify mechanisms by which microRNA 296-3p (miR-296-3p) functions as a tumor suppressor to restrain nasopharyngeal carcinoma (NPC) cell growth, metastasis, and chemoresistance. Mechanistic studies revealed that miR-296-3p negatively regulated by nicotine directly targets the oncogenic protein mitogen-activated protein kinase-activated protein kinase-2 (Mapkapk2) (MK2). Suppression of MK2 downregulated Ras/Braf/Erk/Mek/c-Myc and phosphoinositide-3-kinase (PI3K)/Akt/c-Myc signaling and promoted cytoplasmic translocation of c-Myc, which activated miR-296-3p expression by a feedback loop. This ultimately inhibited cell cycle progression, epithelial-to-mesenchymal transition (EMT), and chemoresistance of NPC. In addition, nicotine as a key component of tobacco was observed to suppress miR-296-3p and thus elevate MK2 expression by inducing PI3K/Akt/c-Myc signaling. In clinical samples, reduced miR-296-3p as an unfavorable factor was inversely correlated with MK2 and c-Myc expression. These results reveal a novel mechanism by which miR-296-3p negatively regulated by nicotine directly targets MK2-induced Ras/Braf/Erk/Mek/c-Myc or PI3K/AKT/c-Myc signaling to stimulate its own expression and suppress NPC cell proliferation and metastasis. miR-296-3p may thus serve as a therapeutic target to reverse chemotherapy resistance of NPC.

show abstract

Section: Discussionmentioning

confidence: 48%

miR-296-3p Negatively Regulated by Nicotine Stimulates Cytoplasmic Translocation of c-Myc via MK2 to Suppress Chemotherapy Resistance

Deng

Liu

et al. 2018

Molecular Therapy

View full text Add to dashboard Cite

show abstract

“…Notch1 promotes EMT during cardiac development, involving down-regulation of epithelial markers (E-cadherin) and up-regulation of mesenchymal markers (Snail, Vimentin, and c-Myc) [ 31 – 33 ]. Notch1 mutations acting through a similar mechanism may also be involved in the EMT process of OSCC cells.…”

Section: Resultsmentioning

confidence: 99%

A novel Notch1 missense mutation (C1133Y) in the Abruptex domain exhibits enhanced proliferation and invasion in oral squamous cell carcinoma

et al. 2018

View full text Add to dashboard Cite

BackgroundNotch1 has been regarded as a fundamental regulator in tissue differentiation and stem cell properties. Recently, Notch1 mutations have been reported intensively both in solid tumors and in hematopoietic malignancies. However, little is known about the biological effect and the clinical implication of these reported mutations. Previously, we discovered several missense mutations in the Notch1 receptor in a Chinese population with oral squamous cell carcinoma (OSCC).MethodsWe selected a ‘hotspot’ mutation in the Abruptex domain (C1133Y). The expression of Notch1 was determined by western blot and real-time qPCR in OSCC cell lines transfected with pcDNA3.1-Notch1WT, pcDNA3.1-Notch1C1133Y, or pcDNA3.1 empty vector. CCK-8 assays were used to assess cell proliferation. Flow cytometry and western blot were used to confirm the alteration of cell cycle after transfection. Transwell assays and the detection of Epithelial-to-mesenchymal transition (EMT) markers were used to determine the invasive ability. The effects of Notch1 C1133Y mutation were analyzed by Immunofluorescence staining and the expression of EGFR-PI3K/AKT signaling.ResultsWe demonstrated that Notch1C1133Y mutation inactivated the canonical Notch1 signaling. We identified an oncogenic phenotype of this mutation by promoting cell proliferation, invasion and by inducing EMT in OSCC cell lines. We found that the Notch1C1133Y mutation exhibited a decreased S1-cleavage due to the impaired transport of Notch1 protein from the endoplasmic reticulum (ER) to the Golgi complex, which was consistent with the observation of the failure of the Notch1C1133Y mutated receptor to present at the cell surface. Importantly, the mutated Notch1 activated the EGFR-PI3K/AKT signaling pathway, which has been confirmed as an overwhelming modulator in OSCC.ConclusionsTaken together, our findings revealed for the first time a novel Notch1 mutation that enhances proliferation and invasion in OSCC cell lines. The Notch1 C1133Y mutation impairs the processing of notch1 protein and the critical links between the mutated Notch1 and the activated EGFR-PI3K/AKT signaling pathway.Electronic supplementary materialThe online version of this article (10.1186/s12935-017-0496-5) contains supplementary material, which is available to authorized users.

