Shh and Fluoride

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Shh and Fluoride

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August 20, 2013

Since the late 1990s it has been known that the Sonic Hedgehog gene (Shh) controls tooth growth and morphogenesis (Dassule et al, 2000).

Shh is a thyroid-hormone (TH)-responsive gene.

Shh and Dental Fluorosis

Although fluoride and dental fluorosis (DF) have been studied for over 80 years, dental researchers claim that the mechanisms leading to DF are not yet known.
SEE: http://poisonfluoride.com/phpBB3/viewtopic.php?t=611

However, they declare the condition to be of "cosmetic concern" only.

For 20 years we have investigated the literature on this matter and have come to the conclusion that DF is caused by disturbances in thyroid hormone metabolism - that DF is a visual sign that TH metabolism and regulated pathways have been disturbed at a time crucial for development.

To further prove our case we have been looking all over the world for any research documenting the effects of fluoride on Shh, and specifically Shh involvement in DF.

We have been astounded by the fact that we could not find ANY scientific literature on Shh and DF in common medical literature databases, such as PUBMED, or SCIFinder.

It appeared that nobody had yet realized that this might be an important issue to investigate.

Today (thanks to Jirong) we found the first studies on the effects of fluoride on Shh in DF. They were found in the Chinese literature. Two papers on the subject had been published, one in 2007 and one in 2012.

As we had expected - the studies show that fluoride affects the expression of Shh.

Wendy

Shh & Dental Fluorosis

Chen L, Wang Y, Yang W, Tian M - "Effects of different selenium levels on tooth germ development in fluorosis rats" Journal of Oral Science Research 5:417-419, 422 (2012) PFPC Library
To study the effect of different selenium levels on dental germ development of rats with fluorosis, methods were employed as follows:

Methods: Sixty male SD rats are divided randomly into 6 groups. The control group is fed with a normal diet and distilled water. The experimental groups are fed with distilled water containing 45m/L fluoride (F−). The fluoride group is fed with a normal diet. The first fluorine and selenium group is fed with a diet containing 1.37mg/kg of selenium. The second fluorine and selenium group is fed with a diet containing 1.6mg/kg of selenium. The third fluorine and selenium group is fed with a diet containing 2.3mg/kg of selenium. The fourth fluorine and selenium group is fed with a diet containing 4mg/kg of selenium. At the end of the experiment, the rats were decapitated. Immunohistochemistry is used to detect the expression of smad3, shh in secretory ameloblasts.

Results: The expression of ameloblasts smad3 and shh is positive in the control group, and the expression in the fluoride group was significantly reduced compared with the control group. The fluorine and selenium groups' smad3 and shh expression were stronger than that of the fluoride groups, especially the third group is best.

Conclusion: The mechanism of the antagonizing effect of selenium with fluorosis may be related to the expression of the signal transduction factors smad3, shh, which control the dental germ development, and 2.3mg/kg selenium is best.
Liu H, Wang O, Zhu F, Luo PP, Liu TL, Wei XL, Wang LL - "Effect of fluorosis on the expression of Shh in rat incisors" Beijing Journal of Stomatology 15(4) (2007) PFPC Library
目的 研究过量氟对大鼠切牙Shh(Sonic Hedgehog)表达的影响,从分子水平探讨氟斑牙的发病机制.方法 20只Wistar大鼠随机分为2组:对照组(饮用蒸馏水)和实验组(饮用100 mg/L氟化水),复制氟斑牙动物模型,8周末处死动物,获取切牙标本,免疫组化染色观察Shh在大鼠切牙的表达定位及在对照组与实验组切牙表达的变化.结果 Shh在分泌期成釉细胞、成牙本质阳性表达.实验组Shh的表达明显弱于对照组,差异有显著性(P<.01).结论 过量氟可能通过抑制Shh的表达,从而影响牙齿发育的启动和随后的细胞分化,导致釉质发育障碍.

Objective To study the excessive fluoride on rat incisor Shh (Sonic Hedgehog) expression, from the molecular level investigate the pathogenesis of dental fluorosis. Methods 20 Wistar rats were randomly divided into two groups: control group (distilled water) and experimental group (drinking 100 mg / L fluoride water), copy dental fluorosis animal models, 8 weeks the animals were sacrificed to obtain incisor specimens, immunohistochemical staining of Shh expression in the rat incisor positioning and in the control group and the experimental group cut Teeth expression changes. Results Shh secretory ameloblasts in, odontoblasts expression. Shh expression in the experimental group was significantly weaker than the control group, the difference was statistically significant (P <.01). Conclusions Shh excessive fluoride may inhibit the expression, thus affecting tooth development startup and subsequent cell differentiation, leading to enamel developmental disorders.

