Spred2 inhibits epithelial‑mesenchymal transition of colorectal cancer cells by impairing ERK signaling

Wang,Hao; Liu,Shuchen; Kong,Fanxuan; Xiao,Fengjun; Li,Yuxiang; Wang,Hua; Zhang,Shun; Huang,Dandan; Wang,Lisheng; Yang,Yuefeng

doi:10.3892/or.2020.7586

Spred2 inhibits epithelial‑mesenchymal transition of colorectal cancer cells by impairing ERK signaling

Authors:
- Hao Wang
- Shuchen Liu
- Fanxuan Kong
- Fengjun Xiao
- Yuxiang Li
- Hua Wang
- Shun Zhang
- Dandan Huang
- Lisheng Wang
- Yuefeng Yang
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Affiliations: Beijing Institute of Radiation Medicine, Beijing 100850, P.R. China, Department of Experimental Medical Science and Key Laboratory of Diagnosis and Treatment of Digestive System Tumors of Zhejiang Province, HwaMei Hospital, University of Chinese Academy of Sciences, Ningbo, Zhejiang 315000, P.R. China
Published online on: April 16, 2020 https://doi.org/10.3892/or.2020.7586
Pages: 174-184
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Downregulation of the sprouty‑related EVH1 domain protein 2 (Spred2) is closely associated with highly metastatic phenotypes in various tumors. However, the roles of Spred2 in the development and progression of colorectal cancer (CRC) are still largely unexplored. As anticipated, Spred2 expression was significantly downregulated in clinical tumor tissues. To restore Spred2 levels, Ad.Spred2, an adenoviral vector expressing Spred2, was transduced into CRC cells. It was revealed that Ad.Spred2 inhibited the proliferation and decreased the survival and migration of SW480 cells. Epithelial‑mesenchymal transition (EMT) is an essential event during tumor metastasis to distant sites. It was revealed that Ad.Spred2 markedly inhibited EMT by promoting F‑actin reorganization, upregulating E‑cadherin levels and reducing vimentin protein expression. Notably, extracellular‑regulated kinase (ERK) signaling inhibition by PD98059 induced similar effects on EMT in CRC cells, indicating that Ad.Spred2 regulated EMT in CRC cells in an ERK‑dependent manner. Transforming growth factor β (TGF‑β), a well‑known inducer of EMT, increased E‑cadherin expression, decreased vimentin expression and promoted migration in CRC cells. However, neither Ad.Spred2 nor PD98059 had an obvious effect on the expression of SMAD2/3 or SMAD4 in SW480 cells, indicating that Ad.Spred2 inhibited EMT in a SMAD‑independent manner. Notably, Ad.Spred2 transduction downregulated SAMD2/3 and SMAD4 levels in HCT116 cells in an ERK‑independent manner. It was speculated that Ad.Spred2 inhibited the EMT of HCT116 cells by both blocking ERK signaling and reducing SMAD signaling. It was concluded that Spred2 inhibited EMT in CRC cells by interfering with ERK signaling, with or without reduced SMAD signaling. Therefore, the introduction of the clinical application of Spred2 has great potential for development as a gene therapy approach for CRC.

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