Structural and Logical Analysis of a Comprehensive Hedgehog Signaling Pathway to Identify Alternative Drug Targets for Glioma, Colon and Pancreatic Cancer

PLoS ONE

Volumn 8, Issue 7, 2013, Pages

  Chowdhury, Saikat ^a   Pradhan, Rachana N ^a   Sarkar, Ram Rup ^a  

^a NATIONAL CHEMICAL LABORATORY   (India)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOPLASM PROTEIN; MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; NUCLEAR PROTEIN; ONCOPROTEIN; PROTEIN HFU; PROTEIN ULK3; RAS PROTEIN; SMOOTHENED PROTEIN; SONIC HEDGEHOG PROTEIN; TRANSCRIPTION FACTOR GLI1; TRANSCRIPTION FACTOR GLI2; UNCLASSIFIED DRUG;

ARTICLE; CELL MEMBRANE; COLON CANCER; DRUG TARGETING; EXTRACELLULAR SPACE; GLIOMA; HUMAN; PANCREAS CANCER; PROTEIN EXPRESSION; PROTEIN INTERACTION; PROTEIN STRUCTURE; SIGNAL TRANSDUCTION; VALIDATION PROCESS;

ANTINEOPLASTIC AGENTS; COLONIC NEOPLASMS; COMPUTER SIMULATION; GLIOMA; HEDGEHOG PROTEINS; HUMANS; MOLECULAR TARGETED THERAPY; PANCREATIC NEOPLASMS; SIGNAL TRANSDUCTION;

EID: 84880758861     PISSN: None     EISSN: 19326203     Source Type: Journal    
DOI: 10.1371/journal.pone.0069132     Document Type: Article

References (101)

1. Samaga R, Saez-Rodriguez J, Alexopoulos LG, Sorger PK, Klamt S, (2009) The Logic of EGFR/ErbB Signaling: Theoretical Properties and Analysis of High-Throughput Data. PLoS Comput Biol 5(8): e1000438 DOI:10.1371/journal.pcbi.1000438.
2. Hornberg JJ, Bruggeman FJ, Westerhoff HV, Lankelma J, (2006) Cancer: A Systems Biology disease. Systems Biology 83: 81-90.
3. Jiang J, Hui C (2008) Hedgehog Signaling in Development and Cancer. Developmental Cell DOI 10.1016/j.devcel.2008.11.010.
4. Evangelista M, Tian H, de Sauvage FJ, (2006) The hedgehog signaling pathway in cancer. Clin Cancer Res 12: 5924-5928.
5. Rubin LL, de Sauvage FJ, (2006) Targeting the Hedgehog pathway in cancer. Nature Reviews Drug Discovery 5: 1026-1033 DOI:10.1038/nrd2086.
6. Katoh Y, Katoh M, (2006) Hedgehog signaling pathway and gastrointestinal stem cell signaling network (review). International Journal of Molecular Medicine 18: 1019-23.
7. Ogdena SK, Ascano M Jr, Stegmana MA, Robbins DJ, (2004) Regulation of Hedgehog signaling: a complex story. Biochemical Pharmacology 67: 805-814 DOI:10.1016/j.bcp.2004.01.002.
8. Xie J, Epstein E (2011) Activation of Hedgehog Signaling in Human Cancer. In: Jingwu Xie, editors. Hedgehog signaling activation in human cancer and its clinical implications. Springer New York, 85-104; DOI:10.1007/978-1-4419-8435-7-7.
9. Rohatgi R, Scott MP, (2007) Patching the gaps in Hedgehog signalling. Nature Cell Biology 9: 1005-1009 DOI:10.1038/ncb435.
10. Beachy PA, Liu J (2012) Hedgehog pathway antagonists to treat cancer. European Patent Application EP2404602. Available: http://www.freepatentsonline.com/EP2404602.html via the Internet. Accessed 1st Nov 2012.
