Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Activation of the hedgehog-signaling pathway in human cancer and the clinical implications

Oncogene volume 29, pages 469–481 (2010)Cite this article

Abstract

The hedgehog pathway, initially discovered by two Nobel laureates Drs E Wieschaus and C Nusslein-Volhard in Drosophila, is a major regulator for cell differentiation, tissue polarity and cell proliferation. Studies from many laboratories reveal activation of this pathway in a variety of human cancer, including basal cell carcinomas (BCCs), medulloblastomas, leukemia, gastrointestinal, lung, ovarian, breast and prostate cancers. It is thus believed that targeted inhibition of hedgehog signaling may be effective in treatment and prevention of human cancer. Even more exciting is the discovery and synthesis of specific signaling antagonists for the hedgehog pathway, which have significant clinical implications in novel cancer therapeutics. In this review, we will summarize major advances in the last 2 years in our understanding of hedgehog signaling activation in human cancer, interactions between hedgehog signaling and other pathways in carcinogenesis, potential antagonists for hedgehog signaling inhibition and their clinical implications for human cancer treatment.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  • Abe Y, Oda-Sato E, Tobiume K, Kawauchi K, Taya Y, Okamoto K et al. (2008). Hedgehog signaling overrides p53-mediated tumor suppression by activating Mdm2. Proc Natl Acad Sci USA 105: 4838–4843.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Allen BL, Tenzen T, McMahon AP . (2007). The Hedgehog-binding proteins Gas1 and Cdo cooperate to positively regulate Shh signaling during mouse development. Genes Dev 21: 1244–1257.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Amano K, Ichida F, Sugita A, Hata K, Wada M, Takigawa Y et al. (2008). MSX2 stimulates chondrocyte maturation by controlling Ihh expression. J Biol Chem 283: 29513–29521.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Arai MA, Tateno C, Hosoya T, Koyano T, Kowithayakorn T, Ishibashi M . (2008). Hedgehog/GLI-mediated transcriptional inhibitors from Zizyphus cambodiana. Bioorg Med Chem 16: 9420–9424.

    CAS  PubMed  Google Scholar 

  • Aszterbaum M, Beech J, Epstein Jr EH . (1999a). Ultraviolet radiation mutagenesis of hedgehog pathway genes in basal cell carcinomas. J Investig Dermatol Symp Proc 4: 41–45.

    CAS  PubMed  Google Scholar 

  • Aszterbaum M, Epstein J, Oro A, Douglas V, LeBoit PE, Scott MP et al. (1999b). Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice. Nat Med 5: 1285–1291.

    CAS  PubMed  Google Scholar 

  • Athar M, Li C, Tang X, Chi S, Zhang X, Kim AL et al. (2004). Inhibition of smoothened signaling prevents ultraviolet B-induced basal cell carcinomas through regulation of Fas expression and apoptosis. Cancer Res 64: 7545–7552.

    CAS  PubMed  Google Scholar 

  • Baena-Lopez LA, Rodriguez I, Baonza A . (2008). The tumor suppressor genes dachsous and fat modulate different signalling pathways by regulating dally and dally-like. Proc Natl Acad Sci USA 105: 9645–9650.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bailey JM, Mohr AM, Hollingsworth MA . (2009). Sonic hedgehog paracrine signaling regulates metastasis and lymphangiogenesis in pancreatic cancer. Oncogene 28: 3513–3525.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bale AE . (2002). Hedgehog signaling and human disease. Annu Rev Genomics Hum Genet 3: 47–65.

    CAS  PubMed  Google Scholar 

  • Barnfield PC, Zhang X, Thanabalasingham V, Yoshida M, Hui CC . (2005). Negative regulation of Gli1 and Gli2 activator function by Suppressor of fused through multiple mechanisms. Differentiation 73: 397–405.

    CAS  PubMed  Google Scholar 

  • Beauchamp E, Bulut G, Abaan O, Chen K, Merchant A, Matsui W et al. (2009). GLI1 is a direct transcriptional target of EWS-FLI1 oncoprotein. J Biol Chem 284: 9074–9082.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Beckett K, Franch-Marro X, Vincent JP . (2008). Glypican-mediated endocytosis of Hedgehog has opposite effects in flies and mice. Trends Cell Biol 18: 360–363.

    CAS  PubMed  Google Scholar 

  • Bellaiche Y, The I, Perrimon N . (1998). Tout-velu is a Drosophila homologue of the putative tumour suppressor EXT-1 and is needed for Hh diffusion. Nature 394: 85–88.

    CAS  PubMed  Google Scholar 

  • Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, Watkins DN et al. (2002). Medulloblastoma growth inhibition by hedgehog pathway blockade. Science 297: 1559–1561.

    CAS  PubMed  Google Scholar 

  • Berman DM, Karhadkar SS, Maitra A, Montes De Oca R, Gerstenblith MR, Briggs K et al. (2003). Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature 425: 846–851.

    CAS  PubMed  Google Scholar 

  • Bhattacharya R, Kwon J, Ali B, Wang E, Patra S, Shridhar V et al. (2008). Role of hedgehog signaling in ovarian cancer. Clin Cancer Res 14: 7659–7666.

    CAS  PubMed  Google Scholar 

  • Bijlsma MF, Spek CA, Zivkovic D, van de Water S, Rezaee F, Peppelenbosch MP . (2006). Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion. PLoS Biol 4: e232.

    PubMed  PubMed Central  Google Scholar 

  • Bitgood MJ, Shen L, McMahon AP . (1996). Sertoli cell signaling by Desert hedgehog regulates the male germline. Curr Biol 6: 298–304.

    CAS  PubMed  Google Scholar 

  • Borzillo GV, Lippa B . (2005). The Hedgehog signaling pathway as a target for anticancer drug discovery. Curr Top Med Chem 5: 147–157.

