Sonic hedgehog signalling pathway regulates apoptosis through Smo protein in human umbilical vein endothelial cells

Zhu, Shangling; Luo, Meiling; Weixiang, Peng; Li, Qiuxia; Feng, Zhiying; Li, Zhaoxia; Wang, Mingxia; Xu, Feng; Liu, Fang; Huang, Jianlin

doi:10.1093/rheumatology/keu421

Cited by 22 publications

(17 citation statements)

References 25 publications

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“…Although most of the studies focused on the role of Hh signaling in the morphogenesis, this pathway is multifaceted and regulates a broad spectrum of other processes including tissue maturation, cell fate decisions (proliferation, apoptosis, migration, and differentiation), and maintenance of stem cell population [ 16 , 17 , 18 , 19 , 20 ]. In line with this notion, activation of the Hh signaling is not only a typical feature of embryogenesis, but it has been also observed in the postnatal period, where it maintains tissue homeostasis and drives repair and regeneration following injury [ 21 , 22 , 23 ].…”

Section: Hedgehog Signaling In Cancermentioning

confidence: 99%

Targeting GLI Transcription Factors in Cancer

2018

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Aberrant activation of hedgehog (Hh) signaling has been observed in a wide variety of tumors and accounts for more than 25% of human cancer deaths. Inhibitors targeting the Hh signal transducer Smoothened (SMO) are widely used and display a good initial efficacy in patients suffering from basal cell carcinoma (BCC); however, a large number of patients relapse. Though SMO mutations may explain acquired therapy resistance, a growing body of evidence suggests that the non-canonical, SMO-independent activation of the Hh pathway in BCC patients can also account for this adverse effect. In this review, we highlight the importance of glioma-associated oncogene (GLI) transcription factors (the main downstream effectors of the canonical and the non-canonical Hh cascade) and their putative role in the regulation of multiple oncogenic signaling pathways. Moreover, we discuss the contribution of the Hh signaling to malignant transformation and propose GLIs as central hubs in tumor signaling networks and thus attractive molecular targets in anti-cancer therapies.

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Section: Hedgehog Signaling In Cancermentioning

confidence: 99%

Targeting GLI Transcription Factors in Cancer

2018

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“…Asai et al have shown that SHH directly promotes the migration, adhesion, proliferation and even tube formation of endothelial progenitor cells [42]. Other studies have indicated that SHH application protects against apoptosis in endothelial cells, while the SMO-specific inhibitor enhances TNF-a-induced apoptosis in HUVECs [43,44]. Regarding Hedgehog-Gli1 signaling activation in HUVECs induced by the MNTs, we paid further attention to Hedgehog-Gli1 signaling and investigated its potential roles in mediating biological effects of the biomaterial topographies.…”

Section: Discussionmentioning

confidence: 99%

The hierarchical micro-/nanotextured topographies promote the proliferation and angiogenesis-related genes expression in human umbilical vein endothelial cells by initiation of Hedgehog-Gli1 signaling

Lin

Shao

et al. 2018

Artificial Cells, Nanomedicine, and Biotechnology

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The hierarchical microtextured/nanotextured topographies have been recognized to have better tissue integration properties, but the underlying mechanisms are only partially understood. Hedgehog signaling plays a pivotal role in developmental and homeostatic angiogenesis. We suppose that the Hedgehog-Gli1 signaling may play a significant role in the response of endothelial cells to microtextured/nanotextured topographies (MNTs). To confirm this hypothesis, we produced the MNTs decorated with TiO2 nanotubes of two different diameters (25 and 70 nm), and the proliferation, apoptosis, angiogenesis-related genes expression and Hedgehog signaling activity of human umbilical vein endothelial cells (HUVECs) grown onto these MNTs were measured. Our results showed that the MNTs induced significantly high expression of Sonic Hedgehog (SHH), Smoothened (SMO) and GLI1 in the HUVECs as well as high activation of Hedgehog-Gli1 signaling, compared to the smooth surface. The HUVECs grown on the MNTs showed significantly high levels of adhesion, proliferation and expression of angiogenesis-related genes, including angiopoietin-1 (ANG-1), vascular endothelial growth factor (VEGFA), vascular endothelial growth factor receptor 2 (VEGFR2) and endothelial nitric oxide synthase (ENOS); these enhancements were attenuated by siRNA-mediated depletion of SMO, which indicated a significant role of Hedgehog-Gli1 signaling in mediating the enhanced effect of the MNTs on the angiogenic potential of HUVECs. This study may contribute to the modification of biomaterial surfaces for better tissue integration and clinical performance.