SEE ALSO - smad3

Luo Pingping, Wang Qiang, Liu Hui - "Excessive fluoride during the development of rat incisor smad3 expression" Practical Stomatology, 3:377-379 (2007) PFPC Library


Shh & Thyroid Hormone | Deiodinase

Desouza LA, Sathanoori M, Kapoor R, Rajadhyaksha N, Gonzalez LE, Kottmann AH, Tole S, Vaidya VA - "Thyroid hormone regulates the expression of the sonic hedgehog signaling pathway in the embryonic and adult Mammalian brain" Endocrinology 152(5):1989-2000 (2011)
https://academic.oup.com/endo/article/1 ... 89/2457119

Dentice M - "Hedgehog-mediated regulation of thyroid hormone action through iodothyronine deiodinases" Expert Opin Ther Targets 15(4):493-504 (2011)
https://www.tandfonline.com/doi/full/10 ... 011.553607

Dassule HR, Lewis P, Bei M, Maas R, McMahon AP - "Sonic hedgehog regulates growth and morphogenesis of the tooth" Development 127(22):4775-85 (2000)
http://dev.biologists.org/content/127/22/4775.long


Shh & Tooth Development

Zhang Lu, Sun Zhijun, Wang Zhifeng, Hua Fang, Zhang Qi, Chen Zhi - "Expression of Shh and Its Recepters mRNA in the Late Tooth Development of Murine Lower Incisor" Journal of Wuhan University: Medical Edition 4:419-421 (2004) PFPC Library
Objective: To investigate the temporal and spatial expression of Shh and its receptors Ptc1、Ptc2 mRNA in the late tooth development of murine lower incisor and to discuss its role in cyto diff erentiation.Methods: The embryonic mouse mandibles of late incisor development(E18.5~P 1.5 ) were obtained and 5μm serial sections were made. DIG labeling RNA probes of Shh,Ptc1 and Ptc2 were generated by in vitro transcription from Shh、Ptc1、Ptc2 cDNA template. The expression pattern of Shh,Ptc1 and Ptc2 mRNA was analyzed by means of in situ hybridization. Results: The expression pattern of Shh and Ptc2 was similar. In the late tooth development,they were expressed in the inner dental epithelium and stratum intermedium of the incisor labial side. Ptc1 mRNA was expressed in the inner dental epithelium and stratum intermedium as well as the odontoblast. Conclusion: In the late incisor development,Shh might participate in the ameloblast and odontoblast differentiation as a paracrine or autocrine signaling molecule.
Gritli-Linde A, Bei M, Mass R,et al. - "Shh signaling within the dental epithelium is necessary for cell proliferation, growth and polarization" Development 129(23):5323 (2002)

Hardcastle Z, Hui CC, Sharpe PT - "The Shh signalling pathway in early tooth development" Cell Mol Biol (Noisy-le-grand) 45(5):567-78 (1999) PMID: 10512189.

林媛;吴补领;陆群 Shh在大鼠牙胚发育过程中的表达 [期刊论文] -临床口腔医学杂志2004(04) doi:10.3969/j.issn.1003-1634.2004.04.004

陈智;张露;王志峰 Shh及其受体Ptc1、Ptc2在鼠帽状期磨牙的基因表达 [期刊论文] -中华口腔医学杂志2003(02)

杜娟;刘淑红;范文红 Sonic hedgehog在小鼠胚胎颌面部的表达 [期刊论文] -北京口腔医学2005(01)
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Sonic Hedgehog - SHH and T3

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Ostasov P, Tuma J, Pitule P, Moravec J, Houdek Z, Vozeh F, Kralickova M, Cendelin J, Babuska Vm - "Sonic Hedgehog and Triiodothyronine Pathway Interact in Mouse Embryonic Neural Stem Cells" Int J Mol Sci 21(10):3672 (2020)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279276/
Abstract

