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Mol Carcinog. 2014 Feb;53 Suppl 1:E72-84. doi: 10.1002/mc.22031. Epub 2013 Apr 26.

The role of ERK2 in colorectal carcinogenesis is partly regulated by TRAPPC4.

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1
Division of Gastroenterology and Hepatology, Renji Hospital,Shanghai Jiao-Tong University School of Medicine, Shanghai Institute of Digestive Disease, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, State Key Laboratory of Oncogene and Related Genes, Shanghai, China.

Abstract

The extracellular signal-regulated kinase (ERK), mitogen-activated protein kinase (MAPK) pathway is an important cell proliferation pathway. We previously reported that the transport protein particle complex 4 (TRAPPC4), ERK2 interaction may activate ERK1/2, modulate pERK2 nuclear localization and regulate proliferation and apoptosis in colorectal cancer (CRC) cells. The present study further investigated the function of the TRAPPC4-ERK2 interaction in CRC in vitro and in vivo. Silencing of TRAPPC4 induced G0/G1 phase cell cycle arrest, upregulated p21 and downregulated cyclin B1 in CRC cells. Overexpression of TRAPPC4 after ERK2 silencing decreased the percentage of G0/G1 phase cells, increased the percentage of G2/M and S phase cells, downregulated p21, upregulated cyclin B1, and enhanced CRC cell viability. Immunohistochemical staining revealed that knockdown of TRAPPC4 downregulated pERK2, whereas overexpression of TRAPPC4 upregulated pERK2. Epidermal growth factor (EGF) stimulated upregulation of TRAPPC4 and pERK2 in SW1116 cells; EGF stimulation or overexpression of TRAPPC4 induced pERK2 nuclear translocation. Silencing of TRAPPC4 reduced SW1116 xenograft tumor growth in vivo, whereas overexpression of TRAPPC4 increased tumor growth, compared to control tumors. Moreover, modulation of TRAPPC4 expression in vivo affected the levels of pERK2 in the cytoplasm and nucleus and expression of p21. These results conclusively demonstrate that TRAPPC4 regulates ERK2 activation and also affects the distribution of activated pERK2 in CRC cells. The ability of ERK2 to play a role in colorectal carcinogenesis depends, at least in part, on TRAPPC4.

KEYWORDS:

cancer; cell cycle; cell proliferation

PMID:
23625650
DOI:
10.1002/mc.22031
[Indexed for MEDLINE]
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