Objective To examine the role of CD10, a characteristic marker of liver metastasis of colorectal cancers (CRCs).
Design The effect of CD10 and Met-enkephalin (MENK) in CD10-positive and -negative human CRC cells was investigated under in vitro and in vivo conditions. Human CRC samples were examined.
Main outcome measure CD10-positive and CD10-knockdown HT29 cells and CD10-negative and CD10-transfected Colo320 cells in nude mice were treated with MENK and/or the CD10 inhibitor (thiorphan). Intracellular signalling of MENK and δ-opioid receptor (DOR) was examined by immunoblotting.
Results MENK inhibited the growth, invasion and survival of CRC cells following thiorphan-induced CD10 inactivation. Thiorphan suppressed liver metastasis of CD10-positive CRC cells. Inoculation of mice with CRC cells induced MENK expression in the liver. Inhibition of hepatic MENK expression by cholesterol-conjugated antisense S-oligodeoxynucleotide increased liver metastasis of CRC cells even when the cells did not express CD10. DOR activation by MENK decreased the phosphorylation of epidermal growth factor receptor and extracellular signal-regulated kinase and increased p38-dependent apoptosis. Nitric oxide was found to induce DOR expression in CRC cells. Co-treatment with thiorphan and a nitric oxide donor had a marked anti-tumour effect on liver metastasis of HT29 cells. Of 68 CRC patients, 19 (28%) showed CD10 expression, which was dependent on the extent of liver metastasis. MENK concentration in metastasis-positive human liver was higher than that in the normal liver.
Conclusion CD10 expression in CRC cells abrogates the anti-tumour effect of hepatic MENK by degrading it, which enhances liver metastasis of CD10-positive CRC cells.
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Funding This work was supported in part by Grant-in-Aid for Scientific Research from Ministry of Health, Labour and Welfare, Japan.
Competing interests None.
Ethics approval The procedure regarding the human tissue used in this study was in accordance with the Ethical Guidelines for Human Genome/Gene Research enacted by the Japanese Government. The mice used in this study were maintained according to the institutional guidelines approved by the Committee for Animal Experimentation of Nara Medical University.
Provenance and peer review Not commissioned; externally peer reviewed.
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