Role of the Hedgehog pathway in hepatocellular carcinoma (Review)

Oncology Reports

Volumn 30, Issue 5, 2013, Pages 2020-2026

  Zheng, Xin ^a   Zeng, Wen ^b   Gai, Xiaohong ^a   Xu, Qiuran ^a   Li, Chao ^a   Liang, Zheyong ^a   Tuo, Hang ^a   Liu, Qingguang ^a  

^a THE FIRST AFFILIATED HOSPITAL OF XI AN JIAOTONG UNIVERSITY   (China)

^b XI AN CENTRAL HOSPITAL   (China)

Author keywords

Cell signal; Hedgehog; Hepatocellular carcinoma; Targeting therapy

Indexed keywords

ANTINEOPLASTIC AGENT; CYCLOPAMINE; ESTERASE INHIBITOR; GANT 61; MESSENGER RNA; OKN 007; PLACEBO; PROTEIN PATCHED; PURMORPHAMINE; SMOOTHENED PROTEIN; SONIC HEDGEHOG PROTEIN; SONIDEGIB; TRANSCRIPTION FACTOR GLI1; UNCLASSIFIED DRUG; VISMODEGIB;

ANOREXIA; ANTINEOPLASTIC ACTIVITY; AUTOCRINE EFFECT; AUTOPHAGY; BASAL CELL CARCINOMA; BASAL CELL NEVUS SYNDROME; CANCER GROWTH; CANCER INHIBITION; CANCER RESISTANCE; COLON CANCER; DRUG TARGETING; DRUG TOLERABILITY; DYSGEUSIA; ESOPHAGUS CANCER; FATIGUE; GENE MUTATION; HUMAN; HYPONATREMIA; LIVER CARCINOGENESIS; LIVER CELL CARCINOMA; LUNG CANCER; MEDULLOBLASTOMA; MUSCLE CRAMP; MUSCLE SPASM; NAUSEA; NONHUMAN; OVARY CANCER; PANCREAS CANCER; PARACRINE SIGNALING; PRIORITY JOURNAL; PROTEIN EXPRESSION; REVIEW; SIDE EFFECT; SIGNAL TRANSDUCTION; SOLID TUMOR; STOMACH CANCER; TASTE DISORDER; VIRUS CARCINOGENESIS; VOMITING; WEIGHT REDUCTION;

CARCINOGENESIS; CARCINOMA, HEPATOCELLULAR; CELL DIFFERENTIATION; HEDGEHOG PROTEINS; HUMANS; LIVER; LIVER CIRRHOSIS; LIVER NEOPLASMS; SIGNAL TRANSDUCTION;

EID: 84885027595     PISSN: 1021335X     EISSN: 17912431     Source Type: Journal    
DOI: 10.3892/or.2013.2690     Document Type: Review

References (69)

