Combined Erlotinib and PF‐03084014 treatment contributes to synthetic lethality in head and neck squamous cell carcinoma

Zheng, Yang; Wang, Zhao; Ding, Xu; Dong, Yibo; Zhang, Wei; Zhong, Yi; Gu, Wenyi; Wu, Yunong; Song, Xiaomeng

doi:10.1111/cpr.12424

Cited by 13 publications

(11 citation statements)

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“…EGFR-PI3K-AKT signal has been linked with oncogenic transformation, autonomous cell growth, invasion, angiogenesis, and development of metastases in oral cancers (Sos et al, 2015). Notch1 has been shown to interact with EGFR-PI3K-AKT pathway and thus to regulate cell proliferation and invasion (Kolev et al, 2012;Staberg et al, 2016;Zheng et al, 2017).…”

Section: Membrane-tethered Notch1 Enhanced Invasion and Induced Epithelial-to-mesenchymal Transition (Emt) In Oscc Cell Linesmentioning

confidence: 99%

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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

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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 |

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Section: Membrane-tethered Notch1 Enhanced Invasion and Induced Epithelial-to-mesenchymal Transition (Emt) In Oscc Cell Linesmentioning

confidence: 99%

“…Notch proteins are highly conserved cell surface receptors which play essential roles in cellular differentiation, proliferation, and apoptotic events at all stages of development (Jeffries & Capobianco, ; Sun et al, ; Zheng et al, ). Notch1 receptor is synthesized as a single 300‐kDa polypeptide in the endoplasmic reticulum (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

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“…Our previous study screened out miR-619-5p from exosomes of erlotinib-resistant cells [25]. Erlotinib is a classic inhibitor of the EGFR signaling pathway, and PI3K/AKT is a critical downstream signaling of EGFR, which is also essential in developing acquired drug resistance [48]. A relevant study implied that miR-32-5p in exosomes is able to induce multidrug resistance of liver cancer cells through activating the PI3K/AKT signaling pathway [49].…”

Section: Discussionmentioning

confidence: 99%

Involvement of miR-619-5p in resistance to cisplatin by regulating ATXN3 in oral squamous cell carcinoma

An¹,

Chu²,

Yang³

et al. 2021

Int. J. Biol. Sci.

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MicroRNAs are major post-transcriptional regulators responsible for the development of human cancers, including OSCC. The specific role of miR-619-5p in OSCC, however, is rarely reported. Cisplatin is one of the mostly applied chemotherapy drugs of OSCC. Nevertheless, drug resistance of cisplatin following the initial chemotherapy largely restricts its clinical benefits, and the mechanism of cisplatin resistance is unclear. This study intends to explore the biological function of miR-619-5p in the development of cisplatin resistance in OSCC cell lines and a xenograft model, as well as the potential molecular mechanism. Our results showed that miR-619-5p was down-regulated in OSCC samples and cisplatin-resistant OSCC cells. Ectopically expressed miR-619-5p inhibited proliferative, migratory and invasive abilities of OSCC cisplatin-resistant cells. The putative target gene ATXN3 was predicted by bioinformatic analysis and confirmed by dual-luciferase reporter assay. Importantly, ATXN3 was responsible for the regulatory effects of miR-619-5p on biological behaviors of cisplatin-resistant OSCC cells. Moreover, miR-619-5p mimics and ATXN3-siRNA significantly enhanced ATXN3 knockdown in both HN6/CDDPR and CAL27/CDDPR cells and inhibited expression of PI3K and AKT. In vivo evidences demonstrated that intratumoral injection of miR-619-5p agomir remarkably slowed down the growth of OSCC in xenograft mice. Collectively, microRNA-619-5p was the vital regulator for regulating cisplatin resistance of OSCC, which may be served as a potential therapeutic target.

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“…The CAL27 and HEK293T (293T) cell lines were obtained from the American Type Culture Collection (ATCC). Human HNSCC WSU-HN4 and WSU-HN6 (hereafter simplified to HN4 and HN6) cell lines were obtained from Dr. Silvio Gutkind of the NIH (Bethesda, MD) [ 24 , 25 ]. CAL27 cells (authenticated at July 2017) and HEK293T cells (authenticated at March 2018) were tested by short tandem repeat testing done in the Fragment Analysis Facility, Tian Lin Biology and Technology Company (Shanghai, China).…”

Section: Methodsmentioning

confidence: 99%

MiR-876-5p modulates head and neck squamous cell carcinoma metastasis and invasion by targeting vimentin

et al. 2018

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BackgroundLocal or distant metastasis remains the main course of death in head and neck squamous cell carcinoma (HNSCC) patients. MicroRNAs (miRNAs) have been implicated in metastasis of HNSCC, but the mechanisms of their action are mainly undocumented. Through public head and neck cancer miRNA expression datasets, we found that miR-876-5p was a novel potential tumor suppressor targeting HNSCC metastasis.MethodsClinical significance and mechanism of miR-876-5P was systematically analyzed in HNSCC. Quantitative RT-PCR was used to evaluate miR-876-5p levels in HNSCC cell lines and in 20 pairs of HNSCC with associated regional nodal metastases and HNSCC without metastatic primary tumors. Scratch and invasion assays were evaluated to determine the role of miR-876-5p in the regulation of HNSCC cell migration and invasion, respectively. Western blotting was used to investigate the mechanism by which miR-876-5p suppresses HNSCC cell invasion and migration. Luciferase assays were performed to assess miR-876-5p binding to the vimentin gene. The animal model was used to support the in vitro experimental findings.ResultsMiR-876-5p mimics inhibited HNSCC cell migration and invasion. Vimentin protein and mRNA levels were decreased in the miR-876-5p mimics group but increased in the miR-876-5p inhibitors group, which demonstrated that miR-876-5p inhibits vimentin expression in HNSCC cells. By directly targeting the vimentin 3′-UTR, we used dual-luciferase reporter assays to verify that vimentin is a functional downstream target of miR-876-5p. Importantly, increased vimentin expression promoted cell migration and invasion, and co-transfection with miR-876-5p mimics and vimentin restored cell aggressiveness to the original level. Moreover, miR-876-5p overexpression significantly downregulated vimentin expression level and inhibited the distal metastasis of HNSCC cells in vivo.ConclusionsmiR-876-5p, which functions as a tumor suppressor in HNSCC, inhibits metastasis by targeting vimentin and provides a novel therapeutic target for HNSCC treatment.Electronic supplementary materialThe online version of this article (10.1186/s12935-018-0619-7) contains supplementary material, which is available to authorized users.

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Combined Erlotinib and PF‐03084014 treatment contributes to synthetic lethality in head and neck squamous cell carcinoma

Abstract: These results suggested that concomitant inhibition of the Notch1 and EGFR pathways represented a rational strategy for promoting apoptosis in HNSCC and overcoming treatment resistance.

Cited by 13 publications

References 46 publications

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

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

Involvement of miR-619-5p in resistance to cisplatin by regulating ATXN3 in oral squamous cell carcinoma

MiR-876-5p modulates head and neck squamous cell carcinoma metastasis and invasion by targeting vimentin

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