CD10 enhances metastasis of colorectal cancer by abrogating the anti-tumoural effect of methionine-enkephalin in the liver.
OBJECTIVE
To examine the role of CD10, a characteristic marker of liver metastasis of colorectal cancers (CRCs).


METHODS
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.


METHODS
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 delta-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.


CONCLUSIONS
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.
Kuniyasu
H
H
Department of Molecular Pathology, Nara Medical University, Kashihara, Japan. cooninh@zb4.so-net.ne.jp
Luo
Y
Y
Fujii
K
K
Sasahira
T
T
Moriwaka
Y
Y
Tatsumoto
N
N
Sasaki
T
T
Yamashita
Y
Y
Ohmori
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology*; D004744:Enkephalin, Methionine / Q000494:pharmacology* / Q000627:therapeutic use; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000517:prevention & control / Q000556:secondary*; D008207:Lymphatic Metastasis; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000378:metabolism; D015260:Neprilysin / Q000378:metabolism / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology; D017465:Receptors, Opioid, delta / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D017465:Receptors, Opioid, delta; D009569:Nitric Oxide; D004744:Enkephalin, Methionine; D066246:ErbB Receptors; D015260:Neprilysin