1. Yang JD and Roberts LR: Hepatocellular carcinoma: a global view. Nat Rev Gastroenterol Hepatol 7: 448-458, 2010.
2. Sandhu DS, Tharayil VS, Lai JP and Roberts LR: Treatment options for hepatocellular carcinoma. Expert Rev Gastroenterol Hepatol 2: 81-92, 2008.
3. Zheng X, Gai X, Han S, et al: The human sulfatase 2 inhibitor 2,4-disulfonylphenyl-tert-butylnitrone (OKN-007) has an antitumor effect in hepatocellular carcinoma mediated via suppression of TGFB1/SMAD2 and Hedgehog/GLI1 signaling. Genes Chromosomes Cancer 52: 225-236, 2013.
4. Zheng X, Vittar NB, Gai X, et al: The transcription factor GLI1 mediates TGFβ1 driven EMT in hepatocellular carcinoma via a SNAI1-dependent mechanism. PLoS One 7: e49581, 2012.
5. Xu QR, Zheng X, Zan XF, Yao YM, Yang W and Liu QG: Gli1 expression and its relationship with the expression of Shh, Vimentin and E-cadherin in human hepatocellular carcinoma. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 28: 536-539, 2012 (In Chinese).
6. Zheng X, Yao Y, Xu Q, Tu K and Liu Q: Evaluation of glioma-associated oncogene 1 expression and its correlation with the expression of sonic hedgehog, E-cadherin and S100a4 in human hepatocellular carcinoma. Mol Med Rep 3: 965-970, 2010.
7. Nüsslein-Volhard C and Wieschaus E: Mutations affecting segment number and polarity in Drosophila. Nature 287: 795-801, 1980.
8. Heretsch P, Tzagkaroulaki L and Giannis A: Modulators of the hedgehog signaling pathway. Bioorg Med Chem 18: 6613-6624, 2010.
9. Pepinsky RB, Zeng C, Wen D, et al: Identification of a palmitic acid-modified form of human Sonic hedgehog. J Biol Chem 273: 14037-14045, 1998.
10. Porter JA, Young KE and Beachy PA: Cholesterol modification of hedgehog signaling proteins in animal development. Science 274: 255-259, 1996.
11. Kinzler KW, Bigner SH, Bigner DD, et al: Identification of an amplified, highly expressed gene in a human glioma. Science 236: 70-73, 1987.
12. Corbit KC, Aanstad P, Singla V, Norman AR, Stainier DY and Reiter JF: Vertebrate Smoothened functions at the primary cilium. Nature 437: 1018-1021, 2005.
13. Huangfu D and Anderson KV: Cilia and Hedgehog responsiveness in the mouse. Proc Natl Acad Sci USA 102: 11325-11330, 2005.
14. Ruiz i Altaba A, Mas C and Stecca B: The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol 17: 438-447, 2007.
15. Kenney AM, Cole MD and Rowitch DH: Nmyc upregulation by sonic hedgehog signaling promotes proliferation in developing cerebellar granule neuron precursors. Development 130: 15-28, 2003.
16. Kasper M, Schnidar H, Neill GW, et al: Selective modulation of Hedgehog/GLI target gene expression by epidermal growth factor signaling in human keratinocytes. Mol Cell Biol 26: 6283-6298, 2006.
17. Yoon JW, Kita Y, Frank DJ, et al: Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J Biol Chem 277: 5548-5555, 2002.
18. Teh MT, Blaydon D, Chaplin T, et al: Genomewide single nucleotide polymorphism microarray mapping in basal cell carcinomas unveils uniparental disomy as a key somatic event. Cancer Res 65: 8597-8603, 2005.
19. Eichberger T, Kaser A, Pixner C, et al: GLI2-specific transcriptional activation of the bone morphogenetic protein/activin antagonist follistatin in human epidermal cells. J Biol Chem 283: 12426-12437, 2008.
20. Kump E, Ji J, Wernli M, Häusermann P and Erb P: Gli2 upregulates cFlip and renders basal cell carcinoma cells resistant to death ligand-mediated apoptosis. Oncogene 27: 3856-3864, 2008.
21. Hallikas O, Palin K, Sinjushina N, et al: Genome-wide prediction of mammalian enhancers based on analysis of transcription-factor binding affinity. Cell 124: 47-59, 2006.
