Ovarian cancer (OC) is the eighth leading cause of cancer-related deaths in women and is the third most common gynecological malignancy . This disease is a major clinical challenge in gynecologic oncology, with the highest mortality rate of all malignancies of the female reproductive system . Most patients have almost no symptoms in the early stage of the disease, while nonspecific symptoms, associated with more frequent benign conditions, occur in the advanced stage of OC that significantly complicates the diagnosis of this disease [2, 3]. The diagnosis is further complicated because there are different histological subtypes of ovarian cancer with different biological and clinical features .
Serous ovarian carcinomas are the most common form of ovarian cancer and account for approximately 75% of all ovarian epithelial tumors. High- (HGSC) and low-grade (LGSC) serous ovarian carcinomas represent about 70% and < 5% of all epithelial ovarian cancers, respectively . Although both are serous in histological type, HGSCs and LGSCs are two different entities with different pathogenesis, molecular and genetic changes, origin, and prognosis . The exact origin of the LGSC and HGSC is still unknown. LGSC most likely arises from fallopian tube epithelium (FTE) , while the origin of HGSC is probably dual, and it may arise from ovarian surface epithelium (OSE) or FTE .
Aberrant activation of several signaling pathways, including the Hedgehog (Hh) signaling pathway, has been observed in ovarian cancer [8–10]. The Hh signaling pathway is an evolutionarily conserved signaling pathway that is essential for the development of a normal embryo . However, in the adult organism, this signaling pathway is inactive in most organs, so its aberrant activation in adulthood is associated with the development of various tumors [11, 12].
The Hh signaling pathway is activated when one of the three Hh ligands, Sonic Hedgehog (SHH), Indian Hedgehog (IHH) or Desert Hedgehog (DHH), binds to 12-pass transmembrane receptor Patched 1 (PTCH1) or Patched 2 (PTCH2) thus suppressing its activity. In the absence of Hh ligands, activated PTCH1 represses Hh signaling [13, 14]. PTCH1 is the main receptor of the Hh signaling pathway. The human PTCH1 gene encodes a transmembrane glycoprotein of 1447 amino acids (~ 161 kDa) . PTCH1 receptor contains transmembrane domain (TMD), two large extracellular domains (ECDs), ECD1 and ECD2, and three large cytoplasmic domains, N-terminal domain (NTD), middle loop (ML) and C-terminal domain (CTD) [16, 17].
Although PTCH1 is a negative regulator of Hh signaling, this receptor serves as a marker of canonical Hh signaling activation . Since the PTCH1 gene contains binding sites for GLI transcription factors, its expression is enhanced when Hh signaling is activated, creating a negative feedback loop [19, 20]. If this protein loses its function, either due to gene mutations or epimutations, aberrant activation of the Hh signaling will occur . Inactivating mutations and hypermethylation of the PTCH1 gene have been observed in various cancers [21–27]. However, numerous studies have shown that PTCH1 protein, otherwise known to act as a tumor suppressor, has increased expression in many different cancers, including breast, prostate, lung, colon, brain tumors, and melanoma [28–30]. A recent study has shown that the PTCH1 receptor can also serve as a transporter that releases chemotherapeutic agents out of the cell and thus contributes to chemotherapy resistance . The increased expression of PTCH1 protein in tumor tissue can be explained by possible changes in the structure and function of this protein in malignant tissue. These changes could be triggered by mutations in the PTCH1 gene whereby PTCH1 could lose its original tumor suppressor role and gain a new tumor promoter role .
Increased expression of the PTCH protein has also been observed in ovarian cancer, where expression of this protein was increased stepwise in benign, borderline, and malignant neoplasms . PTCH protein expression was associated with increased tumor cell proliferation and was positively correlated with poor survival of patients with ovarian cancer [31, 32]. On the other hand, there are studies with conflicting results where reduced expression of PTCH1 protein has been observed in tumor tissue and ovarian cancer cell lines [33, 34]. Patients with decreased expression of PTCH1 protein were found to have a poorer prognosis than patients with increased expression of this protein .
Although the studies mentioned above have shown that PTCH1 could be involved in the molecular pathogenesis of ovarian cancer, its role in ovarian cancer, as well as in certain histological subtypes of ovarian cancer, has not been sufficiently investigated. Therefore, we decided to investigate the role of PTCH1 protein, as well as changes in the promoter methylation status of the corresponding gene, in serous ovarian carcinomas. We found that PTCH1 protein may play an active role in the molecular pathogenesis of both LGSCs and HGSCs. Also, we indicated the importance of nuclear localization of PTCH1 protein in cancer cells, which can be linked with the development and progression of these carcinomas, and showed that of DNA methylation of the PTCH1 gene promoter is not a potential mechanism involved in the pathogenesis of serous ovarian carcinomas.