ETS2 Mediated Tumor Suppressive Function and MET Oncogene Inhibition in Human Non–Small Cell Lung Cancer

Kabbout, Mohamed; Garcia, Melinda; Fujimoto, Junya; Liu, Diane D.; Woods, Denise M.; Chow, Chi Wan; Mendoza, Gabriela; Momin, Amin A.; James, Brian P.; Solis, Luisa M.; Behrens, Carmen; Lee, John; Wistuba, Ignacio I.; Kadara, Humam

doi:10.1158/1078-0432.ccr-13-0341

Cited by 163 publications

(246 citation statements)

References 43 publications

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“…RNA expression data revealed that the overall level of expression of ETS2 was unchanged in this tumor, although the levels of exons 7 and 8 were markedly reduced, suggesting that exon skipping occurs as a result of viral integration. ETS2 is a tumor suppressor gene (35), and previous reports have shown that truncated ETS family proteins may act in a dominant negative fashion (36). Our findings suggest that insertion of viral sequences into one of two copies could result in the loss of function of this gene.…”

Section: Hpv Integrations Are Associated With Somatic Alterations Of Keysupporting

confidence: 49%

Characterization of HPV and host genome interactions in primary head and neck cancers

Parfenov¹,

Pedamallu²,

Gehlenborg³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twentyfive cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter-and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.cancer | head and neck | papilloma virus | genome rearrangement | integration sites H ead and neck cancer (HNC) is a heterogeneous group of tumors characterized by a common anatomic origin, and most such tumors develop from within the mucosa and are classified as head and neck squamous cell carcinomas (HNSCCs) (1). HNSCC, the sixth most common cancer diagnosed worldwide and the eighth most common cause of cancer death (2), is frequently associated with human papillomavirus (HPV) infection (3, 4). Depending on the anatomic site of the tumor, HPV prevalence is estimated at 23-36% (5). HPV-positive HNSCCs form a distinct subset of HNCs that differs from HPV-negative HNSCCs in tumor biology and clinical characteristics, including superior clinical outcomes (6-9).The molecular pathogenesis of HPV-driven HNSCC also seems distinct from HPV-negative tumors, with previous studies showing a divergent spectrum of alterations in gene expression, mutations, amplifications, and deletions as well as distinct epigenome alterations (10-15). HPV is known to drive tumorigenesis through the actions of its major oncoproteins E6 and E7, which target numerous cellular pathways, including inactivation of p53 and the retinoblastoma (Rb) protein (16-18). Together with E5, they also play an important role in immune evasion, being involved in both innate and adaptive immunity (19,20).Initially after infection, HPV is identified in circular extrachromosomal particles or episomes. A critical step in progression to cancer is the integration of viral DNA into the host cell Significance A significant proportion of head and neck cancer is driven by human papil...

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Section: Hpv Integrations Are Associated With Somatic Alterations Of Keysupporting

confidence: 49%

Characterization of HPV and host genome interactions in primary head and neck cancers

Parfenov¹,

Pedamallu²,

Gehlenborg³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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338

474

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“…The mRNA expression profile data of GSE43458 [12], including 80 lung cancer samples and 30 normal samples, was downloaded from the GEO (Gene Expression Omnibus) database in NCBI (National Center for Biotechnology Information) (http://www. ncbi.nlm.nih.gov/geo/) based on the platform of GPL6244 [HuGene-1_0-st] Affymetrix Human Gene 1.0 ST Array [transcript (gene) version].…”

Section: Methodsmentioning

confidence: 99%

“…Chan et al [11] used the GSE43458 microarrays to construct the molecular probes for lung cancer, while Kabbout et al [12] proved the suppression role of ETS2 in human non-small lung cancer cells by inhibiting of the MET proto-oncogene using the same profile data. In this study, we used the microarray analysis to screen the differentially expressed genes (DEGs) in lung cancer based on the mRNA microarray GSE43458 and SNP microarray GSE33355.…”

mentioning

confidence: 99%

Identification of lung cancer oncogenes based on the mRNA expression and single nucleotide polymorphism profile data

