A non‐coding mutation in the 5′ untranslated region of patched homologue 1 predisposes to basal cell carcinoma

Tietze, Julia K.; Pfob, Martina; Eggert, Marlene; Preußen, A. von; Mehraein, Yasmin; Ruzicka, Thomas; Herzinger, Thomas

doi:10.1111/exd.12267

Cited by 4 publications

(4 citation statements)

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“…In a recently published analysis, the complete 188nt-long PTCH1b 5'UTR sequence, harboring either 7 or 8 CGG repeats, was cloned into pGL4.10 vector downstream of TK (thymidine kinase) promoter and upstream of Fluc. 33 The results in HEK 293T cells showed dramatically reduced reporter activity for plasmid harboring 8 CGG repeats, with no effect on Fluc transcription compared with the 7 CGGs construct. Consequently, both studies concluded that the CGG-repeat number could potentially alter the PTCH1b expression at translational level, which might have an effect on the severity of the disease in which certain CGGrepeat alleles were found.…”

Section: Discussionmentioning

confidence: 87%

“…20 Up to now, the only studied potential regulatory element has been a (CGG) n repeat polymorphism present immediately upstream the AUG start site, but not clear association between repeat numbers and disease risk was found. 32,33 Here we thoroughly explored cis-element features of the 5'UTR of the PTCH1 transcript 1b applying the methodology previously used for the functional analysis of 5'UTR of the CDKN2A gene. 34 …”

Section: Introductionmentioning

confidence: 99%

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Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

et al. 2015

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Inga (2015) Regulation of human PTCH1b expression by different 5' untranslated region cis-regulatory elements, RNA Biology, 12:3, 290-304, DOI: 10.1080/15476286.2015 PTCH1 gene codes for a 12-pass transmembrane receptor with a negative regulatory role in the Hedgehog-Gli signaling pathway. PTCH1 germline mutations cause Gorlin syndrome, a disorder characterized by developmental abnormalities and tumor susceptibility. The autosomal dominant inheritance, and the evidence for PTCH1 haploinsufficiency, suggests that fine-tuning systems of protein patched homolog 1 (PTC1) levels exist to properly regulate the pathway. Given the role of 5' untranslated region (5'UTR) in protein expression, our aim was to thoroughly explore cis-regulatory elements in the 5'UTR of PTCH1 transcript 1b. The (CGG) n polymorphism was the main potential regulatory element studied so far but with inconsistent results and no clear association between repeat number and disease risk. Using luciferase reporter constructs in human cell lines here we show that the number of CGG repeats has no strong impact on gene expression, both at mRNA and protein levels. We observed variability in the length of 5'UTR and changes in abundance of the associated transcripts after pathway activation. We show that upstream AUG codons (uAUGs) present only in longer 5'UTRs could negatively regulate the amount of PTC1 isoform L (PTC1-L). The existence of an internal ribosome entry site (IRES) observed using different approaches and mapped in the region comprising the CGG repeats, would counteract the effect of the uAUGs and enable synthesis of PTC1-L under stressful conditions, such as during hypoxia. Higher relative translation efficiency of PTCH1b mRNA in HEK 293T cultured hypoxia was observed by polysomal profiling and Western blot analyses. All our results point to an exceptionally complex and so far unexplored role of 5'UTR PTCH1b cis-element features in the regulation of the Hedgehog-Gli signaling pathway.

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Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

et al. 2015

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“…Consistent with previous evidences demonstrating the absence of hot spot mutation in PTCH1 gene [ 51 , 52 , 53 , 54 ], molecular analysis of patients enclosed in this study recorded heterozygotic genetic variation distributed along the entire coding sequence ( Table 1 ). Among these mutations, eight were missense changes resulting in harmful or pathogenic effects based on data from online databases ( , and , accessed on 20 June 2021), 1 was a deletion resulted in a frameshift of the coding sequence, and one insertion of a surplus CGG triplet was at the site of seven times CGG repeat in a functionally important 5′UTR intron region involved in PTCH1b variant transcription and translation [ 55 , 56 ].…”

Section: Resultsmentioning

confidence: 99%

Evaluation of Hedgehog Pathway Inhibition on Nevoid Basal Cell Carcinoma Syndrome Fibroblasts and Basal Cell Carcinoma-Associated Fibroblasts: Are Vismodegib and Sonidegib Useful to Target Cancer-Prone Fibroblasts?

