Tissue dynamic and clinical effect of FOXM1 gene expression in carcinoma of cervix

Abstract

Infection of human papillomavirus (HPV) is strongly associated with cervical cancer. The high-risk types, such as HPV-16 and HPV-18, encode two oncoproteins E6 and E7 that could degrade p53 and pRB, respectively. The loss of p53 and pRB could lead to abnormal cell cycle control and initiate malignant transformation. Recently, it has been found that the fork head domain transcription factor M phase phosphoprotein 2 (FoxM1) is widely expressed in proliferating cells and stimulates S phase progression. In addition, FoxM1 was also found to interact with HPV 16 E7 to enhance malignant transformation, and may thus play an important role in cervical cancer development. In this study, immunohistochemical analysis of FoxM1 was performed on 198 samples of paraffin-embedded cervical tissue, including 125 tumorous and 73 normal tissues. FoxM1 expression was then correlated with Ki-67 which is another proliferation marker and AMP-activated protein kinase alpha 1 (AMPK-α1) subunit expression. The latter is an important molecule in control of cell metabolism and has been found to promote tumor cells survival during serum starvation. In addition, the relationship between FoxM1 expression patterns and clinicopathological parameters including radiosensitivity of cervical cancer cells were also evaluated. Our preliminary results shown that FoxM1 immunoreactivity was predominantly localized in the nuclei of proliferating tumor cells. Besides, FoxM1 was localized in the less differentiated tissues of cervical carcinoma and negative in the better squamoid differentiated cells. On the other hand, in the normal tissue, sparse FoxM1 immunoreactivity was found in the basal cell layer, while the parabasal, intermediate and superficial cells were all negative. Our results also demonstrated statistically significant correlation between FoxM1 immunoreactivity and advanced disease stage of cervical carcinoma (P=0.011). More importantly, patients with higher expression of FoxM1 in terms of percentage of positive cells were more sensitive to radiotherapy (P=0.003) although it did not correlate with survival. In addition, a significant positive correlation was found between FoxM1 and Ki-67 (p=0.000) and AMPK-α1 (P=0.004). Our finding suggests that FoxM1 expression is related to the proliferative status, radiosensitivity and the staging of cervical cancer and may play an important role in cervical carcinogenesis. Clinically, FoxM1 expression appears to be a potential prognostic marker in evaluating the treatment regimens and predicting the outcome of the cervical cancer patients before radiotherapy.