Protein and mRNA expression of Shh, Smo and Gli1 and inhibition by cyclopamine in hepatocytes of rats with chronic fluorosis

Zhao, Lina; Yu, Yu; Deng, Chaonan

doi:10.1016/j.toxlet.2013.12.022

Cited by 27 publications

(21 citation statements)

References 25 publications

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“…(13)(14)(15)(16)(17) Although it has been generally con-sidered that hepatocytes are Hh nonresponsive cells, (7) recent studies have reported increased expression of Smo and Gli1 in primary hepatocytes from damaged livers. (16,18) The latter observations are in support of the hypothesis that Hh signaling in hepatocytes could be activated during liver injury and that this mechanism may contribute to hepatocyte regeneration and repair from liver injury. However, the potential implication of hepatocyte Hh signaling in NAFLD or any other liver diseases has not yet been established.…”

supporting

confidence: 67%

“…The Shh ligand produced by ballooned hepatocytes is known to stimulate hepatic stellate cells and fibroblasts through a paracrine mechanism, thereby promoting a profibrogenic response in a mouse model of NASH . Although it has been generally considered that hepatocytes are Hh nonresponsive cells, recent studies have reported increased expression of Smo and Gli1 in primary hepatocytes from damaged livers . The latter observations are in support of the hypothesis that Hh signaling in hepatocytes could be activated during liver injury and that this mechanism may contribute to hepatocyte regeneration and repair from liver injury.…”

mentioning

confidence: 64%

“…Although Hh signaling activation is predominantly observed in hepatic stellate cells and fibroblasts in NAFLD, increased expression of Hh signaling components was also detected in damaged hepatocytes . To investigate the role of hepatocyte Hh activation in NAFLD, we generated Smo LKO mice using the Cre/loxP system (Alb‐Cre/Smo floxed).…”

Section: Resultsmentioning

confidence: 99%

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Inhibition of hedgehog signaling ameliorates hepatic inflammation in mice with nonalcoholic fatty liver disease

et al. 2015

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Hedgehog (Hh)-signaling plays a critical role in liver development, regeneration, injury repair and carcinogenesis. Activation of Hh signaling has been observed in patients with nonalcoholic fatty liver diseases (NAFLD); however, the pathobiological function and regulatory mechanism of hepatic Hh signaling in the pathogenesis of NAFLD remain to be further defined. This study was designed to examine the effect and mechanism of hepatic Hh signaling in high fat diet (HFD)-induced NAFLD by using pharmacological Smoothened inhibitors (GDC-0449 and LED225) and by using liver specific Smo knockout (Smo LKO) mice. Administration of Smo inhibitors to HFD-fed wild type mice significantly reduced the numbers of activated macrophages and decreased the expression of pro-inflammatory cytokines (TNFα, IL-1β, MCP1 and IL-6) as assessed by F4/80 immunohistochemistry and qRT-PCR, respectively. The Smo inhibitors were noted to have variable effects on hepatic fat accumulation. We observed that liver specific deletion of Smo also reduced macrophage activation and inhibited pro-inflammatory cytokine expression, while it did not significantly alter fat accumulation in the liver. Mechanistically, we found that activation of Gli1 by Hh signaling in primary hepatocytes increased the production of osteopontin (OPN) which subsequently enhanced macrophage-mediated pro-inflammatory response via a paracrine signaling. Conclusions: Hepatocyte Hh signaling can promote liver inflammation through OPN-mediated macrophage activation; this mechanism importantly contributes to the progression of NAFLD.

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supporting

confidence: 67%

mentioning

confidence: 64%

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Inhibition of hedgehog signaling ameliorates hepatic inflammation in mice with nonalcoholic fatty liver disease

et al. 2015

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“…It has been studied that exosomes play an important role in Hedgehog pathway transporting and gradient formation [28], The activation of hedgehog signaling pathway has been attributed in a variety of human cancer, including medulloblastomas, basal cell carcinomas, gastrointestinal, leukemia, breast, lung, ovarian, and prostate cancer [29]. In addition, ligand Shh, Patch, Gli1 and Smoothened, as key molecules in the Hedgehog signaling pathway, are responsible for transduction of the intracellular signal to the nucleus and activity of downstream Hedgehog target genes [30]. …”

Section: Introductionmentioning

confidence: 99%

Exosomes Derived from Human Bone Marrow Mesenchymal Stem Cells Promote Tumor Growth Through Hedgehog Signaling Pathway