11. Xu X, Ding H, Rao G, Arora S, Saclarides CP, et al. (2012) Activation of the Sonic Hedgehog pathway in thyroid neoplasms and its potential role in tumor cell proliferation. Endocr Relat Cancer 19: 167-179 DOI:10.1530/ERC-11-0305.
12. Galimberti F, Busch AM, Chinyengetere F, Ma T, Sekula D, et al. (2012) Response to inhibition of smoothened in diverse epithelial cancer cells that lack smoothened or patched 1 mutations. International Journal of Oncology 41: 1751-1761 DOI:10.3892/ijo.2012.1599.
13. McMillan R, Matsui W, (2012) Molecular Pathways: The Hedgehog Signaling Pathway in Cancer. Clin Cancer Res 18: 4883-4888 DOI:10.1158/1078-0432.CCR-11-2509.
14. Kelleher FC, Cain JE, Healy JM, Watkins DN, Thomas DM, (2012) Prevailing importance of the hedgehog signaling pathway and the potential for treatment advancement in sarcoma. Pharmacology & Therapeutics 136: 153-168.
15. Li Y, Maitah MY, Ahmad A, Kong D, Bao B, (2012) Targeting the Hedgehog signaling pathway for cancer therapy. Expert Opin. Ther. Targets 16(1): 49-66.
16. Olive KP, Tuveson D (2012) Hedgehog Pathway Inhibitors. United States Patent Application Publication. Publication number: US 2012/0020876 A1.
17. Atwood SX, Chang ALS, Oro AE, (2012) Hedgehog pathway inhibition and the race against tumor evolution. J. Cell Biol 199(2): 193-197.
18. Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, et al. (2009) Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449. The New England Journal Of Medicine 361: 1173-8.
19. Dockendorff C, Nagiec MM, Weïwer M, Buhrlage S, Ting A, et al. (2012) Macrocyclic Hedgehog Pathway Inhibitors: Optimization of Cellular Activity and Mode of Action Studies. ACS Med. Chem. Lett. 3: 808-813.
20. Sherriff MR, Sarkar RR, (2008) Computational approaches and modeling of signaling processes in the Immune System. Proc Indian Natn Sci Acad 74: 187-200.
21. Morris MK, Saez-Rodriguez J, Sorger PK, Lauffenburger DA, (2010) Logic-Based Models for the Analysis of Cell Signaling Networks. Biochemistry 49: 3216-3224.
22. Dillon R, Gadgil C, Othmer HG, (2003) Short- and long-range effects of Sonic hedgehog in limb development. Proc Natl Acad Sci U S A 100(18): 10152-10157.
23. Saha K, Schaffer DV, (2006) Signal dynamics in Sonic hedgehog tissue patterning. Development 1411: 889-900.
24. Albert R, Othmer HG, (2003) The topology of the regulatory interactions predicts the expression pattern of the segment polarity genes in Drosophila melanogaster. Journal of Theoretical Biology 223: 1-18 DOI:10.1016/S0022-5193(03)00035-3.
25. Subramanian K, Gadgil C (2009) Robustness of the Drosophila segment polarity network to transient perturbations. Chemical Engineering 1-13.
26. Lum L, Zhang C, Oh S, Mann RK, von Kessler DP, et al. (2003) Hedgehog Signal Transduction via Smoothened Association with a Cytoplasmic Complex Scaffolded by the Atypical Kinesin, Costal-2. Molecular Cell 12: 1261-1274.
27. Varjosalo M, Taipale J, (2007) Hedgehog signaling. Journal of Cell Science 120: 3-6 DOI:10.1242/jcs.03309.
28. Kitano H, Funahashi A, Matsuoka Y, Oda K, (2005) Using process diagram for the graphical representation of biological networks. Nature Biotechnology 23(8): 961-966.
29. Funahashi A, Tanimura N, Morohashi M, Kitano H, (2003) CellDesigner: a process diagram editor for gene-regulatory and biochemical networks. BIOSILICO 1: 159-162 DOI:10.1016/S1478-5382(03)02370-9.
