PURPOSE: Sonic hedgehog (Shh) signaling pathway is known to play a crucial role in carcinogenesis in various malignancies, including lung cancer regarding tumorigenesis, angiogenesis, and cellular differentiation. The aim of this study was to investigate the value of components of Shh pathway as a prognostic marker in extensive stage small cell lung cancer (ES-SCLC) patients. MATERIALS AND METHODS: We retrospectively analyzed data of 36 patients who were diagnosed with ES-SCLC between 2008 and 2012 at a single center. We performed immuo-histochemistry for glioma-associated oncogene homolog zinc finger protein 1 (Gli1), patched, Shh, and Ptch-mediated repression of smoothened (Smo) proteins using formalin-fixed, paraffin-embedded tissue derived from primary tumors. We then conducted survival analysis to evaluate the prognostic impact of these markers. RESULTS: All 36 patients received platinum-based doublet chemotherapy. The median progression free survival and median overall survival were 6.9 months [95% confidence interval (CI), 6.5–7.3] and 11.7 months (95% CI, 9.1–14.3), respectively. The overall response rate was 84%. Of the 36 tissue specimens examined, over-expression of Gli1, Patched, Shh, and Smo was found in 12 (33.3%), five (13.9%), five (13.9%), and six (16.7%) cases, respectively. We found that high expression of Shh was associated with worse progression free survival (6.3 vs. 7.6 months, p=0.005) and overall survival (9.2 vs. 12.0 months, p=0.039) by both univariate and multivariate analyses, whereas other markers were not related to patient prognosis. CONCLUSION: A high proportion of small cell lung cancer tumors express proteins related to Shh pathway, and over-expression of Shh is correlated with poor prognosis.
Carcinogenesis ; Disease-Free Survival ; Drug Therapy ; Hedgehog Proteins ; Hedgehogs ; Humans ; Lung Neoplasms ; Multivariate Analysis ; Oncogenes ; Prognosis ; Repression, Psychology ; Retrospective Studies ; Small Cell Lung Carcinoma ; Zinc Fingers

Medulloblastoma is the most common malignant brain tumor of childhood and remains a major cause of cancer related mortality in children. Significant scientific advancements have transformed the understanding of medulloblastoma, leading to the recognition of four distinct clinical and molecular subgroups, namely wingless (WNT), sonic hedgehog, group 3, and group 4. Subgroup classification combined with the recognition of subgroup specific molecular alterations has also led to major changes in risk stratification of medulloblastoma patients and these changes have begun to alter clinical trial design, in which the newly recognized subgroups are being incorporated as individualized treatment arms. Despite these recent advancements, identification of effective targeted therapies remains a challenge for several reasons. First, significant molecular heterogeneity exists within the four subgroups, meaning this classification system alone may not be sufficient to predict response to a particular therapy. Second, the majority of novel agents are currently tested at the time of recurrence, after which significant selective pressures have been exerted by radiation and chemotherapy. Recent studies demonstrate selection of tumor sub-clones that exhibit genetic divergence from the primary tumor, exist within metastatic and recurrent tumor populations. Therefore, tumor resampling at the time of recurrence may become necessary to accurately select patients for personalized therapy.
Arm ; Brain Neoplasms ; Child ; Classification ; Computational Biology ; Drug Therapy ; Hedgehogs ; Humans ; Medulloblastoma ; Mortality ; Neurosurgery ; Pediatrics ; Population Characteristics ; Recurrence

Obesity has become a common healthcare problem worldwide. Cilia are tiny hair-like organelles on the cell surface that are generated and anchored by the basal body. Non-motile primary cilia have been considered to be evolutionary rudiments until a few decades, but they are now considered as important signaling organelles because many receptors, channels, and signaling molecules are highly expressed in primary cilia. A potential role of primary cilia in metabolic regulation and body weight maintenance has been suspected based on rare genetic disorders termed as ciliopathy, such as Bardet-Biedl syndrome and Alström syndrome, which manifest as obesity. Recent studies have demonstrated involvement of cilia-related cellular signaling pathways in transducing metabolic information in hypothalamic neurons and in determining cellular fate during adipose tissue development. In this review, we summarize the current knowledge about cilia and cilia-associated signaling pathways in the regulation of body metabolism.
Adipose Tissue ; Alstrom Syndrome ; Bardet-Biedl Syndrome ; Basal Bodies ; Body Weight Maintenance ; Cilia* ; Delivery of Health Care ; Energy Metabolism* ; Hedgehogs ; Metabolism ; Neurons ; Obesity ; Organelles ; Wnt Signaling Pathway

