E-cadherin knockdown increases β-catenin reducing colorectal cancer chemosensitivity only in three-dimensional cultures

Int J Oncol. 2015 Oct;47(4):1517-27. doi: 10.3892/ijo.2015.3137. Epub 2015 Aug 27.


Decreased expression of E-cadherin correlates with poor prognosis in colorectal cancer. Certain E-cadherin signaling cascades are triggered by intercellular force or binding to cadherins on adjacent cells. Three-dimensional (3D) cell cultures represent a better approximation of cell-cell adhesion in vivo than two-dimensional (2D) cultures. Here, we explored the role of E-cadherin in colorectal cancer chemosensitivity in 3D cultures. Cell-cell junctions, including tight junctions, gap junctions, intermediate junctions and desmosomes, were commonly found in 3D cultures. Knockdown of E-cadherin by lentiviral delivery of shRNA significantly reduced chemosensitivity to 5-fluorouracil and irinotecan, increased β-catenin protein level in HCT116 3D cultures. However, these effects were not observed in 2D cultures. Knockdown of β-catenin significantly increased chemosensitivity to 5-fluorouracil and irinotecan in HCT116 3D cultures and LoVo 3D cultures. 5-Fluorouracil activated p38, ERK1/2 and JNK1/2 in a time-dependent manner in HCT116 3D cultures. E-cadherin knockdown enhanced p-p38 and p-ERK1/2, except p-JNK1/2 in HCT116 3D cultures. Knockdown of β-catenin attenuated p-p38 and p-ERK1/2 in HCT116 3D cultures and LoVo 3D cultures. Inhibition of p-p38 or p-ERK1/2 in HCT116 3D cultures significantly increased chemosensitivity. Our results indicate E-cadherin knockdown increases β-catenin resulting in reduction of chemosensitivity only in 3D cultures, and β-catenin increasing the p-p38/p-ERK1/2 is involved in this mechanism.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cadherins / genetics
  • Cadherins / metabolism*
  • Cell Adhesion / physiology
  • Cell Communication / physiology*
  • Cell Culture Techniques / methods*
  • Cell Line, Tumor
  • Colorectal Neoplasms / pathology*
  • Drug Resistance, Neoplasm / physiology*
  • Fluorescent Antibody Technique
  • Gene Knockdown Techniques
  • Humans
  • Immunohistochemistry
  • Microscopy, Electron, Transmission
  • RNA, Small Interfering
  • Signal Transduction / physiology
  • Transfection
  • beta Catenin / metabolism*


  • CTNNB1 protein, human
  • Cadherins
  • RNA, Small Interfering
  • beta Catenin