30. Murone M, Luoh SM, Stone D, Li W, Gurney A, et al. (2000) Gli regulation by the opposing activities of Fused and Suppressor of Fused. Nature Cell Biology 2: 310-312 DOI:10.1038/35010610.
31. Maloverjan A, Piirsoo M, Michelson P, Kogerman P, Østerlund T (2010) Identification of a novel serine/threonine kinase ULK3 as a positive regulator of Hedgehog pathway. Experimental Cell Research DOI: 10.1016/j.yexcr.2009.10.018.
32. Kasper M, Schnidar H, Neill GW, Hanneder M, Klingler S, et al. (2006) Selective Modulation of Hedgehog/GLI Target Gene Expression by Epidermal Growth Factor Signaling in Human Keratinocytes. Mol Cell Biol 26(16): 6283-6298 DOI:10.1128/MCB.02317-05.
33. Ji Z, Mei FC, Xie J, Cheng X, (2007) Oncogenic KRAS Activates Hedgehog Signaling Pathway in Pancreatic Cancer Cells. The Journal of Biological Chemistry 282: 14048-14055.
34. Villavicencio EH, Yoon JW, Frank DJ, Füchtbauer EM, Walterhouse DO, et al. (2002) Cooperative E-box regulation of human GLI1 by TWIST and USF. Genesis 32(4): 247-258 DOI:10.1002/gene.10078.
35. Kaesler S, Lüscher B, Rüther U, (2005) Transcriptional Activity of GLI1 is Negatively Regulated by Protein Kinase A. Biological Chemistry. 381(7): 545-551 DOI:10.1515/BC.2000.070.
36. Katoh Y, Katoh M, (2005) Hedgehog Signaling Pathway and Gastric Cancer. Cancer Biology & Therapy 4(10): 1050-1054.
37. Altaba AR, Palma V, Dahmane N (2002) Hedgehog-Gli Signalling and the Growth of the Brain. Nature DOI: 10.1038/nrn704.
38. Mao J, Maye P, Kogerman P, Tejedor FJ, Toftgard R (2002) Regulation of Gli1 Transcriptional Activity in the Nucleus by Dyrk1. The Journal of Biological Chemistry 277 (38): 35156-35161; DOI 10.1074/jbc.M206743200.
39. Marcotullio LD, Ferretti E, Greco A, Smaele ED, Po A, et al. (2006) Numb is a suppressor of Hedgehog signaling and targets Gli1 for Itch-dependent ubiquitination. Nature Cell Biology 8: 1415-1423 DOI:10.1038/ncb1510.
40. Dai P, Shinagawa T, Nomura T, Harada J, Kaul SC, et al. (2002) Ski is involved in transcriptional regulation by the repressor and full-length forms of Gli3. Genes & Dev. 16: 2843-2848 DOI:10.1101/gad.1017302.
41. Berman DM, Karhadkar SS, Hallahan AR, Pritchard JI, Eberhart CG, et al. (2002) Medulloblastoma Growth Inhibition by Hedgehog Pathway Blockade. Science 297 (5586): 1559-1561.
42. Kawahira H, Ma NH, Tzanakakis ES, McMahon AP, Chuang PT, et al. (2003) Combined activities of hedgehog signaling inhibitors regulate pancreas development. Development 130: 4871-4879 DOI:10.1242/dev.00653.
43. Chuang PT, Kawcak TN, McMahon AP, (2003) Feedback Control of mammalian Hedgehog signaling by the Hedgehog-binding protein, Hip1, modulates Fgf signaling during branching morphogenesis of the lung. Genes & Dev. 17: 342-347 DOI:10.1101/gad.1026303.
44. Wagner A, Fell DA, (2001) The small world inside large metabolic networks. Proc Biol Sci. 268(1478): 1803-1810 DOI:10.1098/rspb.2001.1711.
