Tiam1 transgenic mice display increased tumor invasive and metastatic potential of colorectal cancer after 1,2-dimethylhydrazine treatment

PLoS One. 2013 Sep 12;8(9):e73077. doi: 10.1371/journal.pone.0073077. eCollection 2013.

Abstract

Background: T lymphoma invasion and metastasis 1 (Tiam1) is a potential modifier of tumor development and progression. Our previous study in vitro and in nude mice suggested a promotion role of Tiam1 on invasion and metastasis of colorectal cancer (CRC). In the present study, we generated Tiam1/C1199-CopGFP transgenic mice to investigate the tumorigenetic, invasive and metastatic alterations in the colon and rectum of wild-type and Tiam1 transgenic mice under 1,2-dimethylhydrazine (DMH) treatment.

Methods: Transgenic mice were produced by the method of pronuclear microinlectlon. Whole-body fluorescence imaging (Lighttools, Edmonton, Alberta, Canada), PCR, and immunohistochemical techniques (IHC) were applied sequentially to identify the transgenic mice. The carcinogen DMH (20 mg/kg) was used to induce colorectal tumors though intraperitoneal (i.p.) injections once a week for 24 weeks from the age of 4 weeks on Tiam1 transgenic or non-transgenic mice.

Results: We successfully generated Tiam1/C1199-CopGFP transgenic mice and induced primary tumors in the intestine of both wild type and Tiam1 transgenic mice by DMH treatment. In addition, Tiam1 transgenic mice developed larger and more aggressive neoplasm than wild-type mice. Moreover, immunohistochemical staining revealed that upregulation of Tiam1 was correlated with increased expression of β-Catenin and Vimentin, and downregulation of E-Cadherin in these mice.

Conclusions: Our study has provided in vivo evidence supporting that Tiam1 promotes invasion and metastasis of CRC, most probably through activation of Wnt/β-catenin signaling pathway, in a Tiam1 transgenic mouse model.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1,2-Dimethylhydrazine / therapeutic use*
  • Animals
  • Colorectal Neoplasms / drug therapy*
  • Guanine Nucleotide Exchange Factors / genetics
  • Guanine Nucleotide Exchange Factors / metabolism*
  • Mice
  • Mice, Transgenic
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • Wnt Signaling Pathway / drug effects

Substances

  • Guanine Nucleotide Exchange Factors
  • T-Lymphoma Invasion and Metastasis-inducing Protein 1
  • Tiam1 protein, mouse
  • 1,2-Dimethylhydrazine

Grant support

This work was supported by the Natural Science Foundation of China (nos: 81001111, 81071735, 30901791) and the Natural Science Foundation of Guangdong (S2011040003696).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.