Study of hedgehog signaling in cervical cancer

Abstract

Human papillomavirus (HPV) infection is a well-established etiological factor for the development of cervical cancer. However, the number of HPV infected women far exceeds that of women who actually develop cervical cancer. Therefore, the development and progression from low-grade intraepithelial lesion to invasive cancer must involve other genetic alterations apart from HPV virus infection solely. In fact, the E6 and E7 oncoproteins of HPV can degrade p53 and pRB, respectively, leading to abnormal cell cycle control. Besides, the Forkhead box transcription factor FoxM1, which is highly expressed in proliferating cells, can interact with the oncogenic HPV 16 E7 protein to enhance transformation. Indeed, several Forkhead genes have been shown to be transcriptional targets of the Hedgehog-Gli signaling (HHS) pathway. From our immunohistochemical studies on archival cervical cancer samples, elevated expression of FoxM1 and Gli1 was found in proliferating and differentiated cancer cells, respectively. By semi-quantitative RT-PCR analysis, the expression of components of HHS pathway including Gli2 and Gli3 was also found to be up-regulated in four cervical cancer cell lines (SiHa, HeLa, CasKi and C33A). In particular, Indian hedgehog, a class of the hedgehog proteins, was detected in HeLa and SiHa cervical cell lines. Furthermore, we found that, cyclopamine, which inhibits specifically the Smo molecule of the HHS pathway, effectively induces cervical cancer cell death. HeLa cells were found very sensitive to the drug that caused cell detachment within six hours, and 70% cell detachment after overnight incubation of cyclopamine. Since uncontrolled HHS has been implicated in the development of several human cancers, the findings of abnormal expression of components of HHS in cervical cancer indicate that the HHS may play a significant role in cervical cancer development. Furthermore, the HHS pathway could be a potential target for cervical cancer therapy.