Y¹,

Mei²,

Yq³

et al. 2015

neo

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This study aimed to identify the oncogenes associated with lung cancer based on the mRNA and single nucleotide polymorphism (SNP) profile data. The mRNA expression profile data of GSE43458 (80 cancer and 30 normal samples) and SNP profile data of GSE33355 (61 pairs of lung cancer samples and control samples) were downloaded from Gene Expression Omnibus database. Common genes between the mRNA profile and SNP profile were identified as the lung cancer oncogenes. Risk subpathways of the selected oncogenes with the SNP locus were analyzed using the iSubpathwayMiner package in R. Moreover, protein-protein interaction (PPI) network of the oncogenes was constructed using the HPRD database and then visualized using the Cytoscape. Totally, 3004 DEGs (1105 up-regulated and 1899 down-regulated) and 125 significant SNPs closely related to 174 genes in the lung cancer samples were identified. Also, 39 common genes, like PFKP (phosphofructokinase, platelet) and DGKH-rs11616202 (diacylglycerol kinase, eta) that enriched in sub-pathways such as galactose metabolism, fructose and mannose metabolism, and pentose phosphate pathway, were identified as the lung cancer oncogenes. Besides, PIK3R1 (phosphoinositide-3-kinase, regulatory subunit 1), RORA (RAR-related orphan receptor A), MAGI3 (membrane associated guanylate kinase, WW and PDZ domain containing 3), PTPRM (protein tyrosine phosphatase, receptor type, M), and BMP6 (bone morphogenetic protein 6) were the hub genes in PPI network. Our study suggested that PFKP and DGKH that enriched in galactose metabolism, fructose and mannose metabolism pathway, as well as PIK3R1, RORA, and MAGI3, may be the lung cancer oncogenes. Key words: lung cancer, single nucleotide polymorphism (SNP), function analysis, differentially expressed gene, oncogenesAbbreviations: SNP -single nucleotide polymorphism; PPI -proteinprotein interaction; DEGs -differentially expressed genes Lung cancer is one of the most common malignancies with an increasing morbidity and mortality and is a worldwide leading cause of cancer-related death with a 5-year survival rate from 13% to 15% [1]. Mechanism of lung cancer is complicate, mainly due to the late diagnosis and lack of effective treatment [2]. Therefore, underlying the molecular profiles of lung cancer as well as elucidating the roles of oncogenes and tumor suppressors in the development of this malignancy is expected to identify the molecular targets for lung cancer prediction and treatment.Previous studies have demonstrated that environmental factors like smoking and air pollution, and gene polymorphisms were the main factors contributing to the lung cancer progression and metastasis [3]. Chemical constituents in tobacco smoke including compounds of the carcinogenic polycyclic type were the carcinogen for lung cancer [4]. A previous study reveals that mutations of the tumor suppressor genes are a main reason for lung cancer progression, such as the prevalence of p53 mutational patterns G to T transversions is 30% and p53 mutations in lung cancer can be attribu...

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“…The cells were stained with methyl violet prior to end of the incubation and the number of colonies was counted under a light microscope (Olympus Corporation, Tokyo, Japan). (11). Genes that were significantly differentially expressed in cells, with or without WWOX overexpression, were selected based on exhibiting P<0.05 and a 1.5-fold-change (FC).…”

Section: Cellmentioning

confidence: 99%

Exploring the mechanism of WWOX growth inhibitory effects on oral squamous cell carcinoma

et al. 2017

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Abstract. Oral squamous cell carcinoma (OSCC) is one of the most common types of head and neck neoplasms in the world. Patients diagnosed with OSCC exhibit a poor prognosis. WW domain-containing oxidoreductase (WWOX), as a candidate tumor-suppressor gene, is involved in the genesis and progression of tumors. The deletion of the WWOX gene has been identified in OSCC and oral leukoplakia, but the function and mechanism of WWOX in OSCC remain unknown. Therefore, the present study investigated the role of WWOX in oral squamous carcinoma cells. The results revealed that an elevation of WWOX expression had an inhibitory effect on the growth of three types of oral squamous carcinoma cells, with the most evident effect occurring in Tca8113 cells. Also, in the Tca8113 cells, WWOX overexpression significantly inhibited colony formation, and induced apoptosis and cell cycle arrest. Microarray analysis, reverse transcription-quantitative polymerase chain reaction and western blotting methods detected that WWOX overexpression contributed to the differential expression of the genes involved in mediating the extracellular-signal regulated protein kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway. These results suggest that the tumor-suppressor function of the WWOX gene may be associated with the modulation of the ERK/MAPK signaling pathway, thus providing a novel target for OSCC therapy.

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ETS2 Mediated Tumor Suppressive Function and MET Oncogene Inhibition in Human Non–Small Cell Lung Cancer

Cited by 163 publications

References 43 publications

Characterization of HPV and host genome interactions in primary head and neck cancers

Characterization of HPV and host genome interactions in primary head and neck cancers

Identification of lung cancer oncogenes based on the mRNA expression and single nucleotide polymorphism profile data

Exploring the mechanism of WWOX growth inhibitory effects on oral squamous cell carcinoma

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