Nuclear translocation of IGF1R by intracellular amphiregulin contributes to the resistance of lung tumour cells to EGFR-TKI

Guerard, M.; Robin, Thomas; Perron, Pascal; Hatat, Anne‐Sophie; David-Boudet, Laurence; Vanwonterghem, Laetitia; Busser, Benoît; Coll, Jean‐Luc; Lantuéjoul, Sylvie; Eymin, Béatrice; Hurbin, Amandine; Gazzéri, Sylvie

doi:10.1016/j.canlet.2018.01.080

Cited by 20 publications

(29 citation statements)

References 33 publications

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“…Four target genes, BCL2L1, IGF1R, MAPK8, and FAS, regulated by exosomal let-7a-5p were identified. One of these genes, BCL2L1, is known to collaborate with SOX2 to promote cell proliferation in lung cancer [ 18 ]; nuclear translocation of IGF1R induced growth arrest and apoptosis resistance of lung cancer cells [ 19 ]. MAPK8 is associated with the production and elimination of reactive oxygen species (ROS), while FAS mainly participates in cellular apoptosis in lung cancer [ 20 ].…”

Section: Discussionmentioning

confidence: 99%

Downregulation of exosomal let-7a-5p in dust exposed- workers contributes to lung cancer development

et al. 2018

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BackgroundEither chronic or acute exposure to dust particles may lead to pneumoconiosis and lung cancer, and lung cancer mortality among patients diagnosed with pneumoconiosis is increasing. Utilizing genome-wide sequencing technology, this study aimed to identify methods to decrease the number of patients with pneumoconiosis who die from lung cancer.MethodsOne hundred fifty-four subjects were recruited, including 54 pneumoconiosis patients and 100 healthy controls. Exosomes were isolated from the venous blood of every subject. Distinctive miRNAs were identified using high throughput sequencing technology, and bioinformatics analysis predicted target genes involved in lung cancer as well as their corresponding biological functions. Moreover, cross-cancer alterations of genes related to lung cancer were investigated, and survival analysis was performed using 2437 samples with an average follow-up period of 49 months.ResultsLet-7a-5p was revealed to be downregulated by 21.67% in pneumoconiosis. Out of the 683 let-7a-5p target genes identified from bioinformatics analysis, four genes related to five signaling pathways were confirmed to be involved in lung cancer development. Alterations in these four target genes were then explored in 4105 lung cancer patients, and BCL2L1 and IGF1R were demonstrated to be aberrantly expressed. Survival analysis further revealed that high expression of BCL2L1 corresponded to reduced survival of lung cancer patients (HR (95%CI) = 1.75(1.33~2.30)), while patient survival time was unaffected by expression of IGF1R (HR (95%CI) = 1.15 (0.98~1.36)).ConclusionsIn patients with lung adenocarcinoma, simultaneous downregulation of exosomal let-7a-5p and elevated expression of BCL2L1 are useful as predictive biomarkers for poor survival.

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Section: Discussionmentioning

confidence: 99%

Downregulation of exosomal let-7a-5p in dust exposed- workers contributes to lung cancer development

et al. 2018

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“…BRAF secondary mutations have also been implicated to EGFR-TKI resistance [ 15 ]. In recent studies, PAK1 activation, upregulation of BCL2, elevation of CDKN1A (p21), overexpression of PHGDH and IGF1R related with acquire resistance [ 2 , 16 – 19 ]. To sum up, so many mechanisms of drug resistance are very harmful to the target treatment of patients.…”

Section: Introductionmentioning

confidence: 99%

Investigate the mechanisms of Chinese medicine Fuzhengkangai towards EGFR mutation-positive lung adenocarcinomas by network pharmacology

