Increased expression of EHF via gene amplification contributes to the activation of HER family signaling and associates with poor survival in gastric cancer

Shi, Jing; Qu, Yiping; Li, Xinru; Sui, Fang; Yao, Demao; Yang, Qi; Shi, Bingyin; Ji, Meiju; Hou, Peng

doi:10.1038/cddis.2016.346

Cited by 47 publications

(41 citation statements)

References 47 publications

(60 reference statements)

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“…In breast cancer ProteoMix discovers three novel differentially methylated genes of diverse biological functions. ProteoMix detects a functional effect of hypo-methylation in the untranslated region (UTR) of EHF, which is a well-studied transcription factor involved in HER2 mediated epithelial differentiation (35); a likely oncogene, knockdown of EHF has been shown to inhibit tumor invasion and proliferation (36). Next, ProteoMix identifies hyper-methylation of FSTL1, an autoantigen that promotes immune response.…”

Section: Resultsmentioning

confidence: 99%

Proteogenomic view of cancer epigenetics: the impact of DNA methylation on the cancer proteome

Prunello

Brennan

et al. 2018

Preprint

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Aberrant DNA methylation disrupts normal gene expression in cancer and broadly contributes to oncogenesis. We previously developed MethylMix, a model-based algorithmic approach to identify epigenetically regulated driver genes. MethylMix identifies genes where methylation likely executes a functional role by using transcriptomic data to select only methylation events that can be linked to changes in gene expression. However, given that proteins more closely link genotype to phenotype recent high-throughput proteomic data provides an opportunity to more accurately identify functionally relevant abnormal methylation events. Here we present ProteoMix, which refines nominations for epigenetic driver genes by leveraging quantitative highthroughput proteomic data to select only genes where DNA methylation is predictive of protein abundance. Applying our algorithm across three cancer cohorts we find that ProteoMix narrows candidate nominations, where the effect of DNA methylation is often buffered at the protein level. Next, we find that ProteoMix genes are enriched for biological processes involved in cancer including functions involved in epithelial and mesenchymal transition. ProteoMix results are also enriched for tumor markers which are predictive of clinical features like tumor stage and we find clustering on ProteoMix genes captures cancer subtypes.

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Section: Resultsmentioning

confidence: 99%

Proteogenomic view of cancer epigenetics: the impact of DNA methylation on the cancer proteome

Prunello

Brennan

et al. 2018

Preprint

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“…EHF was recently described to regulate HER3 levels in thyroid 57 and gastric cancer 58 and highlights its role in tumor progression. We showed that MET activation limits the cetuximab-induced HER2/HER3 mRNA levels.…”

Section: Discussionmentioning

confidence: 99%

“…We further identified that EHF is the TF that regulates HER2/HER3 expression following cetuximab administration. EHF was recently described to regulate HER3 levels in thyroid 57 and gastric cancer 58 and highlights its role in tumor progression. 67 However, here we also show that EHF plays a key role in the resistance to cetuximab by mediating the HER2/HER3 compensatory feedback loop.…”

Section: Discussionmentioning

confidence: 99%

“…Next, we investigated the transcriptional machinery that regulates the increased HER2/HER3 expression following treatment with cetuximab. There are several TFs known to regulate HER2/HER3 expression in cancer, such as AP-2, 56 EHF, 57,58 FOXO3, 30,31,59 FOXO1 31 and ZNF217. 60 To prioritize these TF candidates for validation, we first explored the correlation between each of them with HER2 and HER3 expression in the HNSCC datasets of the TCGA Data Portal.…”

Section: Ehf Regulates Her2 and Her3 Gene Expression Following Cetuximentioning

confidence: 99%

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MET activation confers resistance to cetuximab, and prevents HER2 and HER3 upregulation in head and neck cancer

