Enhanced expression of hedgehog signaling molecules in squamous cell carcinoma of uterine cervix and its precursor lesions

Abstract

The hedgehog (Hh)-signaling pathway plays an essential role in normal development. Deregulation of this pathway is responsible for several types of cancers. The aim of this study was to determine the expression pattern and the extent of Hh-signaling molecules in squamous cell carcinoma of uterine cervix and its precursor lesions. A total of 106 uterine cervical cancers and related lesions (37 squamous cell carcinomas, 23 cervical intraepithelial neoplasia (CIN) III, 10 CIN II, four CIN I, 32 normal cervical epithelia) were immunohistochemically analyzed with anti-Shh, Indian Hh (Ihh), Patched (PTCH), Smoothened (Smo), Gli-1, Gli-2, Gli-3 antibodies on paraffin blocks. The results showed that the expression of all the Hh-signaling molecules was greatly enhanced in uterine cervical tumors, including carcinoma and its precursor lesions. The staining pattern was mainly cytoplasmic except for Gli-1/2, whose expression was observed in both cytoplasm and nucleus. In case of Ihh, PTCH, Smo and Gli-1, their expression in normal epithelium was completely absent or rare. The expression of all the seven Hh-signaling molecules mentioned above was significantly increased in CIN II/III and carcinoma, compared with that in normal epithelium (Po0.05). The expression of Shh was increased by double; the first increase occurred in normal epithelium-CIN transition, and the second, during the progression of CIN to carcinoma. These results strongly suggest that the Hh-signaling pathways were extensively activated in carcinoma and CIN of uterine cervix. In conclusion, the Hh-signaling pathways may be involved in carcinogenesis of squamous cell carcinoma of uterine cervix and can be considered as a potential therapeutic target.

Association between FOXM1 and hedgehog signaling pathway in human cervical carcinoma by tissue microarray analysis

“…The overexpression of these molecules, which are involved in the Hh signaling pathway, implies that this pathway participates in the formation and invasion of cervical cancer. Xuan et al (41) also studied the expression of the aforementioned Hh signaling molecules in cervical cancer, and observed that their expression was higher in carcinoma tissues and cervical intraepithelial neoplasia of stage II/III than in normal tissues. Furthermore, Samarzija and Beard (42) reported that the overexpression of GLI1, PTCH1, SMO and SHh in cervical cancer cells (including C33-A, SiHa, C4-1, CaSki and HeLa), and the inhibition of the Hh signaling pathway by its inhibitor, reduced the proliferation and survival of cervical cancer cells.…”

Promoter methylation in the PTCH gene in cervical epithelial cancer and ovarian cancer tissue as studied by eight novel Pyrosequencing® assays

“…Therefore, PTCH promoter methylation is probably not a high-prevalence event in squamous cell cervical cancer or ovarian cancer. This is not a surprising finding, since it has been shown that cervical cancer samples usually show increased expression of PTCH protein (12), and the same is true for ovarian cancer (20), although LOH of the PTCH region has been associated with some types of ovarian cancer (21). Extended applications of these newly-developed assays to larger series of cancer tissues from other cell types will be needed to clarify the extent and role of PTCH promoter methylation in other human cancers.…”

“…This particular variant is known to have full inhibitory activity on SMO (18). Recent data suggest an enhanced expression of the PTCH protein in squamous cell carcinoma of uterine cervix and its precursor lesions (12). To link this finding to possible changes in methylation status of the promoter regions of PTCH, in response to ovarian cancer development, is an overarching goal of our current PTCH studies using dye-terminator sequencing.…”

“…PTCH has several alternative splicing sites (a, b, c, d and e) starting from exon 1 (16,17). The most studied of these regions, in relevance to epigenetic changes and regulatory effects of the protein (7,8,12), contains the N-terminus encoded by exon 1B (16,18). This particular variant is known to have full inhibitory activity on SMO (18).…”

“…It has been suggested that the PTCH gene has tumor-suppressor function because it appears to be involved in the development of several cancers such as ovarian dermoids, fibromas (7), medulloblastoma (10), acute myeloid leukemia (11), uterine cervical carcinoma (12), breast cancer (8), sporadic basal cell carcinomas (13) and nevoid basal cell carcinoma (2).…”