Qi¹,

Zhou²,

Zhang³

et al. 2017

Cell Physiol Biochem

159

103

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Background/Aims: Mesenchymal stem/stromal cells (MSCs) are known to home to sites of tumor microenvironments where they participate in the formation of the tumor microenvironment and to interplay with tumor cells. However, the potential functional effects of MSCs on tumor cell growth are controversial. Here, we, from the view of bone marrow MSC-derived exosomes, study the molecular mechanism of MSCs on the growth of human osteosarcoma and human gastric cancer cells. Methods: MSCs derived from human bone marrow (hBMSCs) were isolated and cultured in complete DMEM/F12 supplemented with 10% exosome-depleted fetal bovine serum and 1% penicillin-streptomycin, cell culture supernatants containing exosomes were harvested and exosome purification was performed by ultracentrifugation. Osteosarcoma (MG63) and gastric cancer (SGC7901) cells, respectively, were treated with hBMSC-derived exosomes in the presence or absence of a small molecule inhibitor of Hedgehog pathway. Cell viability was measured by transwell invasion assay, scratch migration assay and CCK-8 test. The expression of the signaling molecules Smoothened, Patched-1, Gli1 and the ligand Shh were tested by western blot and RT-PCR. Results: In this study, we found that hBMSC-derived exosomes promoted MG63 and SGC7901 cell growth through the activation of Hedgehog signaling pathway. Inhibition of Hedgehog signaling pathway significantly suppressed the process of hBMSC-derived exosomes on tumor growth. Conclusion: Our findings demonstrated the new roles of hedgehog signaling pathway in the hBMSCs-derived exosomes induced tumor progression.

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“…Exogenous activation of Shh signaling also significantly stimulates cell proliferation (11). Cyclopamine, a specific inhibitor of the Shh-Gli signaling pathway, decreases Shh-induced malignant cancer cell proliferation (19,20). To determine the effects of Shh-Gli signaling on cell proliferation, MDA-MB-231 cells were treated with exogenous Shh, cyclopamine or exogenous Shh plus cyclopamine for 24, 48, or 72 h, and cell viability was determined using an MTT assay.…”

Section: Effects Of Shh-gli Signaling On Mda-mb-231 Cell Proliferationmentioning

confidence: 99%

Targeting of sonic hedgehog-Gli signaling: A potential therapeutic target for patients with breast cancer

et al. 2016

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Abstract. Breast cancer is the most common malignant cancer among women. The Hedgehog (Hh) signaling pathway serves a key role in malignant cancer cell growth and migration. However, little is known with regard to the specific function of the Hh signaling pathway in human breast cancer. The current study investigated the specific role of Hh signaling in the human breast cancer cell line MDA-MB-231. Expression of components of Shh-Gli signaling, as well as the Gli-responsive genes B-cell lymphoma 2 (Bcl-2) and cyclin D1, were investigated in MDA-MB-231 cells using western blotting. The effects of Shh-Gli signaling on MDA-MB-231 proliferation were analyzed by MTT assay. The role of E-cadherin in the epithelial-mesenchymal transition process was determined by western blot while matrix metalloproteinase (MMP)-9/MMP-2 secretion was studied by enzyme-linked immunosorbent assay. The results indicated that Shh-Gli signaling was activated in MDA-MB-231 cells, significantly enhancing cell viability. Overexpression of Gli positively regulated the transcription of Bcl-2 and cyclin D1 thereby regulating MDA-MB-231 cell proliferation and survival. Treatment of MDA-MB-231 cells with human sonic hedgehog, n-terminus for 72 h significantly reduced E-cadherin protein levels and enhanced secretion of MMP-9 and MMP-2. These findings suggest that Shh-Gli signaling is significantly activated in human breast cancer cells, and is accompanied by enhanced cell viability, proliferation and migration capacities.

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Protein and mRNA expression of Shh, Smo and Gli1 and inhibition by cyclopamine in hepatocytes of rats with chronic fluorosis

Cited by 27 publications

References 25 publications

Inhibition of hedgehog signaling ameliorates hepatic inflammation in mice with nonalcoholic fatty liver disease

Inhibition of hedgehog signaling ameliorates hepatic inflammation in mice with nonalcoholic fatty liver disease

Exosomes Derived from Human Bone Marrow Mesenchymal Stem Cells Promote Tumor Growth Through Hedgehog Signaling Pathway

Targeting of sonic hedgehog-Gli signaling: A potential therapeutic target for patients with breast cancer

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