The NOTCH1-HEY1 pathway regulates self-renewal and epithelial-mesenchymal transition of salivary adenoid cystic carcinoma cells

Xie, Jing; Lin, Lisong; Huang, Xiaoyu; Gan, Rui‐Huan; Ding, Lin‐Can; Su, Bogong; Zhao, Yong; Lu, You‐Guang

doi:10.7150/ijbs.36407

Cited by 37 publications

(30 citation statements)

References 54 publications

(64 reference statements)

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“…Accumulating evidence provided more insights into CSCs and the complex effects of different signaling pathways may trigger the switch of tumor cells to a stem cell-like phenotype 34 - 36 . While PI3K/AKT and MAPK/ERK signaling pathways have been reported to be responsible for numerous oncogenic properties of lung adenocarcinoma 37 - 39 , yet the mechanistic characterization of self-renewal maintenance in lung cancer stem-like cells by manipulating oncogenic and stem cell signaling pathways remain limited and elusive.…”

Section: Discussionmentioning

confidence: 99%

Characteristics of the PI3K/AKT and MAPK/ERK pathways involved in the maintenance of self-renewal in lung cancer stem-like cells

Li¹,

Wang²,

Xie³

et al. 2021

Int. J. Biol. Sci.

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Lung cancer is the leading cause of cancer-related mortality worldwide due to its early asymptomatic and late metastasis. While cancer stem cells (CSCs) may play a vital role in oncogenesis and development of lung cancer, mechanisms underlying CSCs self‐renewal remain less clear. In the present study, we constructed a clinically relevant CSCs enrichment recognition model and evaluated the potential functions of phosphatidylinositol 3-kinase (PI3K)/AKT pathway (PI3K/AKT) and mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) pathways in lung cancer via bioinformatic analysis, providing the basis for in depth mechanistic inquisition. Experimentally, we confirmed that PI3K/AKT pathway predominantly promotes proliferation through anti-apoptosis in lung adenocarcinoma cells, while MAPK/ERK pathway has an overwhelming superiority in regulating the proliferation in lung CSCs. Further, utilizing stemness score model, LLC-Symmetric Division (LLC-SD) cells and mouse orthotopic lung transplantation model, we elucidated an intricate cross-talk between the oncogenic pathway and the stem cell reprograming pathway that impact stem cell characteristics as well as cancer biology features of lung CSCs both in vitro and in vivo . In summary, our findings uncovered a new insight that PI3K/AKT and MAPK/ERK pathways as oncogenic signaling pathway and/or stem cell signaling pathway act distinctively and synergistically to regulate lung CSCs self-renewal.

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Section: Discussionmentioning

confidence: 99%

Characteristics of the PI3K/AKT and MAPK/ERK pathways involved in the maintenance of self-renewal in lung cancer stem-like cells

Li¹,

Wang²,

Xie³

et al. 2021

Int. J. Biol. Sci.

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show abstract

“…The protein matrix metalloproteinases (MMPs) can degrade the extracellular matrix to promote tumor invasion 13 . Previous studies have shown that Hey1 can promote the EMT process and the expression of matrix metalloproteinases expression profile of tumor cells 14 - 16 . Here, Western blotting was used to detect the impact of Hey1 on the expression of EMT-related proteins in A375 cells.…”

Section: Resultsmentioning

confidence: 98%

Hey1 promotes migration and invasion of melanoma cells via GRB2/PI3K/AKT signaling cascade

Lei

Chen

et al. 2021

J. Cancer

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Increasing evidence indicates that Notch signaling regulates multiple intracellular biological processes in malignant melanoma. Whereas how Notch signaling is transduced to influence melanoma cell behaviors remains largely elusive. Here we show that the Notch signaling downstream target Hey1 promotes migration and invasion of melanoma cells via the GRB2/PI3K/AKT pathway. First, bioinformatics tools, immunohistochemistry, and Western blotting analysis showed that the expression of Hey1 is increased in melanoma. Then, both in vivo and in vitro experiments showed that Hey1 promotes the malignant behaviour of the melanoma cells. High-throughput RNA-sequencing analysis revealed that inhibition of Hey1 results in decreased GRB2 expression in melanoma cells. Last, functional experiments confirmed that Hey1 positively regulates GRB2/PI3K/AKT pathway to influence migration and invasion of melanoma cells. In summary, our results suggest that Hey1 promotes the invasion and metastasis of melanoma cells by regulating GRB2/PI3K/AKT pathway. Our study provides potential therapeutics in tumor biology.

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“…Notch1 was predicted to be a potential target of miR-34a based on miRs target prediction software (TargetScan, PicTar, and miRBase). e Notch1 signaling pathway is an apoptosis-related pathway that is involved in the apoptosis of various cell types [39][40][41]. Notch1 acts as an endogenous myocardial protective factor through the RISK/SAFE/HIF-1 alpha signaling, which reduces myocardial intracellular reactive oxygen species (ROS), enhances the myocardiocytes vitality, and significantly reduces the myocardial ischemia reperfusion injury [42].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-34a Promotes Ischemia-Induced Cardiomyocytes Apoptosis through Targeting Notch1

Pan

Zhou

et al. 2022

Evidence-Based Complementary and Alternative Medicine

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Myocardial apoptosis occurs during myocardial ischemia. This study aimed to determine the effect of microRNA-34a (miR-34a) in ischemia-induced myocardial apoptosis. Mainly, SD rats were subjected to myocardial ischemia by ligaturing the left anterior descending branch of coronary artery. After rats had myocardial infarction, HE staining and TUNEL staining confirmed a significant increase in apoptosis. The expression of miR-34a was noticeably upregulated, while the expression of Notch1 was downregulated. An increase in caspase-3 and a decrease in Bcl-2/Bax ratio were observed in myocardium. Similar results were observed in the in vitro model of cardiomyocyte ischemia and anoxia of this study. When rat cardiomyocytes were administered with serum starvation and microaerophilic system, apoptosis-related proteins were significantly increased. However, transfecting the miR-34a inhibitor into the cardiomyocyte before the serum starvation and hypoxia treatment could increase the ratio of Bcl-2/Bax and downregulate the expression of caspase-3, as well as prevent cardiomyocytes from apoptosis. As opposed to the abovementioned points, the upregulation of miR-34a expression by transfecting miR-34a mimics induced Notch1 reduce and apoptosis-related proteins increase apparently, while upregulation of Notch1 could stimulate apoptosis attributed to miR-34a. Mechanistically, we demonstrated that Notch1 is a direct target of miR-34a. In conclusion, our current results suggested that miR-34a significantly stimulates ischemia-induced cardiomyocytes apoptosis by targeting Notch1.

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The NOTCH1-HEY1 pathway regulates self-renewal and epithelial-mesenchymal transition of salivary adenoid cystic carcinoma cells

Cited by 37 publications

References 54 publications

Characteristics of the PI3K/AKT and MAPK/ERK pathways involved in the maintenance of self-renewal in lung cancer stem-like cells

Characteristics of the PI3K/AKT and MAPK/ERK pathways involved in the maintenance of self-renewal in lung cancer stem-like cells

Hey1 promotes migration and invasion of melanoma cells via GRB2/PI3K/AKT signaling cascade

MicroRNA-34a Promotes Ischemia-Induced Cardiomyocytes Apoptosis through Targeting Notch1

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