期刊论文详细信息
BMC Molecular Biology
Genes targeted by the Hedgehog-signaling pathway can be regulated by Estrogen related receptor β
Dennis B. Lubahn2  Jianlin Cheng3  Jilong Li3  Yuan Lu1 
[1] Xiphophorus Genetic Stock Center, Texas State University, San Marcos 78666, TX, USA;MU Center for Botanical Interaction Studies, University of Missouri, Columbia 65211, MO, USA;Informatics Institute, University of Missouri, Columbia 65211, MO, USA
关键词: Gene interactions;    RNA-Seq;    Gene expression profiling;    Hedgehog signaling pathway;    Estrogen related receptor;   
Others  :  1234463
DOI  :  10.1186/s12867-015-0047-3
 received in 2015-07-02, accepted in 2015-11-06,  发布年份 2015
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【 摘 要 】

Background

Nuclear receptor family member, Estrogen related receptor β, and the Hedgehog signal transduction pathway are both reported to relate to tumorigenesis and induced pluripotent stem cell reprogramming. We hypothesize that Estrogen related receptor β can modulate the Hedgehog signaling pathway and affect Hedgehog driven downstream gene expression.

Results

We established an estrogen related receptor β-expressing Hedgehog-responsive NIH3T3 cell line by Esrrb transfection, and performed mRNA profiling using RNA-Seq after Hedgehog ligand conditioned medium treatment. Esrrb expression altered 171 genes, while Hedgehog signaling activation alone altered 339 genes. Additionally, estrogen related receptor β expression in combination with Hedgehog signaling activation affects a group of 109 Hedgehog responsive mRNAs, including Hsd11b1, Ogn, Smoc2, Igf1, Pdcd4, Igfbp4, Stmn1, Hp, Hoxd8, Top2a, Tubb4b, Sfrp2, Saa3, Prl2c3 and Dpt.

Conclusions

We conclude that Estrogen related receptor β is capable of interacting with Hh-signaling downstream targets. Our results suggest a new level of regulation of Hedgehog signaling by Estrogen related receptor β, and indicate modulation of Estrogen related receptor β can be a new strategy to regulate various functions driven by the Hedgehog signaling pathway.

