1. Identification of PTK6, via RNA sequencing analysis, as a suppressor of esophageal squamous cell carcinoma.
- Author
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Ma S, Bao JYJ, Kwan PS, Chan YP, Tong CM, Fu L, Zhang N, Tong AHY, Qin YR, Tsao SW, Chan KW, Lok S, and Guan XY
- Subjects
- Acetylation, Adult, Animals, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell pathology, Cell Line, Tumor, Cell Movement, Cell Proliferation, DNA Methylation, Epigenesis, Genetic, Esophageal Neoplasms genetics, Esophageal Neoplasms pathology, Extracellular Matrix metabolism, Female, G1 Phase Cell Cycle Checkpoints, Gene Expression Profiling, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Glycogen Synthase Kinase 3 metabolism, Glycogen Synthase Kinase 3 beta, Histones metabolism, Humans, Male, Mice, Mice, Nude, Middle Aged, Neoplasm Invasiveness, Neoplasm Proteins genetics, Phosphorylation, Promoter Regions, Genetic, Protein-Tyrosine Kinases genetics, Proto-Oncogene Proteins c-akt metabolism, RNA Interference, RNA, Messenger metabolism, Sequence Analysis, RNA, Signal Transduction, Transcription, Genetic, Transfection, Tumor Suppressor Proteins genetics, beta Catenin metabolism, Carcinoma, Squamous Cell enzymology, Esophageal Neoplasms enzymology, Neoplasm Proteins metabolism, Protein-Tyrosine Kinases metabolism, Tumor Suppressor Proteins metabolism
- Abstract
Background & Aims: Esophageal squamous cell carcinoma (ESCC) is the most commonly observed histologic subtype of esophageal cancer. ESCC is believed to develop via accumulation of numerous genetic alterations, including inactivation of tumor suppressor genes and activation of oncogenes. We searched for transcripts that were altered in human ESCC samples compared with nontumor tissues., Methods: We performed integrative transcriptome sequencing (RNA-Seq) analysis using ESCC samples from 3 patients and adjacent nontumor tissues to identify transcripts that were altered in ESCC tissue. We performed molecular and functional studies of the transcripts identified and investigated the mechanisms of alteration., Results: We identified protein tyrosine kinase 6 (PTK6) as a transcript that was significantly down-regulated in ESCC tissues and cell lines compared with nontumor tissues or immortalized normal esophageal cell lines. The promoter of the PTK6 gene was inactivated in ESCC tissues at least in part via hypermethylation and histone deacetylation. Knockdown of PTK6 in KYSE30 ESCC cells using small hairpin RNAs increased their ability to form foci, migrate, and invade extracellular matrix in culture and form tumors in nude mice. Overexpression of PTK6 in these cells reduced their proliferation in culture and tumor formation in mice. PTK6 reduced phosphorylation of Akt and glycogen synthase kinase (GSK)3β, leading to activation of β-catenin., Conclusions: PTK6 was identified as a transcript that is down-regulated in human ESCC tissues via epigenetic modification at the PTK6 locus. Its product appears to regulate cell proliferation by reducing phosphorylation of Akt and GSK3β, leading to activation of β-catenin. Reduced levels of PTK6 promote growth of xenograft tumors in mice; it might be developed as a marker of ESCC., (Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.)
- Published
- 2012
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