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Open AccessArticle

Whole Transcriptome Analysis Identifies TNS4 as a Key Effector of Cetuximab and a Regulator of the Oncogenic Activity of KRAS Mutant Colorectal Cancer Cell Lines

1
Department of Nanobiomedical Science, Dankook University, Cheonan 31116, Korea
2
Department of Microbiology, Dankook University, Cheonan 31116, Korea
3
Oncology Team, Mogam Institute for Biomedical Research (MIBR), Yongin 16924, Korea
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2019, 8(8), 878; https://doi.org/10.3390/cells8080878
Received: 30 June 2019 / Revised: 31 July 2019 / Accepted: 10 August 2019 / Published: 12 August 2019
(This article belongs to the Special Issue Epidermal Growth Factor Receptor Signaling)
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Abstract

The targeting of activated epidermal growth factor receptor (EGFR) with therapeutic anti-EGFR monoclonal antibodies (mAbs) such as cetuximab and panitumumab has been used as an effective strategy in the treatment of colorectal cancer (CRC). However, its clinical efficacy occurs only in a limited number of patients. Here, we performed whole-transcriptome analysis in xenograft mouse tumors induced by KRASG12D mutation-bearing LS174T CRC cells following treatment with either cetuximab or PBS. Through integrated analyses of differential gene expression with TCGA and CCLE public database, we identified TNS4, overexpressed in CRC patients and KRAS mutation-harboring CRC cell lines, significantly downregulated by cetuximab. While ablation of TNS4 expression via shRNA results in significant growth inhibition of LS174T, DLD1, WiDr, and DiFi CRC cell lines, conversely, its ectopic expression increases the oncogenic growth of these cells. Furthermore, TNS4 expression is transcriptionally regulated by MAP kinase signaling pathway. Consistent with this finding, selumetinib, a MEK1/2 inhibitor, suppressed oncogenic activity of CRC cells, and this effect is more profound in combination with cetuximab. Altogether, we propose that TNS4 plays a crucial role in CRC tumorigenesis, and that suppression of TNS4 would be an effective therapeutic strategy in treating a subset of cetuximab-refractory CRC patients including KRAS activating mutations. View Full-Text
Keywords: TNS4; KRAS; EGFR; cetuximab; selumetinib; colon cancer TNS4; KRAS; EGFR; cetuximab; selumetinib; colon cancer
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Kim, S.; Kim, N.; Kang, K.; Kim, W.; Won, J.; Cho, J. Whole Transcriptome Analysis Identifies TNS4 as a Key Effector of Cetuximab and a Regulator of the Oncogenic Activity of KRAS Mutant Colorectal Cancer Cell Lines. Cells 2019, 8, 878.

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