    CAS  PubMed  Google Scholar 

  • Brellier F, Bergoglio V, Valin A, Barnay S, Chevallier-Lagente O, Vielh P et al. (2008). Heterozygous mutations in the tumor suppressor gene PATCHED provoke basal cell carcinoma-like features in human organotypic skin cultures. Oncogene 27: 6601–6606.

    CAS  PubMed  Google Scholar 

  • Buglino JA, Resh MD . (2008). Hhat is a palmitoylacyltransferase with specificity for N-palmitoylation of Sonic Hedgehog. J Biol Chem 283: 22076–22088.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cai Q, Li J, Gao T, Xie J, Evers BM . (2009). Protein kinase Cdelta negatively regulates hedgehog signaling by inhibition of Gli1 activity. J Biol Chem 284: 2150–2158.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Capurro MI, Xu P, Shi W, Li F, Jia A, Filmus J . (2008). Glypican-3 inhibits Hedgehog signaling during development by competing with patched for Hedgehog binding. Dev Cell 14: 700–711.

    CAS  PubMed  Google Scholar 

  • Chang DT, Lopez A, von Kessler DP, Chiang C, Simandl BK, Zhao R et al. (1994). Products, genetic linkage and limb patterning activity of a murine hedgehog gene. Development 120: 3339–3353.

    CAS  PubMed  Google Scholar 

  • Chen JK, Taipale J, Cooper MK, Beachy PA . (2002a). Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened. Genes Dev 16: 2743–2748.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen JK, Taipale J, Young KE, Maiti T, Beachy PA . (2002b). Small molecule modulation of smoothened activity. Proc Natl Acad Sci USA 99: 14071–14076.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen MH, Gao N, Kawakami T, Chuang PT . (2005). Mice deficient in the fused homolog do not exhibit phenotypes indicative of perturbed hedgehog signaling during embryonic development. Mol Cell Biol 25: 7042–7053.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen MH, Wilson CW, Li YJ, Law KK, Lu CS, Gacayan R et al. (2009). Cilium-independent regulation of Gli protein function by Sufu in Hedgehog signaling is evolutionarily conserved. Genes Dev 23: 1910–1928.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cheng SY, Bishop JM . (2002). Suppressor of Fused represses Gli-mediated transcription by recruiting the SAP18-mSin3 corepressor complex. Proc Natl Acad Sci USA 99: 5442–5447.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cheung HO, Zhang X, Ribeiro A, Mo R, Makino S, Puviindran V et al. (2009). The kinesin protein Kif7 is a critical regulator of Gli transcription factors in mammalian hedgehog signaling. Sci Signal 2: ra29.

    PubMed  Google Scholar 

  • Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H et al. (1996). Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383: 407–413.

    CAS  PubMed  Google Scholar 

  • Chuang PT, McMahon AP . (1999). Vertebrate Hedgehog signalling modulated by induction of a Hedgehog-binding protein. Nature 397: 617–621.

    CAS  PubMed  Google Scholar 

  • Cooper MK, Porter JA, Young KE, Beachy PA . (1998). Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280: 1603–1607.

    CAS  PubMed  Google Scholar 

  • Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY, Reiter JF . (2005). Vertebrate smoothened functions at the primary cilium. Nature 437: 1018–1021.

    CAS  PubMed  Google Scholar 

  • Corcoran RB, Bachar Raveh T, Barakat MT, Lee EY, Scott MP . (2008). Insulin-like growth factor 2 is required for progression to advanced medulloblastoma in patched1 heterozygous mice. Cancer Res 68: 8788–8795.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cortellino S, Wang C, Wang B, Bassi MR, Caretti E, Champeval D et al. (2009). Defective ciliogenesis, embryonic lethality and severe impairment of the Sonic Hedgehog pathway caused by inactivation of the mouse complex A intraflagellar transport gene Ift122/Wdr10, partially overlapping with the DNA repair gene Med1/Mbd4. Dev Biol 325: 225–237.

    CAS  PubMed  Google Scholar 

  • Couve-Privat S, Bouadjar B, Avril MF, Sarasin A, Daya-Grosjean L . (2002). Significantly high levels of ultraviolet-specific mutations in the smoothened gene in basal cell carcinomas from DNA repair-deficient xeroderma pigmentosum patients. Cancer Res 62: 7186–7189.

    CAS  PubMed  Google Scholar 

  • Cummings DE, Brandon EP, Planas JV, Motamed K, Idzerda RL, McKnight GS . (1996). Genetically lean mice result from targeted disruption of the RII beta subunit of protein kinase A. Nature 382: 622–626.

    CAS  PubMed  Google Scholar 

  • Di Marcotullio L, Ferretti E, Greco A, De Smaele E, Po A, Sico MA et al. (2006). Numb is a suppressor of Hedgehog signalling and targets Gli1 for Itch-dependent ubiquitination. Nat Cell Biol 8: 1415–1423.

    CAS  PubMed  Google Scholar 

  • Dierker T, Dreier R, Petersen A, Bordych C, Grobe K . (2009). Heparan sulfate-modulated, metalloprotease-mediated sonic hedgehog release from producing cells. J Biol Chem 284: 8013–8022.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dierks C, Beigi R, Guo GR, Zirlik K, Stegert MR, Manley P et al. (2008). Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 14: 238–249.

    CAS  PubMed  Google Scholar 

  • Dierks C, Grbic J, Zirlik K, Beigi R, Englund NP, Guo GR et al. (2007). Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat Med 13: 944–951.

    CAS  PubMed  Google Scholar 

  • Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA et al. (1993). Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 75: 1417–1430.

    CAS  PubMed  Google Scholar 

  • Eggenschwiler JT, Espinoza E, Anderson KV . (2001). Rab23 is an essential negative regulator of the mouse Sonic hedgehog signalling pathway. Nature 412: 194–198.

    CAS  PubMed  Google Scholar 

  • Ehtesham M, Sarangi A, Valadez JG, Chanthaphaychith S, Becher MW, Abel TW et al. (2007). Ligand-dependent activation of the hedgehog pathway in glioma progenitor cells. Oncogene 26: 5752–5761.

