engleski

Expression of GLI3 and PTCH1 Proteins in Prostate Cancer

The Hedgehog-GLI (HH-GLI) signaling pathway is primarily associated with embryonic development but in the last two decades its role in cancer development has become intensely studied. The HH- GLI pathway is associated with one third of cancer related deaths, which makes it an interesting new therapeutic target. Recent research indicates that the HH-GLI pathway could be a key player in prostate cancer development and progression, as well as in the development of resistance to therapeutics. The aim of this study is to investigate the activity of the HH-GLI pathway in prostate cancer tissue samples in comparison with healthy prostate tissue samples and samples of prostate inflammation. Around 30 formalin-fixed paraffin-embedded prostate tissue samples per group were collected from prostate cancer patients (Grade Groups I-V) and two controls groups (benign prostate tissue and prostate inflammation). Expression of GLI3 and PTCH1 proteins was determined 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. Localization of protein staining (nuclear and/or cytoplasmic) was also determined. Both GLI3 and PTCH1 histoscores were significantly higher in epithelial prostate cancer cells (P<0.0001 for both proteins) compared to controls, but not in prostate stroma (P=0.835 for GLI3 and P=0.175 for PTCH1). GLI3 and PTCH1 expressions were positively correlated (rho=0.48, P<0.0001). Localization of GLI3 in epithelium was generally mostly diffuse (both nuclear and cytoplasmic), while in prostate cancer stroma cytoplasmic localization of GLI3 was negatively associated with higher Grade Group (P<0.0001). The same was observed for PTCH1 localization in prostate cancer epithelium and stroma (P<0.0001 for both). In control samples of prostate inflammation prevails cytoplasmic PTCH1 expression, while in benign prostate tissue it is mostly diffuse. The expression of all HH-GLI pathway components has been found in the androgen- dependent prostate cancer cell line LNCaP. Interestingly, after exposure of these cells to androgen-deprived conditions, the expression of GLI3 was significantly upregulated. Our study has determined an increased activity of HH-GLI pathway in prostate cancer, and a potential role for GLI3 in androgen-independent growth. However, its relation to prostate cancer progression and mechanisms of sustaining androgen independent growth have yet to be determined. Our results showing higher nuclear localization of GLI3 in higher Grade Group could indicate an increase in paracrine HH-GLI signaling, from the tumor cells toward the stroma. This study was funded by dm- drogerie markt donation.

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

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