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“…Our results showed that cyclopamine significantly suppressed the gene and protein expression of Smo and Gli1 nuclear accumulation, which was consistent with previous studies. 50,51 Treatment with cyclopamine decreased the proliferative activity of MG63 cells, especially the cells seeded onto MNTs. Furthermore, the enhanced expressions of the osteogenesis-related genes (BMP-2, ALP, and Runx2) and ALP production enabled by the MNTs were significantly downregulated by the presence of cyclopamine to a similar level as those on the smooth and acid-etched microstructured surfaces in the absence of cyclopamine.…”

Section: Discussionmentioning

confidence: 99%

Role of Hedgehog–Gli1 signaling in the enhanced proliferation and differentiation of MG63 cells enabled by hierarchical micro-/nanotextured topography

Lin¹,

Huang²,

He³

et al. 2017

IJN

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Hedgehog–Gli1 signaling is evolutionarily conserved and plays an essential role in osteoblast proliferation and differentiation as well as bone formation. To evaluate the role of the Hedgehog–Gli1 pathway in the response of osteoblasts to hierarchical biomaterial topographies, human MG63 osteoblasts were seeded onto smooth, microstructured, and micro-/nanotextured topography (MNT) titanium to assess osteoblast proliferation and differentiation in terms of proliferative activity, alkaline phosphatase (ALP) production, and osteogenesis-related gene expression. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the mRNA expression of Sonic hedgehog (Shh), Smoothened (Smo), and Gli1, and the protein levels were assayed by Western blotting. MG63 cells treated with the Smo inhibitor cyclopamine were seeded onto the titanium specimens, and the cell proliferation and differentiation were studied in the presence or absence of cyclopamine. Our results showed that compared to the smooth and microstructured surfaces, the MNTs induced a higher gene expression and protein production of Shh, Smo, and Gli1 as well as the activation of Hedgehog signaling. The enhanced proliferative activity, ALP production, and expression of the osteogenesis-related genes (bone morphogenetic protein-2, ALP, and runt-related transcription factor 2) enabled by the MNTs were significantly downregulated by the presence of cyclopamine to a similar level as those on the smooth and acid-etched microstructured surfaces in the absence of cyclopamine. This evidence explicitly demonstrates pivotal roles of Hedgehog–Gli1 signaling pathway in mediating the enhanced effect of MNTs on MG63 proliferation and differentiation, which greatly advances our understanding of the mechanism involved in the biological responsiveness of biomaterial topographies. These findings may aid in the optimization of hierarchical biomaterial topographies targeting Hedgehog–Gli1 signaling.

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Sonic hedgehog signalling pathway regulates apoptosis through Smo protein in human umbilical vein endothelial cells

Abstract: The Shh signalling pathway plays a role in regulating endothelial cell apoptosis in a Smo-dependent manner.

Cited by 22 publications

References 25 publications

Targeting GLI Transcription Factors in Cancer

Targeting GLI Transcription Factors in Cancer

The hierarchical micro-/nanotextured topographies promote the proliferation and angiogenesis-related genes expression in human umbilical vein endothelial cells by initiation of Hedgehog-Gli1 signaling

Role of Hedgehog–Gli1 signaling in the enhanced proliferation and differentiation of MG63 cells enabled by hierarchical micro-/nanotextured topography

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Sonic hedgehog signalling pathway regulates apoptosis through Smo protein in human umbilical vein endothelial cells

Abstract: The Shh signalling pathway plays a role in regulating endothelial cell apoptosis in a Smo-dependent manner.

Cited by 22 publications

References 25 publications

Targeting GLI Transcription Factors in Cancer

Targeting GLI Transcription Factors in Cancer

The hierarchical micro-/nanotextured topographies promote the proliferation and angiogenesis-related genes expression in human umbilical vein endothelial cells by initiation of Hedgehog-Gli1 signaling

Role of Hedgehog&ndash;Gli1 signaling in the enhanced proliferation and differentiation of MG63 cells enabled by hierarchical micro-/nanotextured topography

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Role of Hedgehog–Gli1 signaling in the enhanced proliferation and differentiation of MG63 cells enabled by hierarchical micro-/nanotextured topography