    CAS  PubMed  Google Scholar 

  • Endoh-Yamagami S, Evangelista M, Wilson D, Wen X, Theunissen JW, Phamluong K et al. (2009). The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development. Curr Biol 19: 1320–1326.

    CAS  PubMed  Google Scholar 

  • Epstein Jr E . (2001). Genetic determinants of basal cell carcinoma risk. Med Pediatr Oncol 36: 555–558.

    PubMed  Google Scholar 

  • Epstein EH . (2008). Basal cell carcinomas: attack of the hedgehog. Nat Rev Cancer 8: 743–754.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Evangelista M, Lim TY, Lee J, Parker L, Ashique A, Peterson AS et al. (2008). Kinome siRNA screen identifies regulators of ciliogenesis and hedgehog signal transduction. Sci Signal 1: ra7.

    PubMed  Google Scholar 

  • Fan L, Pepicelli CV, Dibble CC, Catbagan W, Zarycki JL, Laciak R et al. (2004). Hedgehog signaling promotes prostate xenograft tumor growth. Endocrinology 145: 3961–3970.

    CAS  PubMed  Google Scholar 

  • Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, Mullendore M et al. (2007). Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 67: 2187–2196.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Feldmann G, Fendrich V, McGovern K, Bedja D, Bisht S, Alvarez H et al. (2008). An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer. Mol Cancer Ther 7: 2725–2735.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fiaschi M, Rozell B, Bergstrom A, Toftgard R . (2009). Development of mammary tumors by conditional expression of GLI1. Cancer Res 69: 4810–4817.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Frank-Kamenetsky M, Zhang XM, Bottega S, Guicherit O, Wichterle H, Dudek H et al. (2002). Small-molecule modulators of Hedgehog signaling: identification and characterization of Smoothened agonists and antagonists. J Biol 1: 10.

    PubMed  PubMed Central  Google Scholar 

  • Gao J, Graves S, Koch U, Liu S, Jankovic V, Buonamici S et al. (2009). Hedgehog signaling is dispensable for adult hematopoietic stem cell function. Cell Stem Cell 4: 548–558.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Goodrich LV, Milenkovic L, Higgins KM, Scott MP . (1997). Altered neural cell fates and medulloblastoma in mouse patched mutants. Science 277: 1109–1113.

    CAS  PubMed  Google Scholar 

  • Guardavaccaro D, Kudo Y, Boulaire J, Barchi M, Busino L, Donzelli M et al. (2003). Control of meiotic and mitotic progression by the F box protein beta-Trcp1 in vivo. Dev Cell 4: 799–812.

    CAS  PubMed  Google Scholar 

  • Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A et al. (1996). Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85: 841–851.

    CAS  PubMed  Google Scholar 

  • Hahn H, Wojnowski L, Zimmer AM, Hall J, Miller G, Zimmer A . (1998). Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nat Med 4: 619–622.

    CAS  PubMed  Google Scholar 

  • Han YG, Kim HJ, Dlugosz AA, Ellison DW, Gilbertson RJ, Alvarez-Buylla A . (2009). Dual and opposing roles of primary cilia in medulloblastoma development. Nat Med 15: 1062–1065.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hatton BA, Villavicencio EH, Tsuchiya KD, Pritchard JI, Ditzler S, Pullar B et al. (2008). The Smo/Smo model: hedgehog-induced medulloblastoma with 90% incidence and leptomeningeal spread. Cancer Res 68: 1768–1776.

    CAS  PubMed  Google Scholar 

  • Haycraft CJ, Banizs B, Aydin-Son Y, Zhang Q, Michaud EJ, Yoder BK . (2005). Gli2 and Gli3 localize to cilia and require the intraflagellar transport protein polaris for processing and function. PLoS Genet 1: e53.

    PubMed  PubMed Central  Google Scholar 

  • He J, Sheng T, Stelter AA, Li C, Zhang X, Sinha M et al. (2006). Suppressing Wnt signaling by the hedgehog pathway through sFRP-1. J Biol Chem 281: 35598–35602.

    CAS  PubMed  Google Scholar 

  • Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR . (2000). Requirement for glycogen synthase kinase-3beta in cell survival and NF-kappaB activation. Nature 406: 86–90.

    CAS  PubMed  Google Scholar 

  • Hofmann I, Stover EH, Cullen DE, Mao J, Morgan KJ, Lee BH et al. (2009). Hedgehog signaling is dispensable for adult murine hematopoietic stem cell function and hematopoiesis. Cell Stem Cell 4: 559–567.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hoover AN, Wynkoop A, Zeng H, Jia J, Niswander LA, Liu A . (2008). C2cd3 is required for cilia formation and Hedgehog signaling in mouse. Development 135: 4049–4058.

    CAS  PubMed  Google Scholar 

  • Hosoya T, Arai MA, Koyano T, Kowithayakorn T, Ishibashi M . (2008). Naturally occurring small-molecule inhibitors of hedgehog/GLI-mediated transcription. Chembiochem 9: 1082–1092.

    CAS  PubMed  Google Scholar 

  • Hu D, Helms JA . (1999). The role of sonic hedgehog in normal and abnormal craniofacial morphogenesis. Development 126: 4873–4884.

    CAS  PubMed  Google Scholar 

  • Huang S, He J, Zhang X, Bian X, Yang L, Xie G et al. (2006). Activation of the hedgehog pathway in human hepatocellular carcinomas. Carcinogenesis 27: 1334–1340.

    CAS  PubMed  Google Scholar 

  • Huangfu D, Anderson KV . (2005). Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci USA 102: 11325–11330.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Huangfu D, Anderson KV . (2006). Signaling from Smo to Ci/Gli: conservation and divergence of Hedgehog pathways from Drosophila to vertebrates. Development 133: 3–14.

    CAS  PubMed  Google Scholar 

  • Huangfu D, Liu A, Rakeman AS, Murcia NS, Niswander L, Anderson KV . (2003). Hedgehog signalling in the mouse requires intraflagellar transport proteins. Nature 426: 83–87.