Bing

Cheng²,

Shi

et al. 2018

BMC Complement Altern Med

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BackgroundChinese traditional herbal medicine Fuzhengkangai (FZKA) formulation combination with gefitinib can overcome drug resistance and improve the prognosis of lung adenocarcinoma patients. However, the pharmacological and molecular mechanisms underlying the active ingredients, potential targets, and overcome drug resistance of the drug are still unclear. Therefore, it is necessary to explore the molecular mechanism of FZKA.MethodsA systems pharmacology and bioinformatics-based approach was employed to investigate the molecular pathogenesis of EGFR-TKI resistance with clinically effective herb formula. The differential gene expressions between EGFR-TKI sensitive and resistance cell lines were calculated and used to find overlap from targets as core targets. The prognosis of core targets was validated from the cancer genome atlas (TCGA) database by Cox regression. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment is applied to analysis core targets for revealing mechanism in biology.ResultsThe results showed that 35 active compounds of FZKA can interact with eight core targets proteins (ADRB2, BCL2, CDKN1A, HTR2C, KCNMA1, PLA2G4A, PRKCA and LYZ). The risk score of them were associated with overall survival and relapse free time (HR = 6.604, 95% CI: 2.314–18.850; HR = 5.132, 95% CI: 1.531–17.220). The pathway enrichment suggested that they involved in EGFR-TKI resistance and non-small cell lung cancer pathways, which directly affect EGFR-TKI resistance. The molecular docking showed that licochalcone a and beta-sitosterol can closely bind two targets (BCL2 and PRKCA) that involved in EGFR-TKI resistance pathway.ConclusionsThis study provided a workflow for understanding mechanism of CHM for against drug resistance.Electronic supplementary materialThe online version of this article (10.1186/s12906-018-2347-x) contains supplementary material, which is available to authorized users.

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“…At physiological levels, insulin and IGF-1 fully activate their cognate receptors, IGF-1 can also activate IR/IGF1R hybrid receptors, and at supraphysiological levels they can also bind and activate the other receptor in cell culture models, although with reduced affinity [ 38 ]. Today it is known that IGF1R is involved in mitogenesis, transformation and protection from apoptosis [ 39 , 40 ]. A pivotal role of IGF1R signaling in esophageal cancer onset in our animal model was first suggested by the high activation level of the IGF1R in dysplastic and cancer tissues of WT normoinsulinemic mice, suggesting that IGF1R is involved in duodenal reflux-dependent esophageal carcinogenesis even in the absence of hyperinsulinemia.…”

Section: Discussionmentioning

confidence: 99%

Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model

Arcidiacono

Dedja

Giacometti

et al. 2018

IJMS

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Hyperinsulinemia could have a role in the growing incidence of esophageal adenocarcinoma (EAC) and its pre-cancerous lesion, Barrett’s Esophagus, a possible consequence of Gastro-Esophageal Reflux Disease. Obesity is known to mediate esophageal carcinogenesis through different mechanisms including insulin-resistance leading to hyperinsulinemia, which may mediate cancer progression via the insulin/insulin-like growth factor axis. We used the hyperinsulinemic non-obese FVB/N (Friend leukemia virus B strain) MKR (muscle (M)-IGF1R-lysine (K)-arginine (R) mouse model to evaluate the exclusive role of hyperinsulinemia in the pathogenesis of EAC related to duodeno-esophageal reflux. FVB/N wild-type (WT) and MKR mice underwent jejunum-esophageal anastomosis side—to end with the exclusion of the stomach. Thirty weeks after surgery, the esophagus was processed for histological, immunological and insulin/Insulin-like growth factor 1 (IGF1) signal transduction analyses. Most of the WT mice (63.1%) developed dysplasia, whereas most of the MKR mice (74.3%) developed squamous cell and adenosquamous carcinomas, both expressing Human Epidermal growth factor receptor 2 (HER2). Hyperinsulinemia significantly increased esophageal cancer incidence in the presence of duodenal-reflux. Insulin receptor (IR) and IGF1 receptor (IGF1R) were overexpressed in the hyperinsulinemic condition. IGF1R, through ERK1/2 mitogenic pattern activation, seems to be involved in cancer onset. Hyperinsulinemia-induced IGF1R and HER2 up-regulation could also increase the possibility of forming of IGF1R/HER2 heterodimers to support cell growth/proliferation/progression in esophageal carcinogenesis.

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Nuclear translocation of IGF1R by intracellular amphiregulin contributes to the resistance of lung tumour cells to EGFR-TKI

Cited by 20 publications

References 33 publications

Downregulation of exosomal let-7a-5p in dust exposed- workers contributes to lung cancer development

Downregulation of exosomal let-7a-5p in dust exposed- workers contributes to lung cancer development

Investigate the mechanisms of Chinese medicine Fuzhengkangai towards EGFR mutation-positive lung adenocarcinomas by network pharmacology

Hyperinsulinemia Promotes Esophageal Cancer Development in a Surgically-Induced Duodeno-Esophageal Reflux Murine Model

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