Paper

CD10 enhances metastasis of colorectal cancer by abrogating the antitumoral effect of methionine-enkephalin in the liver

Hiroki Kuniyasu^1,*, Yi Luo¹, Kiyomu Fujii¹, Tomonori Sasahira¹, Yukiko Moriwaka¹, Naokuni Tatsumoto², Takamitsu Sasaki³, Yuichi Yamashita³, Hitoshi Ohmori¹

¹ Nara Medical University, Japan;
² Miyoshi Central Hospital, Japan;
³ Fukuoka University, Japan

Correspondence to: Hiroki Kuniyasu, Molecular Pathology, NARA MEDICAL UNIVERSITY, Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara, 634-8521, Japan; cooninh{at}zb4.so-net.ne.jp

Accepted 16 September 2009

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 signaling of MENK and Ô-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 antitumor 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 antitumor effect of hepatic MENK by degrading it, which enhances liver metastasis of CD10-positive CRC cells.

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