45. Kasper M, Regl G, Frischauf AM, Aberger F, (2006) GLI transcription factors: Mediators of oncogenic Hedgehog signaling. European Journal of Cancer 42(4): 437-445.
46. Costenbader E, Valente TW, (2003) The stability of centrality measures when networks are sampled. Social Networks 25: 283-307.
47. Özgür A, Vu T, Erkan G, Radev DR, (2008) Identifying gene-disease associations using centrality on a literature mined gene-interaction network. Bioinformatics 24: i277-i285 DOI:10.1093/bioinformatics/btn182.
48. Wuchty S, Ravasz E, Barabási AL, (2006) The Architecture of Biological Networks: Complex Systems Science In Biomedicine. Topics in Biomedical Engineering. International Book Series, Part II: 165-181 DOI:10.1007/978-0-387-33532-2-5.
49. Klamt S, Rodriguez JS, Lindquist JA, Simeoni L, Gilles ED (2006) A methodology for the structural and functional analysis of signaling and regulatory networks. BMC Bioinformatics DOI: 10.1186/1471-2105-7-56.
50. Klamt S, Rodriguez JS, Gilles ED (2007) Structural and functional analysis of cellular networks with CellNetAnalyzer. BMC Systems Biology DOI: 10.1186/1752-0509-1-2.
51. Klamt S, Kamp A (2011) An application programming interface for CellNetAnalyzer. BioSystems, DOI: 10.1016/j.biosystems.2011.02.002.
52. Clement V, Sanchez P, Tribolet N, Radovanovic I, Altaba AR (2007) Hedgehog-Gli1 Signaling Regulates Human Glioma Growth, Cancer Stem Cell Self Renewal, and Tumorigenicity. Current Biology 17: 165-172; DOI 10.1016/j.cub.2006.11.033.
53. Bar EE, Chaudhry A, Lin A, Fan X, Schreck K, et al. (2007) Cyclopamine-Mediated Hedgehog Pathway Inhibition Depletes Stem-Like Cancer Cells in Glioblastoma. Stem Cells 25(10): 2524-2533 DOI:10.1634/stemcells.2007-0166.
54. Hsieh A, Ellsworth R, Hsieh D, (2011) Hedgehog/GLI1 regulates IGF dependent malignant behaviors in glioma stem cells. Journal of Cellular Physiology 226(4): 1118-1127 DOI:10.1002/jcp.22433.
55. Elias MC, Tozer KR, Silber JR, Mikheeva S, Deng M, et al. (2005) TWIST is Expressed in Human Gliomas and Promotes Invasion. Neoplasia 7(9): 824-837.
56. Ding H, Roncari L, Shannon P, Wu X, Lau N, et al. (2001) Astrocyte-specific Expression of Activated p21-ras Results in Malignant Astrocytoma Formation in a Transgenic Mouse Model of Human Gliomas. Cancer Res 61: 3826-3836.
57. Lo HW, Zhu H, Cao X, Aldrich A, Osman FA, (2009) A Novel Splice Variant of GLI1 That Promotes Glioblastoma Cell Migration and Invasion. Cancer Res 69: 6790 DOI:10.1158/0008-5472.CAN-09-0886.
58. Liu M, Dai B, Kang SH, Ban K, Huang FJ, et al. (2006) FoxM1B Is Overexpressed in Human Glioblastomas and Critically Regulates the Tumorigenicity of Glioma Cells. Cancer Res. 66: 3593-3602.
59. Joensuu H, Puputti M, Sihto H, Tynninen O, Nupponen NN (2005) Amplification of genes encoding KIT, PDGFRα and VEGFR2 receptor tyrosine kinases is frequent in glioblastoma multiforme. The Journal of Pathology DOI: 10.1002/path.1823.
60. Saitoh Y, Kuratsu J, Takeshima H, Yamamoto S, Ushio Y, (1995) Expression of osteopontin in human glioma. Its correlation with the malignancy. Lab Invest 72(1): 55-63.