Neural stem cells are fundamental to development of the central nervous system (CNS)-as well as its plasticity and regeneration-and represent a potential tool for neuro transplantation therapy and research. This study is focused on examination of the proliferation dynamic and fate of embryonic neural stem cells (eNSCs) under differentiating conditions. In this work, we analyzed eNSCs differentiating alone and in the presence of sonic hedgehog (SHH) or triiodothyronine (T3) which play an important role in the development of the CNS. We found that inhibition of the SHH pathway and activation of the T3 pathway increased cellular health and survival of differentiating eNSCs. In addition, T3 was able to increase the expression of the gene for the receptor smoothened (Smo), which is part of the SHH signaling cascade, while SHH increased the expression of the T3 receptor beta gene (Thrb). This might be the reason why the combination of SHH and T3 increased the expression of the thyroxine 5-deiodinase type III gene (Dio3), which inhibits T3 activity, which in turn affects cellular health and proliferation activity of eNSCs.

Keywords: cell differentiation; embryonic neural stem cells; sonic hedgehog; triiodothyronine.
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Re: Shh and Gq/11

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Adachi C, Kakinuma N, Jo SH, Ishii T, Arai Y, Arai S, Kitaguchi T, Takeda S, Inoue T - "Sonic hedgehog enhances calcium oscillations in hippocampal astrocytes" J Biol Chem 294(44):16034-16048 (2019) doi: 10.1074/jbc.RA119.007883. Epub 2019 Sep 10. PMID: 31506300; PMCID: PMC6827318.
https://pubmed.ncbi.nlm.nih.gov/31506300/
Abstract

Sonic hedgehog (SHH) is important for organogenesis during development. Recent studies have indicated that SHH is also involved in the proliferation and transformation of astrocytes to the reactive phenotype. However, the mechanisms underlying these are unknown. Involvement of SHH signaling in calcium (Ca) signaling has not been extensively studied. Here, we report that SHH and Smoothened agonist (SAG), an activator of the signaling receptor Smoothened (SMO) in the SHH pathway, activate Ca oscillations in cultured murine hippocampal astrocytes. The response was rapid, on a minute time scale, indicating a noncanonical pathway activity. Pertussis toxin blocked the SAG effect, indicating an involvement of a Gi coupled to SMO. Depletion of extracellular ATP by apyrase, an ATP-degrading enzyme, inhibited the SAG-mediated activation of Ca oscillations. These results indicate that SAG increases extracellular ATP levels by activating ATP release from astrocytes, resulting in Ca oscillation activation. We hypothesize that SHH activates SMO-coupled Gi in astrocytes, causing ATP release and activation of Gq/11-coupled P2 receptors on the same cell or surrounding astrocytes. Transcription factor activities are often modulated by Ca patterns; therefore, SHH signaling may trigger changes in astrocytes by activating Ca oscillations. This enhancement of Ca oscillations by SHH signaling may occur in astrocytes in the brain in vivo because we also observed it in hippocampal brain slices. In summary, SHH and SAG enhance Ca oscillations in hippocampal astrocytes, Gi mediates SAG-induced Ca oscillations downstream of SMO, and ATP-permeable channels may promote the ATP release that activates Ca oscillations in astrocytes.
El-Zaatari M, Zavros Y, Tessier A, Waghray M, Lentz S, Gumucio D, Todisco A, Merchant JL - "Intracellular calcium release and protein kinase C activation stimulate sonic hedgehog gene expression during gastric acid secretion" Gastroenterology 139(6):2061-2071.e2 (2010). doi: 10.1053/j.gastro.2010.08.047
https://linkinghub.elsevier.com/retriev ... 10)01297-7
Abstract
Background & aims: Hypochlorhydria during Helicobacter pylori infection inhibits gastric Sonic Hedgehog (Shh) expression. We investigated whether acid-secretory mechanisms regulate Shh gene expression through intracellular calcium (Ca2(+)(i))-dependent protein kinase C (PKC) or cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) activation.

Methods: We blocked Hedgehog signaling by transgenically overexpressing a secreted form of the Hedgehog interacting protein-1, a natural inhibitor of hedgehog ligands, which induced hypochlorhydria. Gadolinium, ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) + 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA), PKC-overexpressing adenoviruses, and PKC inhibitors were used to modulate Ca(2+)(i)-release, PKC activity, and Shh gene expression in primary gastric cell, organ, and AGS cell line cultures. PKA hyperactivity was induced in the H(+)/K(+)-β-cholera-toxin-overexpressing mice.