【 授权许可】

   
2015 Lu et al.

【 预 览 】
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【 参考文献 】
  • [1]Litingtung Y, Lei L, Westphal H, Chiang C. Sonic Hedgehog is essential to foregut development. Nat Genet. 1998; 20:58-61.
  • [2]Lum L, Beachy PA. The Hedgehog response network: sensors, switches, and routers. Science. 2004; 304:1755-1759.
  • [3]Jessell TM. Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nat Rev Genet. 2000; 1:20-29.
  • [4]Zhang Y, Kalderon D. Hedgehog acts as a somatic stem cell factor in the Drosophila ovary. Nature. 2001; 410:599-604.
  • [5]Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001; 414:105-111.
  • [6]Machold R, Hayashi S, Rutlin M, Muzumdar MD, Nery S et al.. Sonic Hedgehog is required for progenitor cell maintenance in telencephalic stem cell niches. Neuron. 2003; 39:937-950.
  • [7]Lai K, Kaspar BK, Gage FH, Schaffer DV. Sonic Hedgehog regulates adult neural progenitor proliferation in vitro and in vivo. Nat Neurosci. 2003; 6:21-27.
  • [8]Moon JH, Heo JS, Kim JS, Jun EK, Lee JH et al.. Reprogramming fibroblasts into induced pluripotent stem cells with Bmi1. Cell Res. 2011; 21:1305-1315.
  • [9]Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001; 15:3059-3087.
  • [10]Lamm ML, Catbagan WS, Laciak RJ, Barnett DH, Hebner CM et al.. Sonic Hedgehog activates mesenchymal Gli1 expression during prostate ductal bud formation. Dev Biol. 2002; 249:349-366.
  • [11]Freestone SH, Marker P, Grace OC, Tomlinson DC, Cunha GR et al.. Sonic Hedgehog regulates prostatic growth and epithelial differentiation. Dev Biol. 2003; 264:352-362.
  • [12]Berman DM, Desai N, Wang X, Karhadkar SS, Reynon M et al.. Roles for Hedgehog signaling in androgen production and prostate ductal morphogenesis. Dev Biol. 2004; 267:387-398.
  • [13]Zeiss CJ, Zarfoss MK, Johnson EE, Dubielzig RR. Ocular anomalies and holoprosencephaly in a lamb. Vet Ophthalmol. 2008; 11:30-33.
  • [14]Lipinski RJ, Dengler E, Kiehn M, Peterson RE, Bushman W. Identification and characterization of several dietary alkaloids as weak inhibitors of Hedgehog signaling. Toxicol Sci. 2007; 100:456-463.
  • [15]Lee ST, Panter KE, Gaffield W, Stegelmeier BL. Development of an enzyme-linked immunosorbent assay for the veratrum plant teratogens: cyclopamine and jervine. J Agric Food Chem. 2003; 51:582-586.
  • [16]Bale AE. Sheep, lilies and human genetics. Nature. 2000; 406:944-945.
  • [17]Keeler RF, Binns W. Chemical compounds of veratrum californicum related to congenital ovine cyclopian malformations: extraction of active material. Proc Soc Exp Biol Med. 1964; 116:123-127.
  • [18]Taipale J, Beachy PA. The Hedgehog and Wnt signalling pathways in cancer. Nature. 2001; 411:349-354.
  • [19]Fei DL, Li H, Kozul CD, Black KE, Singh S et al.. Activation of Hedgehog signaling by the environmental toxicant arsenic may contribute to the etiology of arsenic-induced tumors. Cancer Res. 2010; 70:1981-1988.
  • [20]Mechlin CW, Tanner MJ, Chen M, Buttyan R, Levin RM et al.. Gli2 expression and human bladder transitional carcinoma cell invasiveness. J Urol. 2010; 184:344-351.
  • [21]Hatsell S, Frost AR. Hedgehog signaling in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia. 2007; 12:163-173.
  • [22]Varnat F, Duquet A, Malerba M, Zbinden M, Mas C et al.. Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signalling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Mol Med. 2009; 1:338-351.
  • [23]Xuan YH, Jung HS, Choi YL, Shin YK, Kim HJ et al.. Enhanced expression of Hedgehog signaling molecules in squamous cell carcinoma of uterine cervix and its precursor lesions. Mod Pathol. 2006; 19:1139-1147.
  • [24]Ma X, Chen K, Huang S, Zhang X, Adegboyega PA et al.. Frequent activation of the Hedgehog pathway in advanced gastric adenocarcinomas. Carcinogenesis. 2005; 26:1698-1705.
  • [25]Wu WK, Cho CH, Lee CW, Fan D, Wu K et al.. Dysregulation of cellular signaling in gastric cancer. Cancer Lett. 2010; 295:144-153.
  • [26]Chung CH, Dignam JJ, Hammond ME, Klimowicz AC, Petrillo SK et al.. Glioma-associated oncogene family zinc finger 1 expression and metastasis in patients with head and neck squamous cell carcinoma treated with radiation therapy (RTOG 9003). J Clin Oncol. 2011; 29:1326-1334.
