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
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 num...
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MDPI AG
2019-08-01
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| Online Access: | https://www.mdpi.com/2073-4409/8/8/878 |
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| author | Sujin Kim Nayoung Kim Keunsoo Kang Wonkyung Kim Jonghwa Won Jeonghee Cho |
| author_facet | Sujin Kim Nayoung Kim Keunsoo Kang Wonkyung Kim Jonghwa Won Jeonghee Cho |
| author_sort | Sujin Kim |
| collection | DOAJ |
| description | 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 <i>KRAS</i><sup>G12D</sup> 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 <i>KRAS</i> 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 <i>KRAS</i> activating mutations. |
| first_indexed | 2024-03-12T05:50:33Z |
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| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T05:50:33Z |
| publishDate | 2019-08-01 |
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| spelling | doaj.art-6f1c0e084ad0474fb01056dc0e039c2a2023-09-03T05:10:41ZengMDPI AGCells2073-44092019-08-018887810.3390/cells8080878cells8080878Whole Transcriptome Analysis Identifies TNS4 as a Key Effector of Cetuximab and a Regulator of the Oncogenic Activity of KRAS Mutant Colorectal Cancer Cell LinesSujin Kim0Nayoung Kim1Keunsoo Kang2Wonkyung Kim3Jonghwa Won4Jeonghee Cho5Department of Nanobiomedical Science, Dankook University, Cheonan 31116, KoreaDepartment of Nanobiomedical Science, Dankook University, Cheonan 31116, KoreaDepartment of Microbiology, Dankook University, Cheonan 31116, KoreaDepartment of Microbiology, Dankook University, Cheonan 31116, KoreaOncology Team, Mogam Institute for Biomedical Research (MIBR), Yongin 16924, KoreaDepartment of Nanobiomedical Science, Dankook University, Cheonan 31116, KoreaThe 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 <i>KRAS</i><sup>G12D</sup> 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 <i>KRAS</i> 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 <i>KRAS</i> activating mutations.https://www.mdpi.com/2073-4409/8/8/878TNS4KRASEGFRcetuximabselumetinibcolon cancer |
| spellingShingle | Sujin Kim Nayoung Kim Keunsoo Kang Wonkyung Kim Jonghwa Won Jeonghee Cho 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 TNS4 KRAS EGFR cetuximab selumetinib colon cancer |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | TNS4 KRAS EGFR cetuximab selumetinib colon cancer |
| url | https://www.mdpi.com/2073-4409/8/8/878 |
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