show abstract

“…Despite Notch1 has been reported to be mutated at a significant frequency in OSCC, the possible role and the consequence of the regulation of Notch1 signaling remain controversial (Inamura et al, ; Kwon et al, ; Purow et al, ; Weijzen et al, ). It has been previously found that the intracellular cleavage (S3) of Notch1 occurs between the amino acids Gly1753 and Val1754 in human in a highly conserved manner (Schroeter, Kisslinger, & Kopan, ; Figure a).…”

Section: Introductionmentioning

confidence: 99%

Membrane‐tethered Notch1 exhibits oncogenic property via activation of EGFR–PI3K–AKT pathway in oral squamous cell carcinoma

Zheng

Wang

Xiong

et al. 2018

Journal Cellular Physiology

View full text Add to dashboard Cite

Notch proteins are highly conserved cell surface receptors which play essential roles in cellular differentiation, proliferation, and apoptotic events at all stages of development. Recently, NOTCH1 mutations have been extensively observed in oral squamous cell carcinoma (OSCC) and are hinted to be Notch1-inactivating mutations. However, little is known about the biological effect of these reported mutations in OSCC. To mimic the inactivation of Notch1 due to inappropriate mutations and to determine the potential mechanisms, we utilized wild-type Notch1 vectors (Notch1 WT ) or mutant Notch1 vectors (Notch1 V1754L ) to transfect into OSCC cell lines. Membrane-tethered Notch1 induced by mutation was analyzed by immunofluorescence staining. γ-Secretase inhibitor PF-03084014 was utilized to determine the phenotype in the absence of endogenous Notch1 activation. Here we demonstrated that membrane-tethered Notch1 inactivated the canonical Notch1 signaling and oncogenic phenotypes were identified by promoting cell proliferation and invasion and by inducing epithelial-to-mesenchymal transition in cells. The γsecretase inhibitor PF-03084014 also showed distinct oncogenic property after treatment. Importantly, both membrane-tethered Notch1 and PF-03084014 inhibitor activated the epidermal growth factor receptor (EGFR)-phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway, which has been confirmed as an overwhelming modulator in OSCC. This was the first time that we clearly simulated the mutated Notch1 activities and determined the oncogenic phenotypes of membrane-tethered Notch1. Compared with wild-type Notch1, J Cell Physiol. 2019;234:5940-5952. wileyonlinelibrary.com/journal/jcp 5940 |

show abstract

Notch1 regulates invasion and metastasis of head and neck squamous cell carcinoma by inducing EMT through c-Myc

Cited by 26 publications

References 35 publications

miR-296-3p Negatively Regulated by Nicotine Stimulates Cytoplasmic Translocation of c-Myc via MK2 to Suppress Chemotherapy Resistance

miR-296-3p Negatively Regulated by Nicotine Stimulates Cytoplasmic Translocation of c-Myc via MK2 to Suppress Chemotherapy Resistance

A novel Notch1 missense mutation (C1133Y) in the Abruptex domain exhibits enhanced proliferation and invasion in oral squamous cell carcinoma

Membrane‐tethered Notch1 exhibits oncogenic property via activation of EGFR–PI3K–AKT pathway in oral squamous cell carcinoma

Contact Info

Product

Resources

About