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

Liang,Xi; Xu,Xueqing; Wang,Fengchao; Chen,Xuedan; Li,Ni; Wang,Cancan; He,Jianming

doi:10.3892/ijo.2015.3137

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

Authors:
- Xi Liang
- Xueqing Xu
- Fengchao Wang
- Xuedan Chen
- Ni Li
- Cancan Wang
- Jianming He
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Affiliations: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China, Molecular Biology Center, State Key Laboratory of Trauma, Burn, and Combined Injury, Daping Hospital, Third Military Medical University, Chongqing 400042, P.R. China, Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing 400038, P.R. China, Department of Medical Genetics, Third Military Medical University, Chongqing 400038, P.R. China
Published online on: August 27, 2015 https://doi.org/10.3892/ijo.2015.3137
Pages: 1517-1527

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Abstract

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.

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