scholarly journals Hedgehog Signaling for Urogenital Organogenesis and Prostate Cancer: An Implication for the Epithelial–Mesenchyme Interaction (EMI)

2019 ◽  
Vol 21 (1) ◽  
pp. 58 ◽  
Author(s):  
Taiju Hyuga ◽  
Mellissa Alcantara ◽  
Daiki Kajioka ◽  
Ryuma Haraguchi ◽  
Kentaro Suzuki ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Hedgehog Signaling ◽  
Malignant Tumors ◽  
External Genitalia ◽  
Growth Factor Signaling ◽  
Cellular Interactions ◽  
Signaling Crosstalk ◽  
Morphogenetic Protein ◽  
The Status ◽  
Hh Signaling

Hedgehog (Hh) signaling is an essential growth factor signaling pathway especially in the regulation of epithelial–mesenchymal interactions (EMI) during the development of the urogenital organs such as the bladder and the external genitalia (EXG). The Hh ligands are often expressed in the epithelia, affecting the surrounding mesenchyme, and thus constituting a form of paracrine signaling. The development of the urogenital organ, therefore, provides an intriguing opportunity to study EMI and its relationship with other pathways, such as hormonal signaling. Cellular interactions of prostate cancer (PCa) with its neighboring tissue is also noteworthy. The local microenvironment, including the bone metastatic site, can release cellular signals which can affect the malignant tumors, and vice versa. Thus, it is necessary to compare possible similarities and divergences in Hh signaling functions and its interaction with other local growth factors, such as BMP (bone morphogenetic protein) between organogenesis and tumorigenesis. Additionally, this review will discuss two pertinent research aspects of Hh signaling: (1) the potential signaling crosstalk between Hh and androgen signaling; and (2) the effect of signaling between the epithelia and the mesenchyme on the status of the basement membrane with extracellular matrix structures located on the epithelial–mesenchymal interface.

scholarly journals Ectopic Hedgehog Signaling Causes Cleft Palate and Defective Osteogenesis

2018 ◽  
Vol 97 (13) ◽  
pp. 1485-1493 ◽  
Author(s):  
N.L. Hammond ◽  
K.J. Brookes ◽  
M.J. Dixon
Keyword(s):  
Cleft Palate ◽  
Hedgehog Signaling ◽  
Regulatory Networks ◽  
Neural Crest Cell ◽  
Bmp Signaling ◽  
The Novel ◽  
Morphogenetic Protein ◽  
Secondary Palate ◽  
Hh Signaling ◽  
Crest Cell

Cleft palate is a common birth defect that frequently occurs in human congenital malformations caused by mutations in components of the Sonic Hedgehog (S HH) signaling cascade. Shh is expressed in dynamic, spatiotemporal domains within epithelial rugae and plays a key role in driving epithelial-mesenchymal interactions that are central to development of the secondary palate. However, the gene regulatory networks downstream of Hedgehog (Hh) signaling are incompletely characterized. Here, we show that ectopic Hh signaling in the palatal mesenchyme disrupts oral-nasal patterning of the neural crest cell–derived ectomesenchyme of the palatal shelves, leading to defective palatine bone formation and fully penetrant cleft palate. We show that a series of Fox transcription factors, including the novel direct target Foxl1, function downstream of Hh signaling in the secondary palate. Furthermore, we demonstrate that Wnt/bone morphogenetic protein (BMP) antagonists, in particular Sostdc1, are positively regulated by Hh signaling, concomitant with downregulation of key regulators of osteogenesis and BMP signaling effectors. Our data demonstrate that ectopic Hh-Smo signaling downregulates Wnt/BMP pathways, at least in part by upregulating Sostdc1, resulting in cleft palate and defective osteogenesis.

scholarly journals Chondroitin sulfate proteoglycan Windpipe modulates Hedgehog signaling in Drosophila