61. Büschges R, Weber RG, Actor B, Lichter P, Collins VP, et al. (1999) Amplification and expression of cyclin D genes (CCND1, CCND2 and CCND3) in human malignant gliomas. Brain Pathology 9(3): 435-42.
62. Zhang X, Zha M, Huang A, Fei Z, Zhang W, et al. (2005) The effect of cyclinD expression on cell proliferation in human gliomas. Journal of Clinical Neuroscience 12(2): 166-168.
63. Chakravarti A, Delaney MA, Noll E, Black PM, Loeffler JS, et al. (2001) Prognostic and Pathologic Significance of Quantitative Protein Expression Profiling in Human Gliomas. Clin Cancer Res 7: 2387-2395.
64. Godlewski J, Nowicki MO, Bronisz A, Williams S, Otsuki A, et al. (2008) Targeting of the Bmi-1 Oncogene/Stem Cell Renewal Factor by MicroRNA-128 Inhibits Glioma Proliferation and Self-Renewal. Cancer Res DOI: 10.1158/0008-5472.CAN-08-2629.
65. Han SP, Kim JH, Han ME, Sim HE, Kim KS (2011) SNAI1 is Involved in the Proliferation and Migration of Glioblastoma Cells. Cell. Mol. Neurobiol. 31: 489-496. DOI 10.1007/s10571-010-9643-4.
66. Reichratha S, Müllerb CSL, Gleissnera B, Pfreundschuha M, Vogt T, (2010) Notch- and vitamin D signaling in 1,25(OH)2D3-resistant glioblastoma multiforme (GBM) cell lines. The Journal of Steroid Biochemistry and Molecular Biology 121(1-2): 420-424.
67. Roth W, Wild-Bode C, Platten M, Grimmel C, Melkonyan HS, (2000) Secreted Frizzled-related proteins inhibit motility and promote growth of human malignant glioma cells. Oncogene 19(37): 4210-20.
68. Rudin CM, Hann CL, Laterra J, Yauch RL, Callahan CA, et al. (2009) Treatment of Medulloblastoma with Hedgehog Pathway Inhibitor GDC-0449. The New England journal o f Medicine 361: 1173-8.
69. Qualtrough D, Buda A, Gaffield W, Williams AC, Paraskeva C, (2004) Hedgehog signaling in colorectal tumour cells: Induction of apoptosis with cyclopamine treatment. International Journal of Cancer 110(6): 831-837.
70. Mazumdar T, Vecchio JD, Agyeman A, Shi T, Houghton JA, (2011) The GLI genes as the molecular switch in disrupting Hedgehog signaling in colon cancer. Oncotarget 2: 638-645.
71. Douard R, Moutereau S, Pernet P, Chimingqi M, Allory Y, et al. (2006) Sonic Hedgehog-dependent proliferation in a series of patients with colorectal cancer. Surgery 139(5): 665-670.
72. Varnat F, Duquet A, Malerba M, Zbinden M, Mas C, et al. (2009) Human colon cancer epithelial cells harbour active HEDGEHOG-GLI signaling that is essential for tumour growth, recurrence, metastasis and stem cell survival and expansion. EMBO Molecular Medicine DOI 10.1002/emmm.200900039.
73. Fan L, Pepicelli CV, Dibble CC, Catbagan W, Zarycki JL, (2004) Hedgehog Signaling Promotes Prostate Xenograft Tumor Growth. Endocrinology 145(8): 3961-3970 DOI:10.1210/en.2004-0079.
74. Shimoyama A, Wada M, Ikeda F, Hata K, Matsubara T, et al. (2007) Ihh/Gli2 Signaling Promotes Osteoblast Differentiation by Regulating Runx2 Expression and Function. Molecular Biology of the Cell 18: 2411-2418.
75. Tanaka M, Omura K, Watanabe Y, Oda Y, Nakanishi I, (1994) Prognostic factors of colorectal cancer: K-ras mutation, overexpression of the p53 protein, and cell proliferative activity. Journal of Surgical Oncology 57 (1): 57-64.