  • [27]Huang S, He J, Zhang X, Bian Y, Yang L et al.. Activation of the Hedgehog pathway in human hepatocellular carcinomas. Carcinogenesis. 2006; 27:1334-1340.
  • [28]Dierks C, Grbic J, Zirlik K, Beigi R, Englund NP et al.. Essential role of stromally induced Hedgehog signaling in B-cell malignancies. Nat Med. 2007; 13:944-951.
  • [29]Ferretti E, De Smaele E, Di Marcotullio L, Screpanti I, Gulino A. Hedgehog checkpoints in medulloblastoma: the chromosome 17p deletion paradigm. Trends Mol Med. 2005; 11:537-545.
  • [30]Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA et al.. Treatment of medulloblastoma with Hedgehog pathway inhibitor GDC-0449. N Engl J Med. 2009; 361:1173-1178.
  • [31]Morton JP, Mongeau ME, Klimstra DS, Morris JP, Lee YC et al.. Sonic Hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci USA. 2007; 104:5103-5108.
  • [32]Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D et al.. Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature. 2004; 431:707-712.
  • [33]De Smaele E, Ferretti E, Gulino A. Vismodegib, a small-molecule inhibitor of the Hedgehog pathway for the treatment of advanced cancers. Curr Opin Investig Drugs. 2010; 11:707-718.
  • [34]Metcalfe C, Alicke B, Crow A, Lamoureux M, Dijkgraaf GJ et al.. PTEN loss mitigates the response of medulloblastoma to Hedgehog pathway inhibition. Cancer Res. 2013; 73:7034-7042.
  • [35]Sarris EG, Syrigos KN, Saif MW. Novel agents and future prospects in the treatment of pancreatic adenocarcinoma. JOP. 2013; 14:395-400.
  • [36]Gonnissen A, Isebaert S, Haustermans K. Hedgehog signaling in prostate cancer and its therapeutic implication. Int J Mol Sci. 2013; 14:13979-14007.
  • [37]Ansell PJ, Espinosa-Nicholas C, Curran EM, Judy BM, Philips BJ et al.. In vitro and in vivo regulation of antioxidant response element-dependent gene expression by estrogens. Endocrinology. 2004; 145:311-317.
  • [38]Robarge KD, Brunton SA, Castanedo GM, Cui Y, Dina MS et al.. GDC-0449-a potent inhibitor of the Hedgehog pathway. Bioorg Med Chem Lett. 2009; 19:5576-5581.
  • [39]Pettersson K, Svensson K, Mattsson R, Carlsson B, Ohlsson R et al.. Expression of a novel member of estrogen response element-binding nuclear receptors is restricted to the early stages of chorion formation during mouse embryogenesis. Mech Dev. 1996; 54:211-223.
  • [40]Giguere V, Yang N, Segui P, Evans RM. Identification of a new class of steroid hormone receptors. Nature. 1988; 331:91-94.
  • [41]Chen F, Zhang Q, McDonald T, Davidoff MJ, Bailey W et al.. Identification of two hERR2-related novel nuclear receptors utilizing bioinformatics and inverse PCR. Gene. 1999; 228:101-109.
  • [42]Luo J, Sladek R, Bader JA, Matthyssen A, Rossant J et al.. Placental abnormalities in mouse embryos lacking the orphan nuclear receptor ERR-beta. Nature. 1997; 388:778-782.
  • [43]Feng B, Jiang J, Kraus P, Ng JH, Heng JC et al.. Reprogramming of fibroblasts into induced pluripotent stem cells with orphan nuclear receptor Esrrb. Nat Cell Biol. 2009; 11:197-203.
  • [44]Takahashi K, Okita K, Nakagawa M, Yamanaka S. Induction of pluripotent stem cells from fibroblast cultures. Nat Protoc. 2007; 2:3081-3089.
  • [45]Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T et al.. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007; 131:861-872.
  • [46]Okita K, Ichisaka T, Yamanaka S. Generation of germline-competent induced pluripotent stem cells. Nature. 2007; 448:313-317.
  • [47]Buganim Y, Faddah DA, Cheng AW, Itskovich E, Markoulaki S et al.. Single-cell expression analyses during cellular reprogramming reveal an early stochastic and a late hierarchic phase. Cell. 2012; 150:1209-1222.
  • [48]Yu S, Wong YC, Wang XH, Ling MT, Ng CF et al.. Orphan nuclear receptor estrogen-related receptor-beta suppresses in vitro and in vivo growth of prostate cancer cells via p21(WAF1/CIP1) induction and as a potential therapeutic target in prostate cancer. Oncogene. 2008; 27:3313-3328.