22. Li X, Deng W, Lobo-Ruppert SM and Ruppert JM: Gli1 acts through Snail and E-cadherin to promote nuclear signaling by β-catenin. Oncogene 26: 4489-4498, 2007.
23. Kasper M, Regl G, Frischauf AM and Aberger F: GLI transcription factors: mediators of oncogenic Hedgehog signalling. Eur J Cancer 42: 437-445, 2006.
24. Fernandez-Zapico ME: Primers on molecular pathways GLI: more than just Hedgehog? Pancreatology 8: 227-229, 2008.
25. Stecca B, Mas C, Clement V, et al: Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci USA 104: 5895-5900, 2007.
26. Kudchadkar R, Lewis K and Gonzalez R: Advances in the treatment of Basal cell carcinoma: Hedgehog inhibitors. Semin Oncol 39: 139-144, 2012.
27. Wang X, Venugopal C, Manoranjan B, et al: Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells. Oncogene 31: 187-199, 2012.
28. Singh S, Wang Z, Liang Fei D, et al: Hedgehog-producing cancer cells respond to and require autocrine Hedgehog activity. Cancer Res 71: 4454-4463, 2011.
29. Saqui-Salces M and Merchant JL: Hedgehog signaling and gastrointestinal cancer. Biochim Biophys Acta 1803: 786-795, 2010.
30. Chung MK, Kim HJ, Lee YS, et al: Hedgehog signaling regulates proliferation of prostate cancer cells via stathmin1. Clin Exp Med 10: 51-57, 2010.
31. Tian H, Callahan CA, DuPree KJ, et al: Hedgehog signaling is restricted to the stromal compartment during pancreatic carcinogenesis. Proc Natl Acad Sci USA 106: 4254-4259, 2009.
32. Dierks C, Grbic J, Zirlik K, et al: Essential role of stromally induced hedgehog signaling in B-cell malignancies. Nat Med 13: 944-951, 2007.
33. Becher OJ, Hambardzumyan D, Fomchenko EI, et al: Gli activity correlates with tumor grade in platelet-derived growth factor-induced gliomas. Cancer Res 68: 2241-2249, 2008.
34. Romer JT, Kimura H, Magdaleno S, et al: Suppression of the Shh pathway using a small molecule inhibitor eliminates medulloblastoma in Ptc1+/-p53-/- mice. Cancer Cell 6: 229-240, 2004.
35. Gailani MR, Ståhle-Bäckdahl M, Leffell DJ, et al: The role of the human homologue of Drosophila patched in sporadic basal cell carcinomas. Nat Genet 14: 78-81, 1996.
36. Watkins DN, Berman DM, Burkholder SG, Wang B, Beachy PA and Baylin SB: Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer. Nature 422: 313-317, 2003.
37. Lauth M, Bergström A, Shimokawa T, et al: DYRK1B-dependent autocrine-to-paracrine shift of Hedgehog signaling by mutant RAS. Nat Struct Mol Biol 17: 718-725, 2010.
38. Katano M: Hedgehog signaling pathway as a therapeutic target in breast cancer. Cancer Lett 227: 99-104, 2005.
39. Hatsell S and Frost AR: Hedgehog signaling in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia 12: 163-173, 2007.
40. Kasper M, Jaks V, Fiaschi M and Toftgård R: Hedgehog signalling in breast cancer. Carcinogenesis 30: 903-911, 2009.
41. Wang LH, Choi YL, Hua XY, et al: Increased expression of sonic hedgehog and altered methylation of its promoter region in gastric cancer and its related lesions. Mod Pathol 19: 675-683, 2006.
42. Varnat F, Duquet A, Malerba M, 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 1: 338-351, 2009.
43. Mazumdar T, DeVecchio J, Agyeman A, Shi T and Houghton JA: The GLI genes as the molecular switch in disrupting Hedgehog signaling in colon cancer. Oncotarget 2: 638-645, 2011.
44. Wang WS, Chen PM and Su Y: Colorectal carcinoma: from tumorigenesis to treatment. Cell Mol Life Sci 63: 663-671, 2006.
45. Theunissen JW and de Sauvage FJ: Paracrine Hedgehog signaling in cancer. Cancer Res 69: 6007-6010, 2009.
