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Odontogenic keratocysts (OKCs) are common cystic lesions of odontogenic epithelial origin that can occur sporadically or in association with naevoid basal cell carcinoma syndrome (NBCCS). OKCs are locally aggressive, cause marked destruction of the jaw bones and have a propensity to recur. PTCH1 mutations (at ∼80%) are frequently detected in the epithelia of both NBCCS-related and sporadic OKCs, suggesting that PTCH1 inactivation might constitutively activate sonic hedgehog (SHH) signalling and play a major role in disease pathogenesis. Thus, small molecule inhibitors of SHH signalling might represent a new treatment strategy for OKCs. However, studies on the molecular mechanisms associated with OKCs have been hampered by limited epithelial cell yields during OKC explant culture. Here, we constructed an isogenic PTCH1 cellular model of PTCH1 inactivation by introducing a heterozygous mutation, namely, c.403C>T (p.R135X), which has been identified in OKC patients, into a human embryonic stem cell line using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system. This was followed by the induction of epithelial differentiation. Using this in vitro isogenic cellular model, we verified that the PTCH1 heterozygous mutation causes ligand-independent activation of SHH signalling due to PTCH1 haploinsufficiency. This activation was found to be downregulated in a dose-dependent manner by the SHH pathway inhibitor GDC-0449. In addition, through inhibition of activated SHH signalling, the enhanced proliferation observed in these induced cells was suppressed, suggesting that GDC-0449 might represent an effective inhibitor of the SHH pathway for use during OKC treatment.
This article was published in the following journal.
Name: International journal of oral science
To explore the changes of Sonic Hedgehog (Shh) signaling pathway in the stomach mucosa during the formation of gastric precancerous lesions.
Peritoneal fibrosis is a devastating complication of peritoneal dialysis. However, its precise mechanism is unclear, and specific treatments have not yet been established. Recent evidence suggests tha...
Adipocyte-derived exosomes (ADEs) stimulate the activation of macrophages and contribute to the development of insulin resistance. Sonic Hedgehog (Shh) is an exosome-carrying protein and stimulates ma...
To investigate export of Hedgehog pathway (Hh) proteins Patched1, Smoothened, Sonic hedgehog and Indian hedgehog in cervical cancer cell line (CaCx) exosomes.
The current investigation was intended to elucidate the molecular mechanism of α-Mangostin in the regulation of pancreatic cancer stem cell (CSC) characteristics. Here, we demonstrate that α-Mangost...
This is a multicenter, open-label extension study. Patients receiving GDC-0449 in a Genentech-sponsored study who have completed the parent study or who continue to receive GDC-0449 at th...
This is an open-label, single arm, multi-center, Phase II trial to evaluate the progression free survival in patients with metastatic adenocarcinoma of the pancreas treated with a hedgehog...
The proposed study is a Phase II, randomized, placebo-controlled, double-blind, multicenter clinical trial of GDC-0449 in patients with ovarian cancer in a second or third complete remissi...
This is an open-label, Phase I, single-center, single-dose administration study to determine the absolute bioavailability, clearance, and volume of distribution of GDC-0449 (Part A) and to...
RATIONALE: GDC-0449 and RO4929097 may slow the growth of tumor cells and may be an effective treatment for advanced breast cancer. PURPOSE: This phase I trial is studying the side effects...
A frizzled-like, G-protein-coupled receptor that associates with PATCHED RECEPTORS to transduce signals from HEDGEHOG PROTEINS and initiate hedgehog signaling to ZINC FINGER PROTEIN GLI1. It may normally inhibit signaling in the absence of SONIC HEDGEHOG PROTEIN binding to PATCHED RECEPTOR-1.
A transcriptional activator and oncogene protein that contains two CYS2-HIS2 ZINC FINGERS. Two isoforms are expressed; both regulate the expression of specific genes during development of craniofacial features, digits, the CENTRAL NERVOUS SYSTEM; and the GASTROINTESTINAL TRACT. They also regulate SONIC HEDGEHOG PROTEIN signaling and cell proliferation.
A zinc finger transcription factor that contains five CYS2-HIS2 ZINC FINGERS and binds to the GLI consensus sequence 5'-GGGTGGTC-3'. The full-length protein functions as a transcriptional activator whereas the truncated C-terminal form functions as a transcriptional repressor of the Sonic Hedgehog (Shh) signaling pathway; a balance between these two forms is critical for limb and digit development. GLI3 also plays a critical role in the differentiation and proliferation of CHONDROCYTES.
A family of intercellular signaling proteins that play and important role in regulating the development of many TISSUES and organs. Their name derives from the observation of a hedgehog-like appearance in DROSOPHILA embryos with genetic mutations that block their action.
A potent inhibitor of the high affinity uptake system for CHOLINE. It has less effect on the low affinity uptake system. Since choline is one of the components of ACETYLCHOLINE, treatment with hemicholinium can deplete acetylcholine from cholinergic terminals. Hemicholinium 3 is commonly used as a research tool in animal and in vitro experiments.
There are three main types of skin cancer: basal cell carcinoma, squamous cell carcinoma and malignant melanoma. Basal cell carcinoma Basal cell carcinoma, or BCC, is a cancer of the basal cells at the bottom of the epidermis. It’s very common ...
Arthroplasty Joint Disorders Orthopedics Spinal Cord Disorders Orthopedics is the science or practice of correcting deformities caused by disease or damage to the bones and joints of the skeleton. This specialized branch of surgery may ...