Abstract
Neuroendocrine tumor of uterine cervix (NTUC) is a relative rare subtype of cervical cancer. In comparison to other subtypes of gynecologic cancers, such as squamous cell carcinoma and adenocarcinoma, the NTUC is much more aggressive. Consequently, patients of NTUC have poor prognosis. In collaboration with gynecologic oncologists at Hsinchu branch of MacKay memorial hospital, we obtained a tissue sample of suspected NTUC from a 75-year-old patient. Using enzymatic and mechanical dissociation methods, we established the primary culture (HM-1) from this specimen, and the STR analysis result showed that HM-1 is a novel cancer cell line. HM-1 cells are bipolar or multipolar and showed fibroblast-like, elongated and spindle shape, which is different to common types of cervical cancer. In addition, we found HM-1 has a cell doubling time of 34 hours, which is significantly longer than the 19 hours cell doubling time of the common cervical cancer HeLa cells. Immunocytochemical staining validated that high expression level of the neuroendocrine marker, neuroendocrine synaptophysin (SYP), was present in the HM-1 cells, which suggested that HM-1 cells were originated from neuroendocrine cells. In addition, the presence of human papillomavirus 16 (HPV16) was detected in HM-1 cells, suggesting its potential association with HPV infection. To test its tumorigenesis capacity, the HM-1 cells were subcutaneously inoculated into BALB/c female nude mice. The result showed the HM-1 cells could proliferate in vivo, with a tumor volume doubling time of 13 days, which was higher than that HeLa. In term of anti-cancer drug sensitivity, Docetaxel has the highest inhibitory effect on HM-1 cell viability, followed by Cisplatin and Etoposide respectively, while the cells was shown to be least sensitive to Gemcitabine. On the other hand, HM-1 cells were highly sensitive to the combination treatment of etoposide and cisplatin. In order to develop a more effective treatment, we found that inhibition of MDM2 by nutlin-3 would decreased FoxM1 expression in cervical cancer cell lines CasKi, HeLa and NTUC. Inhibition of MDM2 can also decrease the migration ability of cervical cancer cells. Our findings suggested that the inhibition of MDM2 pathways and FoxM1-dependent pathway may be novel therapeutic targets for cervical cancers, including NTUC. We believe this new neuroendocrine cancer cell line HM-1 will be useful as a research model of NTUC. HM-1-based assay may help in developing effective diagnosis test or therapy for this rare subtype of gynecological malignancy.