    CAS  PubMed  Google Scholar 

  • Huntzicker EG, Estay IS, Zhen H, Lokteva LA, Jackson PK, Oro AE . (2006). Dual degradation signals control Gli protein stability and tumor formation. Genes Dev 20: 276–281.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hyman JM, Firestone AJ, Heine VM, Zhao Y, Ocasio CA, Han K et al. (2009). Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade. Proc Natl Acad Sci USA 106: 14132–14137.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ingham PW, Placzek M . (2006). Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nat Rev Genet 7: 841–850.

    CAS  PubMed  Google Scholar 

  • Ji Z, Mei FC, Xie J, Cheng X . (2007). Oncogenic kras supresses GLI1 degradation and activates hedgehog signaling pathway in pancreatic cancer cells. J Biol Chem 282: 14048–14055.

    CAS  PubMed  Google Scholar 

  • Jia J, Kolterud A, Zeng H, Hoover A, Teglund S, Toftgard R et al. (2009). Suppressor of Fused inhibits mammalian Hedgehog signaling in the absence of cilia. Dev Biol 330: 452–460.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jia J, Tong C, Wang B, Luo L, Jiang J . (2004). Hedgehog signalling activity of smoothened requires phosphorylation by protein kinase A and casein kinase I. Nature 432: 1045–1050.

    CAS  PubMed  Google Scholar 

  • Jiang J . (2006). Regulation of Hh/Gli signaling by dual ubiquitin pathways. Cell Cycle 5: 2457–2463.

    CAS  PubMed  Google Scholar 

  • Jiang J, Hui CC . (2008). Hedgehog signaling in development and cancer. Dev Cell 15: 801–812.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM et al. (1996). Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272: 1668–1671.

    CAS  PubMed  Google Scholar 

  • Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A et al. (2004). Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431: 707–712.

    CAS  PubMed  Google Scholar 

  • Kasai K, Inaguma S, Yoneyama A, Yoshikawa K, Ikeda H . (2008). SCL/TAL1 interrupting locus derepresses GLI1 from the negative control of suppressor-of-fused in pancreatic cancer cell. Cancer Res 68: 7723–7729.

    CAS  PubMed  Google Scholar 

  • Kasper M, Schnidar H, Neill GW, Hanneder M, Klingler S, Blaas L et al. (2006). Selective modulation of Hedgehog/GLI target gene expression by epidermal growth factor signaling in human keratinocytes. Mol Cell Biol 26: 6283–6298.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kasper M, Jaks V, Fiaschi M, Toftgard R . (2009). Hedgehog signalling in breast cancer. Carcinogenesis 30: 903–911.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kasperczyk H, Baumann B, Debatin KM, Fulda S . (2009). Characterization of sonic hedgehog as a novel NF-kappaB target gene that promotes NF-kappaB-mediated apoptosis resistance and tumor growth in vivo. FASEB J 23: 21–33.

    CAS  PubMed  Google Scholar 

  • Kawakami T, Kawcak T, Li YJ, Zhang W, Hu Y, Chuang PT . (2002). Mouse dispatched mutants fail to distribute hedgehog proteins and are defective in hedgehog signaling. Development 129: 5753–5765.

    CAS  PubMed  Google Scholar 

  • Kinzler KW, Ruppert JM, Bigner SH, Vogelstein B . (1988). The GLI gene is a member of the Kruppel family of zinc finger proteins. Nature 332: 371–374.

    CAS  PubMed  Google Scholar 

  • Kinzler KW, Vogelstein B . (1990). The GLI gene encodes a nuclear protein, which binds specific sequences in the human genome. Mol Cell Biol 10: 634–642.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kise Y, Morinaka A, Teglund S, Miki H . (2009). Sufu recruits GSK3beta for efficient processing of Gli3. Biochem Biophys Res Commun 387: 569–574.

    CAS  PubMed  Google Scholar 

  • Koga K, Nakamura M, Nakashima H, Akiyoshi T, Kubo M, Sato N et al. (2008). Novel link between estrogen receptor alpha and hedgehog pathway in breast cancer. Anticancer Res 28: 731–740.

    CAS  PubMed  Google Scholar 

  • Kogerman P, Grimm T, Kogerman L, Krause D, Unden AB, Sandstedt B et al. (1999). Mammalian suppressor-of-fused modulates nuclear-cytoplasmic shuttling of Gli-1. Nat Cell Biol 1: 312–319.

    CAS  PubMed  Google Scholar 

  • Kovacs JJ, Whalen EJ, Liu R, Xiao K, Kim J, Chen M et al. (2008). Beta-arrestin-mediated localization of smoothened to the primary cilium. Science 320: 1777–1781.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Koziel L, Kunath M, Kelly OG, Vortkamp A . (2004). Ext1-dependent heparan sulfate regulates the range of Ihh signaling during endochondral ossification. Dev Cell 6: 801–813.

    CAS  PubMed  Google Scholar 

  • Krauss S, Concordet JP, Ingham PW . (1993). A functionally conserved homolog of the Drosophila segment polarity gene hh is expressed in tissues with polarizing activity in zebrafish embryos. Cell 75: 1431–1444.

    CAS  PubMed  Google Scholar 

  • Kubo M, Nakamura M, Tasaki A, Yamanaka N, Nakashima H, Nomura M et al. (2004). Hedgehog signaling pathway is a new therapeutic target for patients with breast cancer. Cancer Res 64: 6071–6074.

    CAS  PubMed  Google Scholar 

  • Lam CW, Xie J, To KF, Ng HK, Lee KC, Yuen NW et al. (1999). A frequent activated smoothened mutation in sporadic basal cell carcinomas. Oncogene 18: 833–836.

    CAS  PubMed  Google Scholar 

  • Laner-Plamberger S, Kaser A, Paulischta M, Hauser-Kronberger C, Eichberger T, Frischauf AM . (2009). Cooperation between GLI and JUN enhances transcription of JUN and selected GLI target genes. Oncogene 28: 1639–1651.