Eibenschutz

Caputo

Camera

et al. 2021

Cancers

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Activating mutations in the Hh pathway underlies the development of sporadic and familial skin BCC. For these oncogenic proliferations displaying ligand-independent activation of the intracellular pathway, two molecules have been approved for therapeutic purposes: vismodegib and sonidegib. Improper Hh signalling occurs in many human tumours also via a paracrine mechanism (ligand-dependent) in which the secretion of Hh ligands by stromal cells support tumour growth. On the other hand, the mobilization of neoplastic stroma by cancer cells is sustained by the activation of Hh signalling in surrounding fibroblasts suggesting a central role of this bidirectional crosstalk in carcinogenesis. Additionally, loss-of-function mutations in the PTCH1 gene in the context of NBCCS, an autosomal dominant disorder predisposing to multiple BCCs, determine tumour permissive phenotypes in dermal fibroblasts. Here, profiling syndromic and BCC-associated fibroblasts unveiled an extraordinary similarity characterized by overexpression of several Hh target genes and a marked pro-inflammatory outline. Both cell types exposed to Hh inhibitors displayed reversion of the tumour-prone phenotype. Under vismodegib and sonidegib treatment, the Wnt/β-catenin pathway, frequently over-active in tumour stroma, resulted down-regulated by pAKT-GSK3β axis and consequent increase of β-catenin turnover. Overall, this study demonstrated that vismodegib and sonidegib impacting on fibroblast tumour supportive functions might be considered in therapy for BCC independently to the mutation status of Hh components in neoplastic cells.

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“…Major genetic changes causing BCC include inactivating mutations of PTCH-1 and activating mutations of Smoothened (27,28). Vismodegib is a small molecule that is able to inhibit Smoothened, and is commonly used in the treatment of advanced BCCs (29,30). A mounting body of evidence has demonstrated that, in a number of solid tumours, the ligand-dependent activation of HH signalling is potentiated through cross-talk with other critical molecular signalling pathways (31).…”

Section: Biology Of Nmsc and The Rationale For Using Targeted Therapymentioning

confidence: 99%

Concomitant cetuximab and radiation therapy: A possible promising strategy for locally advanced inoperable non-melanoma skin carcinomas

Scarpati

Perri

Pisconti

et al. 2016

Molecular and Clinical Oncology

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Abstract. Non-melanoma skin cancers (NMSCs) include a heterogeneous group of malignancies arising from the epidermis, comprising squamous cell carcinoma (SCC), basal cell carcinoma (BCC), Merkel cell carcinoma and more rare entities, including malignant pilomatrixoma and sebaceous gland tumours. The treatment of early disease depends primarily on surgery. In addition, certain patients present with extensive local invasion or metastasis, which renders these tumours surgically unresectable. Improving the outcome of radiotherapy through the use of concurrent systemic therapy has been demonstrated in several locally advanced cancer-treatment paradigms. Recently, agents targeting the human epidermal growth factor receptor (EGFR) have exhibited a consolidated activity in phase II clinical trials and case series reports. Cetuximab is a monoclonal antibody that binds to and completely inhibits the EGFR, which has been revealed to be up-regulated in a variety of SCCs, including NMSCs. The present review aimed to summarize the role of anti-EGFR agents in the predominant types of NMSC, including SCC and BCC, and focuses on the cetuximab-based studies, highlighting the biological rationale of this therapeutic option. In addition, the importance of the association between cetuximab and radiotherapy for locally advanced NMSC is discussed.

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A non‐coding mutation in the 5′ untranslated region of patched homologue 1 predisposes to basal cell carcinoma

Cited by 4 publications

References 12 publications

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

Regulation of humanPTCH1bexpression by different 5' untranslated regioncis-regulatory elements

Evaluation of Hedgehog Pathway Inhibition on Nevoid Basal Cell Carcinoma Syndrome Fibroblasts and Basal Cell Carcinoma-Associated Fibroblasts: Are Vismodegib and Sonidegib Useful to Target Cancer-Prone Fibroblasts?

Concomitant cetuximab and radiation therapy: A possible promising strategy for locally advanced inoperable non-melanoma skin carcinomas

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