title: Phosphotyrosine profiling identifies ephrin receptor A2 as a potential therapeutic target in esophageal squamous-cell carcinoma.
abstract: Esophageal squamous-cell carcinoma (ESCC) is one of the most common malignancies in Asia. Currently, surgical resection of early-stage tumor is the best available treatment. However, most patients present late when surgery is not an option. Data suggest that chemotherapy regimens are inadequate for clinical management of advanced cancer. Targeted therapy has emerged as one of the most promising approaches to treat several malignancies. A prerequisite for developing targeted therapy is prior knowledge of proteins and pathways that drive proliferation in malignancies. We carried out phosphotyrosine profiling across four different ESCC cell lines and compared it to non-neoplastic Het-1A cell line to identify activated tyrosine kinase signaling pathways in ESCC. A total of 278 unique phosphopeptides were identified across these cell lines. This included several tyrosine kinases and their substrates that were hyperphosphorylated in ESCC. Ephrin receptor A2 (EPHA2), a receptor tyrosine kinase, was hyperphosphorylated in all the ESCC cell lines used in the study. EPHA2 is reported to be oncogenic in several cancers and is also known to promote metastasis. Immunohistochemistry-based studies have revealed EPHA2 is overexpressed in nearly 50% of ESCC. We demonstrated EPHA2 as a potential therapeutic target in ESCC by carrying out siRNA-based knockdown studies. Knockdown of EPHA2 in ESCC cell line TE8 resulted in significant decrease in cell proliferation and invasion, suggesting it is a promising therapeutic target in ESCC that warrants further evaluation.
authors.affiliation: Institute of Bioinformatics, International Technology Park, Bangalore, India; Department of Biochemistry and Molecular Biology, Pondicherry University, Puducherry, India.
authors.forename: Nazia
authors.initials: N
authors.lastname: Syed
authors.forename: Mustafa A
authors.initials: MA
authors.lastname: Barbhuiya
authors.forename: Sneha M
authors.initials: SM
authors.lastname: Pinto
authors.forename: Raja Sekhar
authors.initials: RS
authors.lastname: Nirujogi
authors.forename: Santosh
authors.initials: S
authors.lastname: Renuse
authors.forename: Keshava K
authors.initials: KK
authors.lastname: Datta
authors.forename: Aafaque Ahmad
authors.initials: AA
authors.lastname: Khan
authors.forename: Kotteazeth
authors.initials: K
authors.lastname: Srikumar
authors.forename: T S Keshava
authors.initials: TS
authors.lastname: Prasad
authors.forename: M Vijaya
authors.initials: MV
authors.lastname: Kumar
authors.forename: Rekha Vijay
authors.initials: RV
authors.lastname: Kumar
authors.forename: Aditi
authors.initials: A
authors.lastname: Chatterjee
authors.forename: Akhilesh
authors.initials: A
authors.lastname: Pandey
authors.forename: Harsha
authors.initials: H
authors.lastname: Gowda
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D036383:Ephrin-A2 / Q000235:genetics / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D004947:Esophagus / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D013058:Mass Spectrometry; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D036383:Ephrin-A2; D019000:Phosphotyrosine; D011505:Protein-Tyrosine Kinases
keywords: Biomedicine; In vivo labeling; Mass spectrometry; Post-translational modifications