    CAS  PubMed  Google Scholar 

  • Lauth M, Bergstrom A, Shimokawa T, Toftgard R . (2007). Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci USA 104: 8455–8460.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lee JJ, Ekker SC, von Kessler DP, Porter JA, Sun BI, Beachy PA . (1994). Autoproteolysis in hedgehog protein biogenesis. Science 266: 1528–1537.

    CAS  PubMed  Google Scholar 

  • Lee Y, Kawagoe R, Sasai K, Li Y, Russell HR, Curran T et al. (2007). Loss of suppressor-of-fused function promotes tumorigenesis. Oncogene 26: 6442–6447.

    CAS  PubMed  Google Scholar 

  • Liao X, Siu MK, Au CW, Wong ES, Chan HY, Ip PP et al. (2009). Aberrant activation of hedgehog signaling pathway in ovarian cancers: effect on prognosis, cell invasion and differentiation. Carcinogenesis 30: 131–140.

    CAS  PubMed  Google Scholar 

  • Lindemann RK . (2008). Stroma-initiated hedgehog signaling takes center stage in B-cell lymphoma. Cancer Res 68: 961–964.

    CAS  PubMed  Google Scholar 

  • Lum L, Yao S, Mozer B, Rovescalli A, Von Kessler D, Nirenberg M et al. (2003). Identification of Hedgehog pathway components by RNAi in Drosophila cultured cells. Science 299: 2039–2045.

    CAS  PubMed  Google Scholar 

  • Ma X, Chen K, Huang S, Zhang X, Adegboyega PA, Evers BM et al. (2005). Frequent activation of the hedgehog pathway in advanced gastric adenocarcinomas. Carcinogenesis 26: 1698–1705.

    CAS  PubMed  Google Scholar 

  • Ma X, Sheng T, Zhang Y, Zhang X, He J, Huang S et al. (2006). Hedgehog signaling is activated in subsets of esophageal cancers. Int J Cancer 118: 139–148.

    CAS  PubMed  Google Scholar 

  • Martinelli DC, Fan CM . (2007). Gas1 extends the range of Hedgehog action by facilitating its signaling. Genes Dev 21: 1231–1243.

    CAS  PubMed  PubMed Central  Google Scholar 

  • May SR, Ashique AM, Karlen M, Wang B, Shen Y, Zarbalis K et al. (2005). Loss of the retrograde motor for IFT disrupts localization of Smo to cilia and prevents the expression of both activator and repressor functions of Gli. Dev Biol 287: 378–389.

    CAS  PubMed  Google Scholar 

  • McLellan JS, Zheng X, Hauk G, Ghirlando R, Beachy PA, Leahy DJ . (2008). The mode of Hedgehog binding to Ihog homologues is not conserved across different phyla. Nature 455: 979–983.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Merchant M, Evangelista M, Luoh SM, Frantz GD, Chalasani S, Carano RA et al. (2005). Loss of the serine/threonine kinase fused results in postnatal growth defects and lethality due to progressive hydrocephalus. Mol Cell Biol 25: 7054–7068.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mistretta CM, Liu HX, Gaffield W, MacCallum DK . (2003). Cyclopamine and jervine in embryonic rat tongue cultures demonstrate a role for Shh signaling in taste papilla development and patterning: fungiform papillae double in number and form in novel locations in dorsal lingual epithelium. Dev Biol 254: 1–18.

    CAS  PubMed  Google Scholar 

  • Molckovsky A, Siu LL . (2008). First-in-class, first-in-human phase I results of targeted agents: Highlights of the 2008 American Society of Clinical Oncology meeting. J Hematol Oncol 1: 20.

    PubMed  PubMed Central  Google Scholar 

  • Molnar C, Holguin H, Mayor Jr F, Ruiz-Gomez A, de Celis JF . (2007). The G protein-coupled receptor regulatory kinase GPRK2 participates in Hedgehog signaling in Drosophila. Proc Natl Acad Sci USA 104: 7963–7968.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Morton JP, Mongeau ME, Klimstra DS, Morris JP, Lee YC, Kawaguchi Y et al. (2007). Sonic hedgehog acts at multiple stages during pancreatic tumorigenesis. Proc Natl Acad Sci USA 104: 5103–5108.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Motoyama J, Liu J, Mo R, Ding Q, Post M, Hui CC . (1998). Essential function of Gli2 and Gli3 in the information of lung, trachea and oesophagus. Nat Genet 20: 54–57.

    CAS  PubMed  Google Scholar 

  • Nieuwenhuis E, Motoyama J, Barnfield PC, Yoshikawa Y, Zhang X, Mo R et al. (2006). Mice with a targeted mutation of patched2 are viable but develop alopecia and epidermal hyperplasia. Mol Cell Biol 26: 6609–6622.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nolan-Stevaux O, Lau J, Truitt ML, Chu GC, Hebrok M, Fernandez-Zapico ME et al. (2009). GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev 23: 24–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nusslein-Volhard C, Wieschaus E . (1980). Mutations affecting segment number and polarity in Drosophila. Nature 287: 795–801.

    CAS  PubMed  Google Scholar 

  • Ogden SK, Fei DL, Schilling NS, Ahmed YF, Hwa J, Robbins DJ . (2008). G protein Galphai functions immediately downstream of smoothened in Hedgehog signalling. Nature 456: 967–970.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Okada A, Charron F, Morin S, Shin DS, Wong K, Fabre PJ et al. (2006). Boc is a receptor for sonic hedgehog in the guidance of commissural axons. Nature 444: 369–373.

    CAS  PubMed  Google Scholar 

  • Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D et al. (2009). Inhibition of hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324: 457–461.

    Google Scholar 

  • Pan Y, Bai CB, Joyner AL, Wang B . (2006). Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation. Mol Cell Biol 26: 3365–3377.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Parathath SR, Mainwaring LA, Fernandez LA, Campbell DO, Kenney AM . (2008). Insulin receptor substrate 1 is an effector of sonic hedgehog mitogenic signaling in cerebellar neural precursors. Development 135: 3291–3300.