Ticks are the vectors of various pathogens, threatening human health and animal production across the globe. Here, for the first time we detected Ricketssia spp., Borrelia spp. and protozoan in ticks from Poyang Lake region in Jiangxi Province of eastern China. In 3 habitat categories and on 12 host species, 311 ticks from 11 species were collected. Haemaphysalis longicornis was the predominant species, accounting for 55.63%, followed by Rhipicephalus microplus, Haemaphysalis flava and Ixodes granulatus. Of the collected ticks, 7.07% were positive for tick-borne pathogens, and H. longicornis and H. flava were found to be co-infected with Ricketssia spp. and protozoan. H. flava was the most detected positive for tick-borne pathogens, whereas H. longicornis had the lowest infection rate, and the difference in infection rates between tick species was significant (χ²=61.24, P < 0.001). Furthermore, adult ticks demonstrated remarkably greater infection rate than immature ticks (χ²=10.12, P=0.018), meanwhile ticks on Erinaceidae showed significantly higher positivity than ticks collected on other host species (χ²=108.44, P < 0.001). Genetic fragment sequencing and analyses showed at least 4 pathogen species presence in ticks, namely Borrelia yangtzensis, Rickettsia slovaca or Rickettsia raoultii related genospecies, Babesia vogeli and Hepatozoon canis or Hepatozoon felis related genospecies. The finding indicates that the abundant ticks can carry diverse pathogens in Poyang Lake region, and pathogen infection is highly related to species, vertebrate hosts and life stages of ticks.
Adult ; Animals ; Babesia ; Borrelia ; Cats ; China ; Ecosystem ; Epidemiology ; Felis ; Hedgehogs ; Humans ; Ixodes ; Lakes ; Rhipicephalus ; Rickettsia ; Risk Factors ; Ticks ; Vertebrates

We studied a family with Gorlin-Goltz syndrome. The novel mutations of our cases were located on the 21st exon of the PTCH1 gene (c.3450C>G). The father, who received a strategic 56-day vismodegib treatment for disease control, was the first patient with Gorlin syndrome treated with the hedgehog inhibitor in Taiwan. The lesions regressed gradually, with scar formation, and were subsequently removed via a wide excision. Further details are provided below.
Basal Cell Nevus Syndrome* ; Cicatrix ; Exons ; Fathers ; Hedgehogs ; Humans ; Taiwan

The aim of this study was to understand the roles of Sonic Hedgehog (SHH) signaling during tooth root and periodontium formation. In this study, we generated the dental mesenchyme-specific Smoothened (Smo) activated/inactivated mice with the activity of Cre recombinase under the control of osteocalcin promoter.In the Smo activated mutant molar sections at the postnatal 28 days, we found extremely thin root dentin and widened pulp chamber. Picrosirius red staining showed loosely arranged fibers in the periodontal space and decreased cellular cementum with some root resorption. Immunohistochemical staining showed less localization of matrix proteins such as Bsp, Dmp1, Pstn, and Ank in the cementum, periodontal ligament, and/or cementoblast.In the Smo inactivated mutant mouse, there was not any remarkable differences in the localization of these matrix proteins compared with the wild type. These findings suggest that adequate suppressing regulation of SHH signaling is required in the development of tooth root and periodontium.
Animals ; Dental Cementum ; Dental Pulp Cavity ; Dentin ; Hedgehogs ; Mice ; Molar ; Osteocalcin ; Periodontal Ligament ; Periodontium ; Recombinases ; Root Resorption ; Tooth Root ; Tooth

Incidence of basal and squamous cell carcinoma is increasing among Korean. With increasing this incidence we need to attend the management and prevention of these cutaneous malignancies. Basal cell carcinoma (BCC) is the most common skin malignancy. Sun exposure is the most important environmental cause of BCC. Daily sun protection especially avoiding sun exposure between 10 a.m. and 4 p.m. provides most effective prevention against chronic ultraviolet-induced skin damage. Hedgehog pathway inhibitors are used locally advanced and metastatic BCC lesions in Korea. Until recently, there are no reports whether it developed resistance of Hedgehog pathway inhibitors with advanced BCC in Korean patients. Among malignant skin tumors, 19.1% were squamous cell carcinoma (SCC). The incidence of SCC was rapidly increased over the past years. However, the incidence rate of SCC in Japan has not been changed from the period 1976–1980 to 1986–1990. Sentinel lymph node biopsy for SCC did not provide diagnostic value. Bowen's disease and Erythroplasia of Queyrat are considered as carcinoma in situ of the skin. Erythroplasia of Queyrat have worse prognosis with a higher rate of malignant degeneration. Dermoscopy may helpful tool in assisting the noninvasive diagnosis of carcinoma in situ of the skin.
Bowen's Disease ; Carcinoma in Situ ; Carcinoma, Basal Cell ; Carcinoma, Squamous Cell ; Dermoscopy ; Diagnosis ; Epithelial Cells ; Erythroplasia ; Hedgehogs ; Humans ; Incidence ; Japan ; Korea ; Prognosis ; Sentinel Lymph Node Biopsy ; Skin ; Solar System