46. Lu JT, Zhao WD, He W and Wei W: Hedgehog signaling pathway mediates invasion and metastasis of hepatocellular carcinoma via ERK pathway. Acta Pharmacol Sin 33: 691-700, 2012.
47. Wang Y, Han C, Lu L, Magliato S and Wu T: Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells. Hepatology: Mar 16, 2013 (Epub ahead of print).
48. Sicklick JK, Li YX, Jayaraman A, et al: Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis 27: 748-757, 2006.
49. Tada M, Kanai F, Tanaka Y, et al: Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma. Clin Cancer Res 14: 3768-3776, 2008.
50. Chan IS, Guy CD, Chen Y, et al: Paracrine Hedgehog signaling drives metabolic changes in hepatocellular carcinoma. Cancer Res 72: 6344-6350, 2012.
51. Arzumanyan A, Sambandam V, Clayton MM, et al: Hedgehog signaling blockade delays hepatocarcinogenesis induced by hepatitis B virus X protein. Cancer Res 72: 5912-5920, 2012.
52. Pereira Tde A, Witek RP, Syn WK, et al: Viral factors induce Hedgehog pathway activation in humans with viral hepatitis, cirrhosis, and hepatocellular carcinoma. Lab Invest 90: 1690-1703, 2010.
53. Philips GM, Chan IS, Swiderska M, et al: Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer. PLoS One 6: e23943, 2011.
54. Chen X, Lingala S, Khoobyari S, Nolta J, Zern MA and Wu J: Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations. J Hepatol 55: 838-845, 2011.
55. Cooper MK, Porter JA, Young KE and Beachy PA: Teratogen-mediated inhibition of target tissue response to Shh signaling. Science 280: 1603-1607, 1998.
56. Rubin LL and de Sauvage FJ: Targeting the Hedgehog pathway in cancer. Nat Rev Drug Discov 5: 1026-1033, 2006.
57. Robarge KD, Brunton SA, Castanedo GM, et al: GDC-0449-a potent inhibitor of the hedgehog pathway. Bioorg Med Chem Lett 19: 5576-5581, 2009.
58. Yauch RL, Gould SE, Scales SJ, et al: A paracrine requirement for hedgehog signalling in cancer. Nature 455: 406-410, 2008.
59. Tian F, Mysliwietz J, Ellwart J, Gamarra F, Huber RM and Bergner A: Effects of the Hedgehog pathway inhibitor GDC-0449 on lung cancer cell lines are mediated by side populations. Clin Exp Med 12: 25-30, 2012.
60. Ailles L and Siu LL: Targeting the Hedgehog pathway in cancer: can the spines be smoothened? Clin Cancer Res 17: 2071-2073, 2011.
61. Singh BN, Fu J, Srivastava RK and Shankar S: Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms. PLoS One 6: e27306, 2011.
62. Von Hoff DD, LoRusso PM, Rudin CM, et al: Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N Engl J Med 361: 1164-1172, 2009.
63. De Smaele E, Ferretti E and Gulino A: Vismodegib, a small-molecule inhibitor of the hedgehog pathway for the treatment of advanced cancers. Curr Opin Investig Drugs 11: 707-718, 2010.
64. Rudin CM: Vismodegib. Clin Cancer Res 18: 3218-3222, 2012.
65. Axelson M, Liu K, Jiang X, et al: U.S. Food and Drug Administration approval: vismodegib for recurrent, locally advanced, or metastatic basal cell carcinoma. Clin Cancer Res 19: 2289-2293, 2013.
66. Skvara H, Kalthoff F, Meingassner JG, et al: Topical treatment of Basal cell carcinomas in nevoid Basal cell carcinoma syndrome with a smoothened inhibitor. J Invest Dermatol 131: 1735-1744, 2011.
67. Li Y, Maitah MY, Ahmad A, Kong D, Bao B and Sarkar FH: Targeting the Hedgehog signaling pathway for cancer therapy. Expert Opin Ther Targets 16: 49-66, 2012.
68. Lauth M, Bergström A, Shimokawa T and Toftgård R: Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci USA 104: 8455-8460, 2007.
69. Fu J, Rodova M, Roy SK, et al: GANT-61 inhibits pancreatic cancer stem cell growth in vitro and in NOD/SCID/IL2R gamma null mice xenograft. Cancer Lett 330: 22-32, 2013.