    CAS  PubMed  Google Scholar 

  • Park HL, Bai C, Platt KA, Matise MP, Beeghly A, Hui CC et al (2000). Mouse Gli1 mutants are viable but have defects in SHH signaling in combination with a Gli2 mutation. Development 127: 1593–1605.

    CAS  PubMed  Google Scholar 

  • Pasca di Magliano M, Hebrok M . (2003). Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 3: 903–911.

    PubMed  Google Scholar 

  • Pasca di Magliano M, Sekine S, Ermilov A, Ferris J, Dlugosz AA, Hebrok M . (2006). Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev 20: 3161–3173.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Petersen PH, Zou K, Hwang JK, Jan YN, Zhong W . (2002). Progenitor cell maintenance requires numb and numblike during mouse neurogenesis. Nature 419: 929–934.

    CAS  PubMed  Google Scholar 

  • Philipp M, Fralish GB, Meloni AR, Chen W, MacInnes AW, Barak LS et al. (2008). Smoothened signaling in vertebrates is facilitated by a G protein-coupled receptor kinase. Mol Biol Cell 19: 5478–5489.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Porter JA, von Kessler DP, Ekker SC, Young KE, Lee JJ, Moses K et al. (1995). The product of hedgehog autoproteolytic cleavage active in local and long-range signalling. Nature 374: 363–366.

    CAS  PubMed  Google Scholar 

  • Porter JA, Young KE, Beachy PA . (1996). Cholesterol modification of hedgehog signaling proteins in animal development. Science 274: 255–259.

    CAS  PubMed  Google Scholar 

  • Qi M, Zhuo M, Skalhegg BS, Brandon EP, Kandel ER, McKnight GS et al. (1996). Impaired hippocampal plasticity in mice lacking the Cbeta1 catalytic subunit of cAMP-dependent protein kinase. Proc Natl Acad Sci USA 93: 1571–1576.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Read TA, Fogarty MP, Markant SL, McLendon RE, Wei Z, Ellison DW et al. (2009). Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma. Cancer Cell 15: 135–147.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Reifenberger J, Wolter M, Knobbe CB, Kohler B, Schonicke A, Scharwachter C et al. (2005). Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol 152: 43–51.

    CAS  PubMed  Google Scholar 

  • Reifenberger J, Wolter M, Weber RG, Megahed M, Ruzicka T, Lichter P et al. (1998). Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res 58: 1798–1803.

    CAS  PubMed  Google Scholar 

  • Reiter JF, Skarnes WC . (2006). Tectonic, a novel regulator of the Hedgehog pathway required for both activation and inhibition. Genes Dev 20: 22–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Reya T, Morrison SJ, Clarke MF, Weissman IL . (2001). Stem cells, cancer, and cancer stem cells. Nature 414: 105–111.

    CAS  PubMed  Google Scholar 

  • Riddle RD, Johnson RL, Laufer E, Tabin C . (1993). Sonic hedgehog mediates the polarizing activity of the ZPA. Cell 75: 1401–1416.

    CAS  PubMed  Google Scholar 

  • Riobo NA, Saucy B, Dilizio C, Manning DR . (2006). Activation of heterotrimeric G proteins by Smoothened. Proc Natl Acad Sci USA 103: 12607–12612.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Roelink H, Augsburger A, Heemskerk J, Korzh V, Norlin S, Ruiz i Altaba A et al. (1994). Floor plate and motor neuron induction by vhh-1, a vertebrate homolog of hedgehog expressed by the notochord. Cell 76: 761–775.

    CAS  PubMed  Google Scholar 

  • Rohatgi R, Milenkovic L, Corcoran RB, Scott MP . (2009). Hedgehog signal transduction by Smoothened: pharmacologic evidence for a 2-step activation process. Proc Natl Acad Sci USA 106: 3196–3201.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Romer JT, Kimura H, Magdaleno S, Sasai K, Fuller C, Baines H et al. (2004). Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1(+/−)p53(−/−) mice. Cancer Cell 6: 229–240.

    CAS  PubMed  Google Scholar 

  • Rubin LL, de Sauvage FJ . (2006). Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov 5: 1026–1033.

    CAS  PubMed  Google Scholar 

  • Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, Fu L et al. (2009). Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449. N Engl J Med 361: 1173–1178.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ruppert JM, Kinzler KW, Wong AJ, Bigner SH, Kao FT, Law ML et al. (1988). The GLI-Kruppel family of human genes. Mol Cell Biol 8: 3104–3113.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sanchez P, Hernandez AM, Stecca B, Kahler AJ, DeGueme AM, Barrett A et al. (2004). Inhibition of prostate cancer proliferation by interference with SONIC HEDGEHOG-GLI1 signaling. Proc Natl Acad Sci USA 101: 12561–12566.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sanchez P, Ruiz i Altaba A . (2005). In vivo inhibition of endogenous brain tumors through systemic interference of Hedgehog signaling in mice. Mech Dev 122: 223–230.

    CAS  PubMed  Google Scholar 

  • Sasaki H, Hui C, Nakafuku M, Kondoh H . (1997). A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro. Development 124: 1313–1322.

    CAS  PubMed  Google Scholar 

  • Scales SJ, de Sauvage FJ . (2009). Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci 30: 303–312.

    CAS  PubMed  Google Scholar 

  • Schnidar H, Eberl M, Klingler S, Mangelberger D, Kasper M, Hauser-Kronberger C et al. (2009). Epidermal growth factor receptor signaling synergizes with Hedgehog/GLI in oncogenic transformation via activation of the MEK/ERK/JUN pathway. Cancer Res 69: 1284–1292.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Scholey JM, Anderson KV . (2006). Intraflagellar transport and cilium-based signaling. Cell 125: 439–442.