Results: Mice that expressed secreted hedgehog-interacting protein-1 had lower levels of gastric acid (hypochlorhydria), reduced production of somatostatin, and increased gastrin gene expression. Hypochlorhydria in these mice repressed Shh gene expression, similar to the levels obtained with omeprazole treatment of wild-type mice. However, Shh expression also was repressed in the hyperchlorhydric H(+)/K(+)-β-cholera-toxin model with increased cAMP, suggesting that the regulation of Shh was not solely acid-dependent, but pertained to specific acid-stimulatory signaling pathways. Based on previous reports that Ca(2+)(i) release also stimulates acid secretion in parietal cells, we showed that gadolinium-, thapsigargin-, and carbachol-mediated release of Ca(2+)(i) induced Shh expression. Ca(2+)-chelation with BAPTA + EGTA reduced Shh expression. Overexpression of PKC-α, -β, and -δ (but not PKC-ϵ) induced an Shh gene expression. In addition, phorbol esters induced a Shh-regulated reporter gene.

Conclusions: Secretagogues that stimulate gastric acid secretion induce Shh gene expression through increased Ca(2+)(i)-release and PKC activation. Shh might be the ligand transducing changes in gastric acidity to the regulation of G-cell secretion of gastrin.
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Re: Shh and fluoride - UPDATE

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Zhao L, Yu Y, Zhu Z, et al, - "Expressions of protein and mRNA relevant to hedgehog signaling pathway in liver of fluorosis rats" Chinese Journal of Public Health 31(9): 1162-1166 (2015) doi: 10.11847/zgggws2015-31-09-16

Zhao L, Yu Y, Deng C - "Expression of sonic hedgehog signaling pathway and its inhibition by cyclopamine in rat liver with chronic fluorosis" Chinese Journal of Pathology 43(12):814-9 (2014)
https://pubmed.ncbi.nlm.nih.gov/25623978/
Abstract
Objective: To investigate the expression of sonic hedgehog (Shh) signaling pathway in liver fluorosis and to explore related mechanism.

Methods: To establish animal model, 48 normal SD rats (aged 4-5 weeks) were randomly divided into 4 groups (12 each): control group, fluoriosis group, blocking group and blocking control group. After 6 months, the blocking group and blocking control group were injected intraperitoneally once every 2 days for 3 times with 10 mg/kg cyclopamine or dimethysulfoxide, respectively. Rats were sacrificed at the end of the experiment and the fluoride content in urine and liver function was determined. The expression of Shh and Gli1 protein and mRNA in hepatocytes was detected by immunohistochemistry and real-time fluorescence quantitative PCR, respectively.

Results: The fluoride contents in the urine and the incidence of dental fluorosis increased in the fluoride and blocking control groups as compared with those in the control group, but decreased in the blocking group compared with those of the fluoride and blocking control group. Compared with the control group, the titers of aspartate transaminase (AST) and alanine transaminase (ALT) significantly increased, while the activity of total protein and albumin decreased in the fluoride and blocking control groups. Compared with the fluoride and blocking control groups, the activity of the ALT slightly declined and the AST, total protein and albumin slightly increased in the blocking group. Histologically, the cells were disorganized and swollen with cytoplasmic clearing (balloon cells), compared with the control group. The expression of Shh and Gli1 significantly increased in all but the control group. Compared with the fluoride and blocking control groups, the expression of Shh and Gli1 declined in the blocking group.

Conclusions: The overexpression and cyclopamine inhibition of the Shh signaling pathway are closely related to the content of fluoride in the liver. The Shh signaling pathway plays an important role in the pathogenesis of liver injury caused by fluorosis, suggesting a preventive and therapeutic target of the disease.
Zhao L, Yu Y, Deng C - "Protein and mRNA expression of Shh, Smo and Gli1 and inhibition by cyclopamine in hepatocytes of rats with chronic fluorosis" Toxicol Lett 225(2):318-24 (2014). doi: 10.1016/j.toxlet.2013.12.022

Zhu Zhijian, Yu Yanni, Tao Xin, Deng Chaonan - "Role of Hh signaling pathway in fluoride-induced primary chondrocyte damage in rats" Chinese Journal of Public Health 5:574-578 (2015) PFPC Library
Objective: To investigate the roles of sonic hedgehog (Shh), smoothened (Smo), and bone morphogenetic protein-2 (BMP-2) in fluoride-induced primary chondrocyte damage in rats in vitro.

