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Expression profile and cellular localisation of GLI3 and PTCH1 proteins inhealthy and tumor prostate tissue

Background & Objectives: The Hedgehog-GLI (HH- GLI) signalling pathway is primarily associated with embryonic development but its role in carcinogenesis has being intensely studied in the last two decades. Recent research indicates that HH-GLI pathway could be a key player in prostate cancer (PC) development and progression, as well as therapeutic resistance. The main objective of this study was to investigate the HH-GLI pathway activity in PC in comparison with healthy prostate and prostate inflammation. Methods: Around 30 formalin-fixed paraffin-embedded tissue samples per group were collected from PC patients (Grade Groups I-V) and two controls groups (benign prostate tissue and prostate inflammation). Expression profiles of GLI3 and PTCH1 proteins was detemined immunohistochemically. The level of protein staining was expressed by multiplying percentage of positive stained cells and staining intensity (histoscore), separately for prostate epithelium and stroma. Cellular localization of protein staining (nuclear and/or cytoplasmic) was also determined. Results: GLI3 and PTCH1 were overexpressed in epithelium (P<0.0001 for both), but not in stroma. GLI3 localization in epithelium was mostly diffuse (nuclear and cytoplasmic), while cytoplasmic GLI3 localization in stroma was negatively associated with Grade Group (P<0.0001). Same was observed for PTCH1 localization in epithelium and stroma (P<0.0001 for both). In prostate inflammation samples prevails cytoplasmic PTCH1, while in benign prostate diffuse. All HH-GLI patway components were expressed in androgen-dependent PC cell line LNCaP. Interestingly, androgen-deprived conditions significantly upregulated GLI3. Conclusion: Our study has determined an increased activity of HH-GLI pathway in PC and potential role of GLI3 in androgen-independent growth. However, its relation to PC progression and mechanisms of sustaining androgen- independent growth has yet to be determined. Observation of higher nuclear localization of GLI3 in higher Grade Group could indicate an increased paracrine HH-GLI signalling, from tumour cells toward stroma.

Hedgehog-GLI signaling pathway ; GLI3 ; PTCH1 ; prostate cancer

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