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Patched-2 functions to limit Patched-1 deficient skin cancer growth
- Source :
- Cellular Oncology (2011. Print), 41, 4, pp. 427-437, Cellular oncology, 41(4), 427-437. IOS Press, Cellular Oncology (Dordrecht), Cellular Oncology (2011. Print), 41, 427-437
- Publication Year :
- 2018
- Publisher :
- Springer Science and Business Media LLC, 2018.
-
Abstract
- Purpose Basal cell carcinoma (BCC) is one of the most common skin cancers, and is typically driven by an aberrantly activated Hedgehog (Hh) pathway. The Hh pathway is regulated by interactions between the Patched-1 (Ptch1) and Smoothened (Smo) receptors. Smo is an activating receptor and is subject to inhibition by Ptch1. Following ligand binding to Ptch1, its inhibitory action is relieved and pathway activation occurs. This receptor interaction is pivotal to restraining uncontrolled cellular growth. Both receptors have been found to be frequently mutated in BCCs. Ptch2 is a Ptch1 paralog that exhibits overlapping functions in both normal development and tissue homeostasis. As yet, its contribution to cancer growth is poorly defined. Here we set out to assess how Ptch2 inhibits BCC growth. Methods We used several in vitro readouts for transcriptional and chemotactic Hh signaling in BCC-derived ASZ001 cells, and a novel xenograft model to assess in vivo BCC tumor growth. Gene editing by TALEN was used to untangle the different Ptch2-dependent responses to its ligand sonic hedgehog (Shh). Results We first defined the signaling competence of Ptch2 in Ptch1-deficient ASZ001 cells in vitro, and found that Ptch2 ligand binding drives their migration rather than eliciting a transcriptional response. We found that subsequent targeting of Ptch2 abrogated the chemotaxic effect. Next, we tested the contribution of Ptch2 to in vivo tumor growth using a xenograft model and found that reduced Ptch function results in increased tumor growth, but that selective pressure appatently acts against complete Ptch2 ablation. Conclusions We conclude that like Ptch1, Ptch2 exerts a tumor-suppressive function in BCC cells, and that after targeting of both paralogs, ligand-independent activation of the Hh pathway contributes to tumor growth. Electronic supplementary material The online version of this article (10.1007/s13402-018-0381-9) contains supplementary material, which is available to authorized users.
- Subjects :
- 0301 basic medicine
Patched
Cancer Research
Skin Neoplasms
Cell Survival
Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2]
Hedgehog signaling
Patched-2 Receptor
Mice
03 medical and health sciences
All institutes and research themes of the Radboud University Medical Center
Cell Line, Tumor
Animals
Humans
Sonic hedgehog
Hedgehog
Tissue homeostasis
Smoothened
Original Paper
biology
Reverse Transcriptase Polymerase Chain Reaction
Chemistry
General Medicine
Hedgehog signaling pathway
Cell biology
Patched-1 Receptor
PTCH2
030104 developmental biology
Oncology
PTCH1
Carcinoma, Basal Cell
Basal cell carcinoma
biology.protein
Molecular Medicine
Signal Transduction
Subjects
Details
- ISSN :
- 22113436 and 22113428
- Volume :
- 41
- Database :
- OpenAIRE
- Journal :
- Cellular Oncology
- Accession number :
- edsair.doi.dedup.....8e7d4fd58d561d51a39e9331c0bcf523