Overexpression of the Hedgehog Signalling Pathway in Head and Neck Squamous Cell Carcinoma

Abstract

Background: Overexpression of the Hedgehog (HH) signalling pathway has been described in several malignancies and is associated with a poor prognosis. HH signalling blockade reduces tumour growth in vitro and in vivo. We aimed to determine whether head and neck squamous cell carcinomas (HNSCCs) express HH proteins in comparison to healthy mucosa. Patients and Methods: Formalin-fixed and paraffin-embedded tissue sections of 10 patients with HNSCC were stained with fluorescence-labelled antibodies for cytokeratin and HH proteins (SHH, PTCH1/2, SMO, Gli1-3) and photographs were taken with a laser scanning microscope. The pixel count and colour intensity were analysed in RGB (red/green/blue) colour mode, and expression levels were compared to healthy mucosa. Results: Image analysis in RGB mode provided objective evidence for the over-expression of HH signalling components in HNSCC, particularly with regard to the transcription factors Gli1 (10-fold) and SHH (5-fold) in comparison with healthy mucosa. The lowest levels were found for Gli3 in HNSCC. Conclusions: We postulate pivotal roles of Gli1 and SHH expression in the carcinogenesis of HNSCC. HH pathway overexpression appears to be involved in the initiation of tumour growth and spread due to its stem cell-modulating properties. Detection of HH pathway components, and especially Gli1 and SHH, in HNSCC might offer a promising target for further anticancer research in HNSCC.

Preferential Activation of the Hedgehog Pathway by Epigenetic Modulations in HPV Negative HNSCC Identified with Meta-Pathway Analysis

“…Promisingly, RT-PCR confirmed the increase of GLI1 expression levels in HNSCC tumors over normals and RNA-seq from TCGA confirmed higher GLI1 expression in HPV-negative samples. The increased expression of GLI1 in HNSCC tumors in this study is consistent with observed GLI1 overexpression in HNSCC [24], [42], [43] and our previously published data showing that high expression of nuclear GLI1 is associated with poor survival and distant metastasis [24].…”

Sonic hedgehog in oral squamous cell carcinoma: An immunohistochemical study

“…[ 19 20 ] Image analysis in red, green, blue (RGB) mode provided objective evidence for over-expression of Hh signaling components in head and neck squamous cell carcinoma (HNSCC), particularly with regard to the transcription factors gli1 (10-fold) and sonic Hh (SHH) (5-fold) in comparison with healthy mucosa. [ 21 ]…”

Hedgehog signaling pathway mediates tongue tumorigenesis in wild-type mice but not in Gal3-deficient mice

“…At first glance, this finding seems to be contradictory because significant overexpression of Shh was detected in Gal3 +/+ mouse lesions, which might indicate increased Hh signaling pathway upregulation in this group when compared with Gal3 −/− mice. However, Gli3 expression is not always accompanied by uncontrolled Hh signaling activity and one recent study showed higher Gli3 expression in healthy mucosa than in head and neck carcinoma samples (Dimitrova et al, 2013). It is well known that Gli3 contains C-terminal activation and N-terminal repressor domains, which allows it to have a dual role in the Hh pathway under influence of the Hh ligand and its proteolytic processing after Sufu-GSK-3b-mediated phosphorylation (Amakye et al, 2013;Briscoe and Therond, 2013;Kise et al, 2009).…”