  • [49]Castet A, Herledan A, Bonnet S, Jalaguier S, Vanacker JM et al.. Receptor-interacting protein 140 differentially regulates estrogen receptor-related receptor transactivation depending on target genes. Mol Endocrinol. 2006; 20:1035-1047.
  • [50]Greschik H, Wurtz JM, Sanglier S, Bourguet W, van Dorsselaer A et al.. Structural and functional evidence for ligand-independent transcriptional activation by the estrogen-related receptor 3. Mol Cell. 2002; 9:303-313.
  • [51]Nam K, Marshall P, Wolf RM, Cornell W. Simulation of the different biological activities of diethylstilbestrol (DES) on estrogen receptor alpha and estrogen-related receptor gamma. Biopolymers. 2003; 68:130-138.
  • [52]Greschik H, Flaig R, Renaud JP, Moras D. Structural basis for the deactivation of the estrogen-related receptor gamma by diethylstilbestrol or 4-hydroxytamoxifen and determinants of selectivity. J Biol Chem. 2004; 279:33639-33646.
  • [53]Abad MC, Askari H, O’Neill J, Klinger AL, Milligan C et al.. Structural determination of estrogen-related receptor gamma in the presence of phenol derivative compounds. J Steroid Biochem Mol Biol. 2008; 108:44-54.
  • [54]Vanacker JM, Bonnelye E, Chopin-Delannoy S, Delmarre C, Cavailles V et al.. Transcriptional activities of the orphan nuclear receptor ERR alpha (estrogen receptor-related receptor-alpha). Mol Endocrinol. 1999; 13:764-773.
  • [55]Nishiyama A, Sharov AA, Piao Y, Amano M, Amano T et al.. Systematic repression of transcription factors reveals limited patterns of gene expression changes in ES cells. Sci Rep. 2013; 3:1390.
  • [56]Yu M, Gipp J, Yoon JW, Iannaccone P, Walterhouse D et al.. Sonic Hedgehog-responsive genes in the fetal prostate. J Biol Chem. 2009; 284:5620-5629.
  • [57]Xu X, Zhou Y, Xie C, Wei SM, Gan H et al.. Genome-wide screening reveals an EMT molecular network mediated by Sonic Hedgehog-Gli1 signaling in pancreatic cancer cells. PLoS One. 2012; 7:e43119.
  • [58]Lee JM, Miyazawa S, Shin JO, Kwon HJ, Kang DW et al.. Shh signaling is essential for rugae morphogenesis in mice. Histochem Cell Biol. 2011; 136:663-675.
  • [59]Mazumdar T, DeVecchio J, Agyeman A, Shi T, Houghton JA. The GLI genes as the molecular switch in disrupting Hedgehog signaling in colon cancer. Oncotarget. 2011; 2:638-645.
  • [60]Franco HL, Lee KY, Broaddus RR, White LD, Lanske B et al.. Ablation of Indian Hedgehog in the murine uterus results in decreased cell cycle progression, aberrant epidermal growth factor signaling, and increased estrogen signaling. Biol Reprod. 2010; 82:783-790.
  • [61]Narita S, So A, Ettinger S, Hayashi N, Muramaki M et al.. GLI2 knockdown using an antisense oligonucleotide induces apoptosis and chemosensitizes cells to paclitaxel in androgen-independent prostate cancer. Clin Cancer Res. 2008; 14:5769-5777.
  • [62]Feldmann G, Habbe N, Dhara S, Bisht S, Alvarez H et al.. Hedgehog inhibition prolongs survival in a genetically engineered mouse model of pancreatic cancer. Gut. 2008; 57:1420-1430.
  • [63]Hochman E, Castiel A, Jacob-Hirsch J, Amariglio N, Izraeli S. Molecular pathways regulating pro-migratory effects of Hedgehog signaling. J Biol Chem. 2006; 281:33860-33870.
  • [64]Mori R, Xiong S, Wang Q, Tarabolous C, Shimada H et al.. Gene profiling and pathway analysis of neuroendocrine transdifferentiated prostate cancer cells. Prostate. 2009; 69:12-23.
  • [65]Arora VK, Schenkein E, Murali R, Subudhi SK, Wongvipat J et al.. Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013; 155:1309-1322.
  • [66]Langmead B, Trapnell C, Pop M, Salzberg SL. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009; 10:R25. BioMed Central Full Text
  • [67]Trapnell C, Pachter L, Salzberg SL. TopHat: discovering splice junctions with RNA-Seq. Bioinformatics. 2009; 25:1105-1111.
  • [68]da Huang W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc. 2009; 4:44-57.
  • [69]da Huang W, Sherman BT, Lempicki RA. Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Res. 2009; 37:1-13.
  • [70]Zhou Q, Chipperfield H, Melton DA, Wong WH. A gene regulatory network in mouse embryonic stem cells. Proc Natl Acad Sci USA. 2007; 104:16438-16443.
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