Cross talk between hedgehog and epithelial-mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers

H. Ohta, K. Aoyagi, M. Fukaya, I. Danjoh, A. Ohta, N. Isohata, N. Saeki, H. Taniguchi, H. Sakamoto, T. Shimoda, T. Tani, T. Yoshida, H. Sasaki

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Abstract

We previously reported hedgehog (Hh) signal activation in the mucus-secreting pit cell of the stomach and in diffuse-type gastric cancer (GC). Epithelial-mesenchymal transition (EMT) is known to be involved in tumour malignancy. However, little is known about whether and how both signallings cooperatively act in diffuse-type GC. By microarray and reverse transcription-PCR, we investigated the expression of those Hh and EMT signalling molecules in pit cells and in diffuse-type GCs. How both signallings act cooperatively in those cells was also investigated by the treatment of an Hh-signal inhibitor and siRNAs of Hh and EMT transcriptional key regulator genes on a mouse primary culture and on human GC cell lines. Pit cells and diffuse-type GCs co-expressed many Hh and EMT signalling genes. Mesenchymal-related genes (WNT5A, CDH2, PDGFRB, EDNRA, ROBO1, ROR2, and MEF2C) were found to be activated by an EMT regulator, SIP1/ZFHX1B/ZEB2, which was a target of a primary transcriptional regulator GLI1 in Hh signal. Furthermore, we identified two cancer-specific Hh targets, ELK1 and MSX2, which have an essential role in GC cell growth. These findings suggest that the gastric pit cell exhibits mesenchymal-like gene expression, and that diffuse-type GC maintains expression through the Hh-EMT pathway. Our proposed extensive Hh-EMT signal pathway has the potential to an understanding of diffuse-type GC and to the development of new drugs.

Original languageEnglish
Pages (from-to)389-398
Number of pages10
JournalBritish Journal of Cancer
Volume100
Issue number2
DOIs
Publication statusPublished - 2009 Jan 27

Keywords

  • Cancer-linked hypomethylation
  • Diffuse-type gastric cancer
  • Epithelial- mesenchymal transition
  • Gastric pit cell
  • Hedgehog

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Ohta, H., Aoyagi, K., Fukaya, M., Danjoh, I., Ohta, A., Isohata, N., Saeki, N., Taniguchi, H., Sakamoto, H., Shimoda, T., Tani, T., Yoshida, T., & Sasaki, H. (2009). Cross talk between hedgehog and epithelial-mesenchymal transition pathways in gastric pit cells and in diffuse-type gastric cancers. British Journal of Cancer, 100(2), 389-398. https://doi.org/10.1038/sj.bjc.6604846