Reduced expression of the metastasis suppressor gene KAI1 in advanced colon cancer and its metastases.

BACKGROUND

The expression of the KAI1 gene and its gene product were studied in metastatic and non-metastatic human colorectal cancer to evaluate its role in the metastatic process.

METHODS

KAI1 mRNA and protein expression was examined in 36 primary colorectal carcinomas and 6 liver metastasis using Northern blot and Western blot analyses. Forty-six normal colonic tissue samples served as controls. The exact site of KAI1 expression was analyzed by in situ hybridization and by immunohistochemistry in primary tumors, in the corresponding normal tissues, in lymph node metastases and liver metastases.

RESULTS

Densitometric analysis of Northern blots revealed overexpression of KAI1 mRNA in 87% of colonic cancer tissues in comparison with the corresponding normal colonic tissues. This increase was 9.1-fold in median (P < .001). KAI1 mRNA expression was strongly dependent on tumor stage. Colorectal cancer at stages II and III revealed significantly higher KAI1 mRNA levels than stage IV tumors (P < .03 and P < .015, respectively) or normal controls. In addition, liver metastases showed reduced KAI1 mRNA expression when compared with their corresponding primary tumor. In situ hybridization confirmed the stage-dependent expression results obtained by Northern blots, in which the KAI1 mRNA signal was exhibited almost exclusively in the epithelial cells. Lymph node and liver metastases were largely devoid of KAI1 mRNA. Western blot analysis showed a highly significant increase of KAI1 protein level in stage II cancers in comparison with the normal colon (P < .001) but also in comparison with the more advanced tumor stages III and IV (P < .03) and P < .02, respectively), when metastases were already present. In accordance, KAI1 immunostaining decreased successively with the advance of the tumor stage and was absent in lymph node and liver metastases.

CONCLUSIONS

These data demonstrate that the KAI1 mRNA expression and the KAI1 protein level increase in an earlier tumor stage of colorectal cancer, decrease in advanced stages, and are lost in metastases. The loss of KAI1 might favor the ability of colorectal cancer cells to metastasize.