2018 ◽  
Author(s):  
Masahiko Takemura ◽  
Fredrik Noborn ◽  
Jonas Nilsson ◽  
Eriko Nakato ◽  
Tsu-Yi Su ◽  
...  
Keyword(s):  
Cell Surface ◽  
Chondroitin Sulfate ◽  
Hedgehog Signaling ◽  
Transmembrane Protein ◽  
Wing Disc ◽  
Chondroitin Sulfate Proteoglycan ◽  
Growth Factor Signaling ◽  
Sulfate Proteoglycan ◽  
Sugar Chain ◽  
Hh Signaling

AbstractProteoglycans, a class of carbohydrate-modified proteins, often modulate growth factor signaling on the cell surface. However, the molecular mechanism by which proteoglycans regulate signal transduction is largely unknown. In this study, using a recently-developed glycoproteomic method, we found that Windpipe (Wdp) is a novel chondroitin sulfate proteoglycan (CSPG) in Drosophila. Wdp is a single-pass transmembrane protein with leucin-rich repeat (LRR) motifs and bears three CS sugar chain attachment sites in the extracellular domain. Here we show that Wdp modulates the Hedgehog (Hh) pathway. Overexpression of wdp inhibits Hh signaling in the wing disc, which is dependent on its CS chains and the LRR motifs. Conversely, loss of wdp leads to the upregulation of Hh signaling. Furthermore, knockdown of wdp increase the cell surface accumulation of Smoothened (Smo), suggesting that Wdp inhibits Hh signaling by regulating Smo stability. Our study demonstrates a novel role of CSPG in regulating Hh signaling.

scholarly journals Unique functions of Sonic hedgehog signaling during external genitalia development

Development ◽  
2001 ◽  
Vol 128 (21) ◽  
pp. 4241-4250 ◽  
Author(s):  
Ryuma Haraguchi ◽  
Rong Mo ◽  
Chi-chung Hui ◽  
Jun Motoyama ◽  
Shigeru Makino ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
External Genitalia ◽  
Sonic Hedgehog Signaling ◽  
Urethral Plate ◽  
Morphogenetic Protein ◽  
Fibroblast Growth Factor 10 ◽  
Dramatic Shift ◽  
Patched 1

Coordinated growth and differentiation of external genitalia generates a proximodistally elongated structure suitable for copulation and efficient fertilization. The differentiation of external genitalia incorporates a unique process, i.e. the formation of the urethral plate and the urethral tube. Despite significant progress in molecular embryology, few attempts have been made to elucidate the molecular developmental processes for external genitalia. The sonic hedgehog (Shh) gene and its signaling genes have been found to be dynamically expressed during murine external genitalia development. Functional analysis by organ culture revealed that Shh could regulate mesenchymally expressed genes, patched 1 (Ptch1), bone morphogenetic protein 4 (Bmp4), Hoxd13 and fibroblast growth factor 10 (Fgf10), in the anlage: the genital tubercle (GT). Activities of Shh for both GT outgrowth and differentiation were also demonstrated. Shh–/– mice displayed complete GT agenesis, which is compatible with such observations. Furthermore, the regulation of apoptosis during GT formation was revealed for the first time. Increased cell death and reduced cell proliferation of the Shh–/– mice GT were shown. A search for alterations of Shh downstream gene expression identified a dramatic shift of Bmp4 gene expression from the mesenchyme to the epithelium of the Shh mutant before GT outgrowth. Regulation of mesenchymal Fgf10 gene expression by the epithelial Shh was indicated during late GT development. These results suggest a dual mode of Shh function, first by the regulation of initiating GT outgrowth, and second, by subsequent GT differentiation.

scholarly journals Roles of the Hedgehog Signaling Pathway in Skin Development, Homeostasis and Cancer

2017 ◽  
Author(s):  
Yoshinori Abe ◽  
Nobuyuki Tanaka
Keyword(s):  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Signaling Pathway ◽  
Basal Cell ◽  
Hedgehog Signaling ◽  
Current Knowledge ◽  
Skin Development ◽  
Morphogenetic Protein ◽  
Hh Signaling