Methods: The primary chondrocytes were obtained from one-week-old healthy Sprague-Dawley rats with a mechanical-enzyme digestion method and identified with immunohistochemical cells. They were then divided into a control group and 5, 10, 20, and 40 mg/L sodium fluoride (NaF) exposure groups. After 48 hours of treatment, the viability of the cells was determined with the methyl thiazolyl tetrazolium test (MTT); the expressions of protein and mRNA of Smo, Shh, and BMP-2 were detected with Western blot and reverse transcription-polymerase chain reaction (RT-PCR), and apoptosis was detected with flow cytometry.

Results: Compared with the control group, the vitality of the cells exposed to NaF of 5 and 10 mg/L significantly increased (113.33 ± 11.74% and 127.25 ± 10.24%, P < 0.05) but decreased significantly for the cells exposed to NaF of 40 mg/L (73.91 ± 9.94%, P < 0.05). The protein and mRNA expressions of Shh, Smo, and BMP-2 increased along with the increment of fluorine concentration. The apoptosis rate of the cells with 40 mg/L NaF exposure was 11.13 ± 1.20%, significantly higher than that of the control group (P < 0.05).

Conclusion: Fluoride can activate the hedgehog (Hh) signaling pathway, and both the Hh signaling pathway and apoptosis may play roles in the pathogenesis of cartilage damage in fluorosis.
Zhang Jiejing - "Effects of Hh signaling pathway on cartilage damage in rats with fluorosis" Chinese Journal of Control of Endemic Diseases1:25-27 (2016) PFPC Library
Objective: To investigate the effect of Hedgehog (Hh) signaling pathway on cartilage damage in rats with fluorosis.

Methods: Sixty healthy Wistar rats were selected and divided into the control group (tap water), low fluorine group (10 mg/L sodium fluoride solution), and high fluorine group (50 mg/L sodium fluoride solution) based on the random number table method. Rats' cartilage cell activity and apoptosis rate were recorded under different strengths of fluoride poison. Chondrocytes Alto speed hedgehog protein (Shh) and Indian hedgehog (IHH), a transmembrane protein (SMO), transmembrane protein receptor (PTCH1), nuclear transcription factor protein Gli1, Gli2, and Gli3 mRNA and protein expression levels of the three groups were compared.

Results: The activity of chondrocytes in the control group, low fluoride group, and high fluoride group were (100 ± 0)%, (116.48 ± 10.27)%, and (76.25 ± 11.38)%, respectively. The apoptosis rate was (4.15 ± 0.78)%, (3.02 ± 0.71)%, and (9.58 ± 1.14)%, respectively. The cartilage expression of Shh, Ihh, Smo, Gli1, Gli2 mRNA, and protein expression of Shh, Ihh, Smo, Ptch1, Gli1, Gli2 in the control, low fluorosis, and high fluorosis group increased in turn, but Gli3 mRNA was gradually decreased (P < 0.05). Smo, Ptch1, Gli1, Gli2, Gli3, and Hh were involved in the activity of cartilage injury in rats.
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Re: Shh and fluoride | More on G proteins

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Pusapati GV, Kong JH, Patel BB, Gouti M, Sagner A, Sircar R, Luchetti G, Ingham PW, Briscoe J, Rohatgi R - "G protein-coupled receptors control the sensitivity of cells to the morphogen Sonic Hedgehog" Sci Signal 11(516):eaao5749 (2016). doi: 10.1126/scisignal.aao5749
https://pubmed.ncbi.nlm.nih.gov/29438014/
Abstract
The morphogen Sonic Hedgehog (SHH) patterns tissues during development by directing cell fates in a concentration-dependent manner. The SHH signal is transmitted across the membrane of target cells by the heptahelical transmembrane protein Smoothened (SMO), which activates the GLI family of transcription factors through a mechanism that is undefined in vertebrates. Using CRISPR-edited null alleles and small-molecule inhibitors, we systematically analyzed the epistatic interactions between SMO and three proteins implicated in SMO signaling: the heterotrimeric G protein subunit GαS, the G protein-coupled receptor kinase 2 (GRK2), and the GαS-coupled receptor GPR161. Our experiments uncovered a signaling mechanism that modifies the sensitivity of target cells to SHH and consequently changes the shape of the SHH dose-response curve. In both fibroblasts and spinal neural progenitors, the loss of GPR161, previously implicated as an inhibitor of basal SHH signaling, increased the sensitivity of target cells across the entire spectrum of SHH concentrations. Even in cells lacking GPR161, GRK2 was required for SHH signaling, and Gαs, which promotes the activation of protein Kinase A (PKA), antagonized SHH signaling. We propose that the sensitivity of target cells to Hedgehog morphogens, and the consequent effects on gene expression and differentiation outcomes, can be controlled by signals from G protein-coupled receptors that converge on Gαs and PKA.
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Re: Shh and fluoride | MAPK and DIO3

