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EP4 upregulation of Ras signaling and feedback regulation of Ras in human colon tissues and cancer cells

  • Genotoxicity and Carcinogenicity
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Abstract

Previous studies indicate that COX-2 and prostaglandin E2 (PGE2) receptor subtypes are involved in intestinal carcinogenesis and activation of downstream pathways. In this report, we try to understand the association of PGE2 receptor and K-ras cellular mechanism during the development of colorectal cancer. We collected 21 colorectal cancer patients and compared the protein expression of tumor tissues and normal mucosa tissues by using immunoblot. Furthermore, we transferred empty vector and pcDNA-K-ras into Ras-HT29 colon cancer cells. Result showed that phosphorylation of Akt and EP1/EP4 were over-expressed in the colorectal tumor tissue. K-ras induces HT29 cells proliferation through the expressions of COX-2, EP1/EP4, pAkt, GSK3β and increases Tcf transcriptional factor activation. Additionally, Ras protein was suppressed when treated with EP4 inhibitor in Ras-HT29 cell. In cell cycle assay, K-ras mutation causing cell cycle S phase was prolonged with an increase in the G2/M phase ratio. In conclusion, we suggested that Ras overexpression leads to cell proliferation through activating Ras/PI3K/GSK3β/EP4 PGE2 receptor signals and caused a feedback regulation of Ras by EP4 in colorectal tumor progression.

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Authors and Affiliations

  1. Institute of Biochemistry and Biotechnology, Chung Shan Medical University, No. 110, Section 1, Chien-kauo N. Road, Taichung, 402, Taiwan, Republic of China

    Cheng-Hsun Wu, Chun-Hua Chang, Ting-Tsz Ou & Chau-Jong Wang

  2. Department of Anatomy, China Medical University, No. 91, Hsueh-Shih Road, Taichung, 404, Taiwan

    Cheng-Hsun Wu

  3. Department of Biological Science and Technology, and Institute of Biomedical Science, Chung Hwa University of Medical Technology, No. 89, Wen-Hwa 1st Street, Jen-Te, 717, Taiwan

    Yuan-Wei Shih

  4. Department of Colorectal Surgery, Chung Shan Medical University Hospital, No. 110, Section 1, Chien-kauo N. Road, Taichung, Taiwan, Republic of China

    Chi-Chou Huang

  5. Department of Pathology, Chung Shan Medical University Hospital, No. 110, Section 1, Chien-kauo N. Road, Taichung, 402, Taiwan

    Jeng-Dong Hsu

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  1. Cheng-Hsun Wu
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Correspondence to Chau-Jong Wang.

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Wu, CH., Shih, YW., Chang, CH. et al. EP4 upregulation of Ras signaling and feedback regulation of Ras in human colon tissues and cancer cells. Arch Toxicol 84, 731–740 (2010). https://doi.org/10.1007/s00204-010-0562-4

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  • DOI: https://doi.org/10.1007/s00204-010-0562-4

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