The epidermis is the outermost layer of skin and provides a protective barrier against environmental insults. It is a rapidly renewing tissue undergoing constant regeneration, maintained by several types of stem cells. Hedgehog (HH) ligands activate one of the fundamental signaling pathways that contribute to epidermal development, homeostasis and repair. The HH pathway interacts with other signal transduction pathways such as those activated by Wnt and bone morphogenetic protein. Furthermore, aberrant activation of HH signaling is associated with various tumors, including basal cell carcinoma. Therefore, an understanding of the regulatory mechanisms of the HH signaling pathway is important to elucidate fundamental mechanisms underlying both organogenesis and carcinogenesis. In this review, we discuss the role of the HH signaling pathway in skin development, homeostasis and basal cell carcinoma formation, providing an update of current knowledge in this field.

scholarly journals Hedgehog Signaling in Cancer: A Prospective Therapeutic Target for Eradicating Cancer Stem Cells

Cells ◽  
2018 ◽  
Vol 7 (11) ◽  
pp. 208 ◽  
Author(s):  
Ita Novita Sari ◽  
Lan Thi Hanh Phi ◽  
Nayoung Jun ◽  
Yoseph Toni Wijaya ◽  
Sanghyun Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Hedgehog Signaling ◽  
Molecular Level ◽  
Malignant Tumors ◽  
Cancer Cell Proliferation ◽  
Comprehensive Understanding ◽  
Human Cancers ◽  
Signaling Inhibitors ◽  
Hh Signaling

The Hedgehog (Hh) pathway is a signaling cascade that plays a crucial role in many fundamental processes, including embryonic development and tissue homeostasis. Moreover, emerging evidence has suggested that aberrant activation of Hh is associated with neoplastic transformations, malignant tumors, and drug resistance of a multitude of cancers. At the molecular level, it has been shown that Hh signaling drives the progression of cancers by regulating cancer cell proliferation, malignancy, metastasis, and the expansion of cancer stem cells (CSCs). Thus, a comprehensive understanding of Hh signaling during tumorigenesis and development of chemoresistance is necessary in order to identify potential therapeutic strategies to target various human cancers and their relapse. In this review, we discuss the molecular basis of the Hh signaling pathway and its abnormal activation in several types of human cancers. We also highlight the clinical development of Hh signaling inhibitors for cancer therapy as well as CSC-targeted therapy.

scholarly journals Selective Targeting of the Hedgehog Signaling Pathway by PBM Nanoparticles in Docetaxel-Resistant Prostate Cancer

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1976
Author(s):  
Santosh Kumar Singh ◽  
Jennifer B. Gordetsky ◽  
Sejong Bae ◽  
Edward P. Acosta ◽  
James W. Lillard ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
Resistant Disease ◽  
Natural Polysaccharide ◽  
Selective Targeting ◽  
Hh Signaling ◽  
Gli 1 ◽  
Specific Membrane

An abnormality in hedgehog (Hh) signaling has been implicated in the progression of prostate cancer (PCa) to a more aggressive and therapy-resistant disease. Our assessments of human PCa tissues have shown an overexpression of the Hh pathway molecules, glioma-associated oncogene homolog 1 (GLI-1), and sonic hedgehog (SHH). The effect of the natural compound thymoquinone (TQ) in controlling the expression of Hh signaling molecules in PCa was investigated in this study. We generated planetary ball-milled nanoparticles (PBM-NPs) made with a natural polysaccharide, containing TQ, and coated with an RNA aptamer, A10, which binds to prostate-specific membrane antigen (PSMA). We prepared docetaxel-resistant C4-2B-R and LNCaP-R cells with a high expression of Hh, showing the integration of drug resistance and Hh signaling. Compared to free TQ, A10-TQ-PBM-NPs were more effective in controlling the Hh pathway. Our findings reveal an effective treatment strategy to inhibit the Hh signaling pathway, thereby suppressing PCa progression.

scholarly journals Genetic Profiling of Malignant Melanoma Arising from an Ovarian Mature Cystic Teratoma: A Case Report