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Aw DK, Sinha RA, Tan HC, Loh LM, Salvatore D, Yen PM - "Studies of molecular mechanisms associated with increased deiodinase 3 expression in a case of consumptive hypothyroidism" J Clin Endocrinol Metab 99(11):3965-71 (2014). doi: 10.1210/jc.2013-3408
https://academic.oup.com/jcem/article/9 ... 65/2836372
Consumptive hypothyroidism (CH) is a rare form of hypothyroidism due to increased catabolic activity of type 3 iodothyronine deiodinase (DIO3) that can occur in large tumors. Patients with CH typically present with markedly increased requirements for exogenous thyroid hormone and resolution after removal of the source of ectopic DIO3. DIO3 is encoded by DIO3, an imprinted gene expressed on the paternal allele that is located in a DIO3/delta-like 1 homolog (DLK1) gene locus regulated by a common control region, intergenic differentially methylated region (IGDMR). Because DIO3 is an imprinted gene, loss of imprinting at the IGDMR is thought to play a role in its increased expression; however, the molecular mechanism for DIO3 in CH currently is not known.

Objective:
The aim of the study was to determine the molecular mechanism for CH in an adult patient.

Setting:
The study was conducted in the Department of Endocrinology of a tertiary care center in Singapore.

Patient:
We report the case of an adult Asian female patient with a large intrathoracic fibrous tumor and severe hypothyroidism that resolved after tumor resection.

Results:
The patient's tumor expressed increased levels of DIO3 and DLK1 mRNA and protein levels. Methylation-specific PCR of the IGDMR showed similar hypomethylation in placenta, thyroid, leukocytes, and tumor. Western blotting showed activation of sonic hedgehog (SHH) and MAPK signaling pathways that can increase DIO3 and DLK1 expression.

Conclusions:
Loss of imprinting did not account for overexpression of DIO3 in the patient's tumor. Instead SHH and MAPK/ERK pathway activation was associated with systemic thyroid hormone catabolism and growth of the tumor. These findings raise the possibility that other tumors that have increased SHH and MAPK/ERK signaling also may have intratumor or systemic effects on thyroid hormone function.
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Re: Shh and fluoride | Glioma & Other cancers | DIO3

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Luongo C, Ambrosio R, Salzano S, Dlugosz AA, Missero C, Dentice M - "The sonic hedgehog-induced type 3 deiodinase facilitates tumorigenesis of basal cell carcinoma by reducing Gli2 inactivation" Endocrinology 155(6):2077-88 (2014). doi: 10.1210/en.2013-2108
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5393316/
Thyroid hormone (TH) is an important regulator of growth, development, and metabolism. Most of the active TH T3 is generated by peripheral TH metabolism mediated by the iodothyronine deiodinases. Type 3 deiodinase (D3) inactivates T3 via specific deiodination reactions. It is an oncofetal protein frequently expressed in neoplastic tissues and is a direct target of the sonic hedgehog (Shh) pathway in basal cell carcinomas (BCCs). However, the molecular mechanisms triggered by T3 in BCC are still mostly unrevealed. Here, we demonstrate that D3 action is critical in the proliferation and survival of BCC cells. D3 depletion or T3 treatment induce apoptosis of BCC cells and attenuate Shh signaling. This is achieved through a direct impairment of Gli2 protein stability by T3. T3 induces protein kinase A, which in turn destabilizes Gli2 protein via its C-terminal degron. Finally, in a mouse model of BCC, T3-topical treatment significantly reduces tumor growth. These results demonstrate the existence of a previously unrecognized cross talk between TH and Gli2 oncogene, providing functional and mechanistic evidence of the involvement of TH metabolism in Shh-induced cancer. TH-mediated Gli2 inactivation would be beneficial for therapeutically purposes, because the inhibition of Shh-Gli2 signaling is an attractive target for several anticancer drugs, currently in clinical trials.
SEE: viewtopic.php?f=97&t=5078
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