Tumor growth is governed by the coordinated action of various types of cells that are present in the tumor environment. Fibroblasts, which constitute a major fraction of the stroma, participate actively in various signaling events and regulate tumor development and metastasis. The Hedgehog (Hh) pathway plays an important role in promoting tumor malignancy via fibroblasts; however, the role of hedgehog interacting protein (hhip; inhibitor of Hh pathway) in tumor growth is poorly understood. Here we implanted B16F10 tumors in hhip+/− mice to study the tumor growth characteristics and the vascular phenotype. Furthermore, the mechanism involved in the observed phenomena was explored to reveal the role of hhip in tumor growth. The tumors that were implanted in hhip+/− mice exhibited accelerated growth and increased tumor angiogenesis. Although we observed a decrease in hypoxia, blood vessels still had abnormal phenotype. We found that increased Hh signaling in tumor fibroblasts induced a high expression of vascular endothelial growth factor (VEGF), which subsequently resulted in an increased proliferation of endothelial cells. Thus, the heterozygous knockdown of hhip in mice could affect Hh signaling in tumor fibroblasts, which could cause the increased production of the growth factor VEGF. This signaling, via a paracrine effect on endothelial cells, increased tumor vascular density.
Animals ; Anoxia ; Blood Vessels ; Endothelial Cells ; Fibroblasts ; Hedgehogs ; Mice ; Neoplasm Metastasis ; Phenotype ; Up-Regulation* ; Vascular Endothelial Growth Factor A

Remyelination via the transplantation of oligodendrocyte precursor cells (OPCs) has been considered as a strategy to improve the locomotor deficits caused by traumatic spinal cord injury (SCI). To date, enormous efforts have been made to derive OPCs from human pluripotent stem cells (hPSCs), and significant progress in the transplantation of such cells in SCI animal models has been reported. The current methods generally require a long period of time (>2 months) to obtain transplantable OPCs, which hampers their clinical utility for patients with SCI. Here we demonstrate a rapid and efficient method to differentiate hPSCs into neural progenitors that retain the features of OPCs (referred to as OPC-like cells). We used cell sorting to select A2B5-positive cells from hPSC-derived neural rosettes and cultured the selected cells in the presence of signaling cues, including sonic hedgehog, PDGF and insulin-like growth factor-1. This method robustly generated neural cells positive for platelet-derived growth factor receptor-α (PDGFRα) and NG2 (~90%) after 4 weeks of differentiation. Behavioral tests revealed that the transplantation of the OPC-like cells into the spinal cords of rats with contusive SCI at the thoracic level significantly improved hindlimb locomotor function. Electrophysiological assessment revealed enhanced neural conduction through the injury site. Histological examination showed increased numbers of axon with myelination at the injury site and graft-derived myelin formation with no evidence of tumor formation. Our method provides a cell source from hPSCs that has the potential to recover motor function following SCI.
Animals ; Axons ; Behavior Rating Scale ; Cues ; Hedgehogs ; Hindlimb ; Humans* ; Methods ; Models, Animal ; Myelin Sheath ; Neural Conduction ; Oligodendroglia ; Platelet-Derived Growth Factor ; Pluripotent Stem Cells* ; Rats ; Spinal Cord Injuries* ; Spinal Cord*

Tissue fibrosis, characterized by excessive accumulation of aberrant extracellular matrix (ECM) produced by myofibroblasts, is a growing cause of mortality worldwide. Understanding the factors that induce myofibroblastic differentiation is paramount to prevent or reverse the fibrogenic process. Integrin-mediated interaction between the ECM and cytoskeleton promotes myofibroblast differentiation. In the present study, we explored the significance of integrin alpha 11 (ITGA11), the integrin alpha subunit that selectively binds to type I collagen during tissue fibrosis in the liver, lungs and kidneys. We showed that ITGA11 was co-localized with α-smooth muscle actin-positive myofibroblasts and was correlatively induced with increasing fibrogenesis in mouse models and human fibrotic organs. Furthermore, transcriptome and protein expression analysis revealed that ITGA11 knockdown in hepatic stellate cells (liver-specific myofibroblasts) markedly reduced transforming growth factor β-induced differentiation and fibrotic parameters. Moreover, ITGA11 knockdown dramatically altered the myofibroblast phenotype, as indicated by the loss of protrusions, attenuated adhesion and migration, and impaired contractility of collagen I matrices. Furthermore, we demonstrated that ITGA11 was regulated by the hedgehog signaling pathway, and inhibition of the hedgehog pathway reduced ITGA11 expression and fibrotic parameters in human hepatic stellate cells in vitro, in liver fibrosis mouse model in vivo and in human liver slices ex vivo. Therefore, we speculated that ITGA11 might be involved in fibrogenic signaling and might act downstream of the hedgehog signaling pathway. These findings highlight the significance of the ITGA11 receptor as a highly promising therapeutic target in organ fibrosis.
Animals ; Collagen ; Collagen Type I ; Cytoskeleton ; Extracellular Matrix ; Fibrosis ; Hedgehogs ; Hepatic Stellate Cells ; Humans ; In Vitro Techniques ; Kidney ; Liver ; Liver Cirrhosis ; Lung ; Mice ; Mortality ; Myofibroblasts* ; Phenotype* ; Transcriptome ; Transforming Growth Factors