    CAS  PubMed  Google Scholar 

  • Seppala M, Depew MJ, Martinelli DC, Fan CM, Sharpe PT, Cobourne MT . (2007). Gas1 is a modifier for holoprosencephaly and genetically interacts with sonic hedgehog. J Clin Invest 117: 1575–1584.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shaw G, Prowse DM . (2008). Inhibition of androgen-independent prostate cancer cell growth is enhanced by combination therapy targeting Hedgehog and ErbB signalling. Cancer Cell Int 8: 3.

    PubMed  PubMed Central  Google Scholar 

  • Sheng T, Chi S, Zhang X, Xie J . (2006). Regulation of Gli1 localization by the cAMP/protein kinase A signaling axis through a site near the nuclear localization signal. J Biol Chem 281: 9–12.

    CAS  PubMed  Google Scholar 

  • Sheng T, Li C, Zhang X, Chi S, He N, Chen K et al. (2004). Activation of the hedgehog pathway in advanced prostate cancer. Mol Cancer 3: 29.

    PubMed  PubMed Central  Google Scholar 

  • Sims-Mourtada J, Izzo JG, Apisarnthanarax S, Wu TT, Malhotra U, Luthra R et al. (2006). Hedgehog: an attribute to tumor regrowth after chemoradiotherapy and a target to improve radiation response. Clin Cancer Res 12: 6565–6572.

    CAS  PubMed  Google Scholar 

  • Singer JD, Gurian-West M, Clurman B, Roberts JM . (1999). Cullin-3 targets cyclin E for ubiquitination and controls S phase in mammalian cells. Genes Dev 13: 2375–2387.

    CAS  PubMed  PubMed Central  Google Scholar 

  • So PL, Fujimoto MA, Epstein Jr EH . (2008). Pharmacologic retinoid signaling and physiologic retinoic acid receptor signaling inhibit basal cell carcinoma tumorigenesis. Mol Cancer Ther 7: 1275–1284.

    CAS  PubMed  PubMed Central  Google Scholar 

  • St-Jacques B, Hammerschmidt M, McMahon AP . (1999). Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation. Genes Dev 13: 2072–2086.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stanton BZ, Peng LF, Maloof N, Nakai K, Wang X, Duffner JL et al. (2009). A small molecule that binds Hedgehog and blocks its signaling in human cells. Nat Chem Biol 5: 154–156.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stecca B, Mas C, Clement V, Zbinden M, Correa R, Piguet V et al. (2007). Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci USA 104: 5895–5900.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stecca B, Ruiz i Altaba A . (2009). A GLI1-p53 inhibitory loop controls neural stem cell and tumour cell numbers. EMBO J 28: 663–676.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stone DM, Hynes M, Armanini M, Swanson TA, Gu Q, Johnson RL et al. (1996). The tumour-suppressor gene patched encodes a candidate receptor for Sonic hedgehog. Nature 384: 129–134.

    CAS  PubMed  Google Scholar 

  • Svard J, Henricson KH, Persson-Lek M, Rozell B, Lauth M, Bergstrom A et al. (2006). Genetic elimination of suppressor of fused reveals an essential repressor function in the Mammalian hedgehog signaling pathway. Dev Cell 10: 187–197.

    PubMed  Google Scholar 

  • Tenzen T, Allen BL, Cole F, Kang JS, Krauss RS, McMahon AP . (2006). The cell surface membrane proteins Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev Cell 10: 647–656.

    CAS  PubMed  Google Scholar 

  • Thayer SP, di Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, Lauwers GY et al. (2003). Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425: 851–856.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tian H, Callahan CA, DuPree KJ, Darbonne WC, Ahn CP, Scales SJ et al. (2009). Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci USA 106: 4254–4259.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Toyoda H, Kinoshita-Toyoda A, Fox B, Selleck SB . (2000). Structural analysis of glycosaminoglycans in animals bearing mutations in sugarless, sulfateless, and tout-velu. Drosophila homologues of vertebrate genes encoding glycosaminoglycan biosynthetic enzymes. J Biol Chem 275: 21856–21861.

    CAS  PubMed  Google Scholar 

  • Tremblay MR, Lescarbeau A, Grogan MJ, Tan E, Lin G, Austad BC et al. (2009). Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926). J Med Chem 52: 4400–4418.

    CAS  PubMed  Google Scholar 

  • Varjosalo M, Bjorklund M, Cheng F, Syvanen H, Kivioja T, Kilpinen S et al. (2008). Application of active and kinase-deficient kinome collection for identification of kinases regulating hedgehog signaling. Cell 133: 537–548.

    CAS  PubMed  Google Scholar 

  • Varjosalo M, Li SP, Taipale J . (2006). Divergence of hedgehog signal transduction mechanism between drosophila and mammals. Dev Cell 10: 177–186.

    CAS  PubMed  Google Scholar 

  • Von Hoff DD, Lorusso PM, Rudin CM, Reddy JC, Yauch RL, Tibes R et al. (2009). Inhibition of the hedgehog pathway in advanced Basal-cell carcinoma. N Engl J Med 361: 1164–1172.

    CAS  PubMed  Google Scholar 

  • Wang B, Li Y . (2006). Evidence for the direct involvement of {beta}TrCP in Gli3 protein processing. Proc Natl Acad Sci USA 103: 33–38.

    CAS  PubMed  Google Scholar 

  • Wang Y, Zhou Z, Walsh CT, McMahon AP . (2009). Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation. Proc Natl Acad Sci USA 106: 2623–2628.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA, Baylin SB . (2003). Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 422: 313–317.

    CAS  PubMed  Google Scholar 

  • Williams JA, Guicherit OM, Zaharian BI, Xu Y, Chai L, Wichterle H et al. (2003). Identification of a small molecule inhibitor of the hedgehog signaling pathway: effects on basal cell carcinoma-like lesions. Proc Natl Acad Sci USA 100: 4616–4621.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wilson CW, Chen MH, Chuang PT . (2009a). Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium. PLoS One 4: e5182.