2021 ◽  
Vol 22 (5) ◽  
pp. 2436
Author(s):  
Kohei Nakamura ◽  
Eriko Aimono ◽  
Reika Takamatsu ◽  
Shigeki Tanishima ◽  
Tomonari Tohyama ◽  
...  
Keyword(s):  
Malignant Melanoma ◽  
Malignant Tumors ◽  
Cystic Teratoma ◽  
Homozygous Deletion ◽  
Mature Cystic Teratoma ◽  
Genetic Profiling ◽  
Improve Treatment ◽  
The Status ◽  
Genetic Mechanisms ◽  
Targeted Gene Sequencing

Ovarian mature cystic teratomas comprise tissues derived from all three germ layers. In rare cases, malignant tumors arise from ovarian mature cystic teratoma. A variety of tumors can arise from mature cystic teratoma, among which primary malignant melanoma (MM), for which no molecular analyses such as genomic sequencing have been reported to date, is exceedingly rare, thereby limiting possible therapeutic options using precision medicine. We used targeted gene sequencing to analyze the status of 160 cancer-related genes in a patient with MM arising from an ovarian mature cystic teratoma (MM-MCT). KRAS amplification and homozygous deletion in PTEN and RB1 were detected in tumor samples collected from the patient. No KRAS amplification has been previously reported in cutaneous MM, indicating that the carcinogenesis of MM-MCT differs from that of primary cutaneous melanomas. A better understanding of the underlying genetic mechanisms will help clarify the carcinogenesis of MM-MCT. In turn, this will enable treatment with novel targeting agents as well as the initial exploration of gene-based precision oncological therapies, which aim to improve treatment outcomes for patients with this disease.

scholarly journals The Role of Sonic Hedgehog-Gli2 Pathway in the Masculinization of External Genitalia

Endocrinology ◽  
2011 ◽  
Vol 152 (7) ◽  
pp. 2894-2903 ◽  
Author(s):  
Shinichi Miyagawa ◽  
Daisuke Matsumaru ◽  
Aki Murashima ◽  
Akiko Omori ◽  
Yoshihiko Satoh ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Hedgehog Signaling ◽  
External Genitalia ◽  
Sexually Dimorphic ◽  
Hedgehog Signaling Pathway ◽  
Initial Development ◽  
Urethral Plate ◽  
Male External Genitalia

During embryogenesis, sexually dimorphic organogenesis is achieved by hormones produced in the gonad. The external genitalia develop from a single primordium, the genital tubercle, and their masculinization processes depend on the androgen signaling. In addition to such hormonal signaling, the involvement of nongonadal and locally produced masculinization factors has been unclear. To elucidate the mechanisms of the sexually dimorphic development of the external genitalia, series of conditional mutant mouse analyses were performed using several mutant alleles, particularly focusing on the role of hedgehog signaling pathway in this manuscript. We demonstrate that hedgehog pathway is indispensable for the establishment of male external genitalia characteristics. Sonic hedgehog is expressed in the urethral plate epithelium, and its signal is mediated through glioblastoma 2 (Gli2) in the mesenchyme. The expression level of the sexually dimorphic genes is decreased in the glioblastoma 2 mutant embryos, suggesting that hedgehog signal is likely to facilitate the masculinization processes by affecting the androgen responsiveness. In addition, a conditional mutation of Sonic hedgehog at the sexual differentiation stage leads to abnormal male external genitalia development. The current study identified hedgehog signaling pathway as a key factor not only for initial development but also for sexually dimorphic development of the external genitalia in coordination with androgen signaling.

Increased expression of bone morphogenetic protein-7 in bone metastatic prostate cancer

The Prostate ◽  
2003 ◽  
Vol 54 (4) ◽  
pp. 268-274 ◽  
Author(s):  
Hiroshi Masuda ◽  
Yoshitatsu Fukabori ◽  
Katsuya Nakano ◽  
Yutaka Takezawa ◽  
Takanori cSuzuki ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Morphogenetic Protein ◽  
Metastatic Prostate Cancer ◽  
Bone Morphogenetic Protein 7 ◽  
Morphogenetic Protein
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