A Long Non-coding RNA Activated by Transforming Growth Factor-β is an Independent Prognostic Marker of Gastric Cancer

Ann Surg Oncol. 2015 Dec:22 Suppl 3:S915-22. doi: 10.1245/s10434-015-4554-8. Epub 2015 May 19.

Abstract

Background: A recent study reported that long non-coding RNA activated by TGF-β (lncRNA-ATB) induced epithelial-mesenchymal transition (EMT) through the transforming growth factor-β (TGF-β)/miR-200s/ZEB axis in hepatocellular carcinoma. Herein, we focused on the clinical significance of lncRNA-ATB in gastric cancer (GC) patients.

Materials and methods: Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to examine expression of lncRNA-ATB, miR-200b, and miR-200c in GC tissues (n = 183). Patients were divided into high and low lncRNA-ATB expression groups using a cutoff of lncRNA-ATB/GAPDH ≥0.60 or <0.60 to determine the clinicopathological significance of lncRNA-ATB in GC. Moreover, we evaluated the expression of TGF-β, lncRNA-ATB, miR-200s, and ZEB1 in GC cell lines by qRT-PCR. GC cell lines were treated by recombinant TGF-β1 or TGF-β receptor inhibitor to examine morphologic changes and genetic alterations, such as lncRNA-ATB, miR-200s, and ZEB1 levels, with respect to the EMT phenotype.

Results: The high lncRNA-ATB group experienced a lower overall survival rate compared with the low lncRNA-ATB group, and multivariate analysis indicated that lncRNA-ATB was an independent prognostic factor (hazard ratio 3.50; 95 % CI 1.73-7.44; p = 0.0004). miR-200c levels were lower and ZEB1 levels were higher in the high lncRNA-ATB group than in the low lncRNA-ATB group. Treatment with TGF-β in GC cell lines resulted in morphological EMT changes, upregulation of lncRNA-ATB and ZEB1, and downregulation of miR-200c and CDH1. SB431542 reduced lncRNA-ATB expression.

Conclusion: LncRNA-ATB plays an important role in EMT to promote invasion and metastasis through the TGF-β/miR-200s/ZEB axis, resulting in a poor prognosis in GC. LncRNA-ATB is a novel biomarker of lncRNA, indicative of a poor prognosis in GC patients.

MeSH terms

  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / secondary*
  • Adenocarcinoma, Mucinous / genetics
  • Adenocarcinoma, Mucinous / metabolism
  • Adenocarcinoma, Mucinous / secondary*
  • Aged
  • Apoptosis
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Carcinoma, Signet Ring Cell / genetics
  • Carcinoma, Signet Ring Cell / metabolism
  • Carcinoma, Signet Ring Cell / secondary*
  • Cell Proliferation
  • Female
  • Follow-Up Studies
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Immunoenzyme Techniques
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / secondary*
  • Lymphatic Metastasis
  • Male
  • MicroRNAs / genetics
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Peritoneal Neoplasms / genetics
  • Peritoneal Neoplasms / metabolism
  • Peritoneal Neoplasms / secondary*
  • Prognosis
  • RNA, Long Noncoding / genetics*
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Stomach Neoplasms / genetics
  • Stomach Neoplasms / metabolism
  • Stomach Neoplasms / pathology*
  • Survival Rate
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism*
  • Tumor Cells, Cultured
  • Zinc Finger E-box-Binding Homeobox 1

Substances

  • Biomarkers, Tumor
  • Homeodomain Proteins
  • MIRN200 microRNA, human
  • MicroRNAs
  • RNA, Long Noncoding
  • RNA, Messenger
  • Transcription Factors
  • Transforming Growth Factor beta
  • ZEB1 protein, human
  • Zinc Finger E-box-Binding Homeobox 1