    PubMed  PubMed Central  Google Scholar 

  • Wilson CW, Nguyen CT, Chen MH, Yang JH, Gacayan R, Huang J et al. (2009b). Fused has evolved divergent roles in vertebrate Hedgehog signalling and motile ciliogenesis. Nature 459: 98–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wong SY, Seol AD, So PL, Ermilov AN, Bichakjian CK, Epstein Jr EH et al. (2009). Primary cilia can both mediate and suppress Hedgehog pathway-dependent tumorigenesis. Nat Med 15: 1055–1061.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xie J . (2005). Hedgehog signaling in prostate cancer. Future Oncol 1: 331–338.

    CAS  PubMed  Google Scholar 

  • Xie J . (2008a). Hedgehog signaling pathway: development of antagonists for cancer therapy. Curr Oncol Rep 10: 107–113.

    CAS  PubMed  Google Scholar 

  • Xie J . (2008b). Implications of hedgehog signaling antagonists for cancer therapy. Acta Biochim Biophys Sin (Shanghai) 40: 670–680.

    CAS  Google Scholar 

  • Xie J . (2008c). Molecular biology of basal and squamous cell carcinomas. Adv Exp Med Biol 624: 241–251.

    CAS  PubMed  Google Scholar 

  • Xie J, Aszterbaum M, Zhang X, Bonifas JM, Zachary C, Epstein E et al. (2001). A role of PDGFRalpha in basal cell carcinoma proliferation. Proc Natl Acad Sci USA 98: 9255–9259.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xie J, Garrossian M . (2009). In: Benjamin A (ed.). SYSTEM TBOROTUOT. WO/2009/099625. Adler & Associates: Houston, TX, USA, pp 1–122.

    Google Scholar 

  • Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C et al. (1998). Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391: 90–92.

    CAS  PubMed  Google Scholar 

  • Yanai K, Nakamura M, Akiyoshi T, Nagai S, Wada J, Koga K et al. (2008). Crosstalk of hedgehog and Wnt pathways in gastric cancer. Cancer Lett 263: 145–156.

    CAS  PubMed  Google Scholar 

  • Yang SH, Andl T, Grachtchouk V, Wang A, Liu J, Syu LJ et al. (2008). Pathological responses to oncogenic Hedgehog signaling in skin are dependent on canonical Wnt/beta3-catenin signaling. Nat Genet 40: 1130–1135.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yao S, Lum L, Beachy P . (2006). The ihog cell-surface proteins bind Hedgehog and mediate pathway activation. Cell 125: 343–357.

    CAS  PubMed  Google Scholar 

  • Yauch RL, Dijkgraaf GJ, Alicke B, Januario T, Ahn CP, Holcomb T et al. (2009). Smoothened mutation confers resistance to a hedgehog pathway inhibitor in medulloblastoma. Science (e-pub ahead of print 2 September 2009).

  • Yauch RL, Gould SE, Scales SJ, Tang T, Tian H, Ahn CP et al. (2008). A paracrine requirement for hedgehog signalling in cancer. Nature 455: 406–410.

    CAS  PubMed  Google Scholar 

  • Yoshikawa R, Nakano Y, Tao L, Koishi K, Matsumoto T, Sasako M et al. (2008). Hedgehog signal activation in oesophageal cancer patients undergoing neoadjuvant chemoradiotherapy. Br J Cancer 98: 1670–1674.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Yue S, Chen Y, Cheng SY . (2009). Hedgehog signaling promotes the degradation of tumor suppressor Sufu through the ubiquitin-proteasome pathway. Oncogene 28: 492–499.

    CAS  PubMed  Google Scholar 

  • Zhang C, Williams EH, Guo Y, Lum L, Beachy PA . (2004). Extensive phosphorylation of Smoothened in Hedgehog pathway activation. Proc Natl Acad Sci USA 101: 17900–17907.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang Q, Davenport JR, Croyle MJ, Haycraft CJ, Yoder BK . (2005). Disruption of IFT results in both exocrine and endocrine abnormalities in the pancreas of Tg737(orpk) mutant mice. Lab Invest 85: 45–64.

    CAS  PubMed  Google Scholar 

  • Zhang W, Kang JS, Cole F, Yi MJ, Krauss RS . (2006). Cdo functions at multiple points in the Sonic Hedgehog pathway, and Cdo-deficient mice accurately model human holoprosencephaly. Dev Cell 10: 657–665.

    CAS  PubMed  Google Scholar 

  • Zhang XM, Ramalho-Santos M, McMahon AP . (2001). Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node. Cell 105: 781–792.

    CAS  PubMed  Google Scholar 

  • Zhang Y, Laterra J, Pomper MG . (2009). Hedgehog pathway inhibitor HhAntag691 is a potent inhibitor of ABCG2/BCRP and ABCB1/Pgp. Neoplasia 11: 96–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J et al. (2009). Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458: 776–779.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhao Y, Tong C, Jiang J . (2007). Hedgehog regulates smoothened activity by inducing a conformational switch. Nature 450: 252–258.

    CAS  PubMed  Google Scholar 

  • Zwerner JP, Joo J, Warner KL, Christensen L, Hu-Lieskovan S, Triche TJ et al. (2008). The EWS/FLI1 oncogenic transcription factor deregulates GLI1. Oncogene 27: 3282–3291.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Current research in my laboratory is supported by grants from the National Cancer Institute CA94160 and Wells Center for Pediatric Research.

Author information

Authors and Affiliations

  1. Division of Hematology and Oncology, Department of Pediatrics and IU Simon Cancer Center, Wells Center for Pediatric Research, Indiana University, Indianapolis, IN, USA

    L Yang, G Xie, Q Fan & J Xie

Authors
  1. L Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Q Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J Xie.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, L., Xie, G., Fan, Q. et al. Activation of the hedgehog-signaling pathway in human cancer and the clinical implications. Oncogene 29, 469–481 (2010). https://doi.org/10.1038/onc.2009.392

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2009.392

Keywords

This article is cited by

Search

Advanced search

Quick links