Novoplansky

Fury

Prasad

et al. 2019

Intl Journal of Cancer

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An understanding of the mechanisms underlying acquired resistance to cetuximab is urgently needed to improve cetuximab efficacy in patients with head and neck squamous cell carcinoma (HNSCC). Here, we present a clinical observation that MET pathway activation constitutes the mechanism of acquired resistance to cetuximab in a patient with HNSCC. Specifically, RNA sequencing and mass spectrometry analysis of cetuximab‐sensitive (CetuxSen) and cetuximab‐resistant (CetuxRes) tumors indicated MET amplification and overexpression in the CetuxRes tumor compared to the CetuxSen lesion. Stimulation of MET in HNSCC cell lines was sufficient to reactivate the MAPK pathway and to confer resistance to cetuximab in vitro and in vivo. In addition to the direct role of MET in reactivation of the MAPK pathway, MET stimulation abrogates the well‐known cetuximab‐induced compensatory feedback loop of HER2/HER3 expression. Mechanistically, we showed that the overexpression of HER2 and HER3 following cetuximab treatment is mediated by the ETS homologous transcription factor (EHF), and is suppressed by MET/MAPK pathway activation. Collectively, our findings indicate that evaluation of MET and HER2/HER3 in response to cetuximab in HNSCC patients can provide the rationale of successive line of treatment.

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“…IHC assay was carried out to evaluate the levels of Ki67 in the xenograft tumors. The detailed protocol was described previously [21].…”

Section: Immunohistochemistry (Ihc)mentioning

confidence: 99%

MiR-218 inhibits malignant phenotypes of glioma by targeting TNC/AKT/AP-1/TGFβ1 feedback signaling loop

Dang

Zhang

Tian

et al. 2020

Preprint

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Background: Gliomas are the most common and malignant tumors in the brain of humans, and the prognosis of glioma patient is very poor. MicroRNAs (miRNAs) play critical roles in different types of cancer by regulating gene expression at the posttranscriptional levels. Although miR-218 has been reported to be downregulated in gliomas, its role in gliomas still remains largely unknown.Methods: MiR-218 expression in gliomas and normal brain tissues (control subjects) were analyzed using TCGA dataset. The biological roles of miR-218 in glioma cells were determined by a series of in vitro and in vivo studies. The dual-luciferase reporter system was performed to identify potential targets of miR-218. The regulatory effect of miR-218 on TNC/AKT/AP-1/TGFβ1 pathway was evaluated by dual-luciferase reporter system and western blot. Results:We demonstrated miR-218 was significantly downregulated in gliomas compared to control subjects, and exerted a potent tumor suppressor in glioma cells by inhibiting cell proliferation, colony formation, migration, invasion and tumorigenic potential in nude mice, as well as inducing cell cycle arrest and apoptosis.Mechanistically, miR-218 inhibited malignant phenotypes of glioma cells by binding to the 3' UTR of its target TNC and subsequently repressing its expression. As a result, it could reduce AKT phosphorylation and subsequently inhibit transcriptional activity of AP-1 by reducing JNK phosphorylation, downregulating the expression of TGFβ1, while TGFβ1 is able to, in turn, activate the TNC/AKT/AP-1 signaling axis. Conclusions:Our data uncover a previously unknown tumor suppressor role of miR-218 in glioma by blocking the TNC/AKT/AP-1/TGFβ1 positive feedback loop. BackgroundGliomas are the most common and malignant tumors in the brain of humans, which represent about 70% of all brain tumors [1]. The current standard of care for newly diagnosed gliomas patients includes maximal safe surgical resection, followed by a combination of radiation and chemotherapy [2,3]. However, despite these treatment, overall survival rate of the patients suffering from glioma is among the lowest of all the main types of cancer and has not improved during recent decades [4].

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Increased expression of EHF via gene amplification contributes to the activation of HER family signaling and associates with poor survival in gastric cancer

Cited by 47 publications

References 47 publications

Proteogenomic view of cancer epigenetics: the impact of DNA methylation on the cancer proteome

Proteogenomic view of cancer epigenetics: the impact of DNA methylation on the cancer proteome

MET activation confers resistance to cetuximab, and prevents HER2 and HER3 upregulation in head and neck cancer

MiR-218 inhibits malignant phenotypes of glioma by targeting TNC/AKT/AP-1/TGFβ1 feedback signaling loop

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