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Stomach
Original article
OCT1 is a determinant of synbindin-related ERK signalling with independent prognostic significance in gastric cancer
  1. Jin Qian1,
  2. Xuan Kong1,
  3. Niantao Deng2,
  4. Patrick Tan2,3,
  5. Haoyan Chen1,
  6. Jilin Wang1,
  7. Zhaoli Li4,
  8. Ye Hu1,
  9. Weiping Zou5,
  10. Jie Xu1,
  11. Jing-Yuan Fang1
  1. 1State Key Laboratory of Oncogenes and Related Genes, Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Cancer Institute, Shanghai Institute of Digestive Disease, Shanghai, China
  2. 2Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore, Singapore
  3. 3Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore, Singapore
  4. 4Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Harbin, China
  5. 5Department of Surgery, University of Michigan, Ann Arbor, Michigan, USA
  1. Correspondence to Dr Jing-Yuan Fang; jingyuanfang{at}yahoo.com and Dr Jie Xu; jiexu@yahoo.com

Abstract

Objective Octamer transcription factor 1 (OCT1) was found to be expressed in intestinal metaplasia and gastric cancer (GC), but the exact roles of OCT1 in GC remain unclear. The objective of this study was to determine the functional and prognostic implications of OCT1 in GC.

Design Expression of OCT1 was examined in paired normal and cancerous gastric tissues and the prognostic significance of OCT1 was analysed by univariate and multivariate survival analyses. The functions of OCT1 on synbindin expression and extracellular signal-regulated kinase (ERK) phosphorylation were studied in vitro and in xenograft mouse models.

Results The OCT1 gene is recurrently amplified and upregulated in GC. OCT1 overexpression and amplification are associated with poor survival in patients with GC and the prognostic significance was confirmed by independent patient cohorts. Combining OCT1 overexpression with American Joint Committee on Cancer staging improved the prediction of survival in patients with GC. High expression of OCT1 associates with activation of the ERK mitogen-activated protein kinase signalling pathway in GC tissues. OCT1 functions by transactivating synbindin, which binds to ERK DEF domain and facilitates ERK phosphorylation by MEK. OCT1-synbindin signalling results in the activation of ERK substrates ELK1 and RSK, leading to increased cell proliferation and invasion. Immunofluorescent study of human GC tissue samples revealed strong association between OCT1 protein level and synbindin expression/ERK phosphorylation. Upregulation of OCT1 in mouse xenograft models induced synbindin expression and ERK activation, leading to accelerated tumour growth in vivo.

Conclusions OCT1 is a driver of synbindin-mediated ERK signalling and a promising marker for the prognosis and molecular subtyping of GC.

  • Gastric Cancer
  • Cancer Genetics
  • Signal Transduction
  • Cell Proliferation
  • Cell Migration

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 3.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/3.0/

https://doi.org/10.1136/gutjnl-2013-306584

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