Sonic Hedgehog signaling pathway in gynecological and genitourinary cancer (Review)

Abstract

Cancers of the urinary tract, as well as those of the female and male reproductive systems, account for a large percentage of malignancies worldwide. Mortality is frequently affected by late diagnosis or therapeutic difficulties. The Sonic Hedgehog (SHH) pathway is an evolutionary conserved molecular cascade, which is mainly associated with the development of the central nervous system in fetal life. The present review aimed to provide an in-depth summary of the SHH signaling pathway, including the characterization of its major components, the mechanism of its upstream regulation and non-canonical activation, as well as its interactions with other cellular pathways. In addition, the three possible mechanisms of the cellular SHH cascade in cancer tissue are discussed. The aim of the present review was to summarize significant findings with regards to the expression of the SHH pathway components in kidney, bladder, ovarian, cervical and prostate cancer. Reports associated with common deficits and de-regulations of the SHH pathway were summarized, despite the differences in molecular and histological patterns among these malignancies. However, currently, neither are SHH pathway elements included in panels of prognostic/therapeutic molecular patterns in any of the discussed cancers, nor have the drugs targeting SMO or GLIs been approved for therapy. The findings of the present review may support future studies on the treatment of and/or molecular targets for gynecological and genitourinary cancers.

Expression levels of sonic hedgehog pathway genes and their targets are upregulated in early clear cell renal cell carcinoma

“…Furthermore, higher mRNA level of GLI2 and GLI3 was observed in 44 and 36 patients with ccRCC, respectively ( Table III ). High (~48-fold upregulation) GLI1 gene expression was observed in tumor tissues of 44 patients with ccRCC ( Table III ), and this also acts as positive feedback in the SHH signaling pathway ( 6 ). Although the mRNA levels of PTCH1 , the second gene involved in negative feedback regulation of the SHH signaling pathway ( 6 ), were not quantitatively changed in direct comparison with normal kidney samples, increased levels were observed in tumor ccRCC tissues of younger patients (<64 years of age; Table III ), which is in line with our previous research ( 16 ).…”

“…Furthermore, in vivo treatment of cancer-bearing mice with both GANT61 and perifosine was found to be associated with higher renal cancer suppression than treatment with either of these agents alone, and this is reflected by the reduction in tumor volume and increased immunoreactivity of an apoptotic marker (cleaved-caspase 3) in cancer tissues ( 17 ). It has been demonstrated that activation of the MAPK/ERK signaling pathway stimulates the transcriptional activity of GLIs in gastric cancer ( 6 ). Therefore, due to the possible involvement of other signaling pathways in the regulation of transcriptional activity of GLIs in kidney cancer, the antitumor properties of GANT61 appear to be weak.…”

“…This stimulates SMO protein to process GLI2 and GLI3, which dissociate from the SUFU protein and finally stimulate the expression of target genes ( MYC , BCL2 , VEGFA , CCND1 , PTCH1 and GLI1 ). The latter encodes another transcriptional activator of SHH signaling ( 6 ). Three SHH pathway inhibitors are presented in the figure: RU-SKI43 blocks the activity of the HHAT enzyme ( 21 ), cyclopamine inhibits conformational changes of the SMO protein ( 23 ) and GANT61 modifies the structure of GLI1 and GLI2, preventing their interaction with double-stranded DNA ( 24 ).…”

Suppressive GLI2 fragment enhances liver metastasis in colorectal cancer

“…When we examined the expression of the SHH signaling-related genes, Shh , Ptch , and Smo , after LA treatment, we observed that only Shh exhibited increased expression ( Figure 1B ). GLIs are responsible for transmitting SHH signals to the nucleus and inducing gene expression [ 15 ]. The expression pattern of GLIs may be involved in the specific signal formation by LA.…”

“…SHH is overexpressed in CRCs [ 13 ], and activation of SHH signaling correlates with the metastatic potential of CRCs [ 14 ]. The hedgehog (Hh) pathway involves signaling via one of the three Hh ligands (SHH, Indian HH [IHH], and Desert HH [DHH]) to the glioma-associated oncogene (GLI) transcription factors [ 15 ]. This process is mediated by interplay between the inhibitory receptor, patched (PTCH1), and the activating receptor, smoothened (SMO); the process is also influenced by protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP).…”