Implication of human nonmetastatic clone 23 Type 1 and its downstream gene lipocalin 2 in metastasis and patient's survival of cancer of uterine cervix.

Human nonmetastatic clone 23 Type 1 (nm23-H1) is demonstrated to have diverse roles in metastasis and survival for many cancers, which are probably caused via different impacts on its downstream genes. Our preliminary study using cDNA genechip found that lipocalin 2 seems to be a significant downstream gene of nm23-H1 in SiHa cancer cells of uterine cervix. Therefore, we investigated the expression and correlation of nm23-H1 and lipocalin 2 in cancer metastasis and their implication in recurrence and survival of cervical cancer patients. In our study, we knocked down SiHa cancer cells by short hairpin RNA for nm23-H to detect its impact on the promoter activity and gene expression of lipocalin 2. In addition to nm23-H1 knockdown, lipocalin 2 gene was overexpressed to detect their implication in metastatic phenotypes. We further used immunohistochemical methods for 100 cancer tissue cores of cervical tissue microarrays to correlate the expression of nm23-H1 and lipocalin 2 with recurrence and survival of cancer patients. Our findings showed that nm23-H1 knockdown SiHa cancer cells increased lipocalin 2 promoter activity and gene expression, then decreased cells migration and invasion. They displayed cobblestone-like appearance and decreased interior fibers. Cervical cancer patients with positive nm23-H1 and negative lipocalin 2 expression had the worst recurrence probability and overall survival. In conclusion, when nm23-H1 gene is knocked down in SiHa cervical cancer cells, cells migration and invasion decrease through elevated expression of lipocalin 2. Cervical cancer patients with positive nm23-H1 and negative lipocalin 2 should be followed and treated intensely.