76. Østerlund T, Kogerman P, (2006) Hedgehog signaling: how to get from Smo to Ci and Gli. Trends in Cell Biology 16(4): 176-180 DOI:10.1016/j.tcb.2006.02.004.
77. Maloverjan A, Piirsoo M, Michelson P, Kogerman P, Østerlund T, (2009) Identification of a novel serine/threonine kinase ULK3 as a positive regulator of Hedgehog pathway. Exp Cell Res 316(4) 627-637DOI.org/10.1016/j.yexcr.2009.10.018.
78. Hany K, Kleeff J, Keleg S, Guo J, Ketterer K, et al. (2004) Indian hedgehog signaling pathway: Expression and regulation in pancreatic cancer. Int. J. Cancer 110(5): 668-676 DOI:10.1002/ijc.20194.
79. Gysin S, Lee SH, Dean NM, McMahon M, (2005) Pharmacologic Inhibition of RAF→MEK→ERK Signaling Elicits Pancreatic Cancer Cell Cycle Arrest Through Induced Expression of p27Kip1. Cancer Res. 65: 4870 DOI:10.1158/0008-5472.CAN-04-2848.
80. Thayer SP, Magliano MP, Heiser PW, Nielsen CM, Roberts DJ, et al. (2003) Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 425: 851-856 DOI:10.1038/nature02009.
81. Katoh M (2007) Networking of WNT, FGF, Notch, BMP, and Hedgehog Signaling Pathways during Carcinogenesis. Stem Cell Rev. 3: 30-38; DOI 10.1007/s12015-007-0006-6.
82. Altaba AR, Sánchez P, Dahmane N, (2002) Gli and Hedgehog in Cancer: Tumours, Embryos and Stem cells. Nature Reviews 2: 361-372 DOI:10.1038/nrc796.
83. Trent J, Meltzer P, Rosenblum M, Harsh G, Kinzler K, et al. (1986) Evidence for rearrangement, amplification, and expression of c-myc in a human glioblastoma. Proc. Natl. Acad. Sci. USA 83: 470-473.
84. Regl G, Kasper M, Schnidar H, Eichberger T, Neill GW, (2004) Activation of the BCL2 Promoter in Response to Hedgehog/GLI Signal Transduction is Predominantly Mediated by GLI2. Cancer Res. 64: 7724 DOI:10.1158/0008-5472.CAN-04-1085.
85. Feldmann G, Dhara S, Fendrich V, Bedja D, Beaty R, (2007) Blockade of Hedgehog Signaling Inhibits Pancreatic Cancer Invasion and Metastases: A New Paradigm for Combination Therapy in Solid Cancers. Cancer Research 67: 2187-2196 DOI:10.1158/0008-5472.CAN-06-3281.
86. Lindstrom E, Shimokawa T, Toftgard R, Zaphiropoulos PG, (2006) PTCH Mutations: Distribution and Analyses. Human Mutation 27(3): 215-219.
87. Tenzen T, Allen BL, Cole F, Kang JS, Krauss RS (2006) The Cell Surface Membrane Proteins Cdo and Boc Are Components and Targets of the Hedgehog Signaling Pathway and Feedback Network in Mice. Developmental Cell 10: 647-656; DOI 10.1016/j.devcel.2006.04.004.
88. Tai CJ, Chang CC, Jiang MC, Yeh CM, Su TC, et al. (2012) Clinical-Pathological Correlation Of K-Ras Mutation and Erk Phosphorylation In Colorectal Cancer. Pol J Pathol 2: 93-100.
89. Julian Downward, (2003) Targeting ras signaling pathways in cancer therapy. Nature Reviews Cancer 3: 11-23.
90. Kloog Y, Cox AD, (2000) RAS inhibitors: potential for cancer therapeutics. Molecular Medicine Today 6: 398-402.
91. Bos JL, (1989) ras Oncogenes in Human Cancer: A Review. Cancer Res 49: 4682.
92. Jensen JB, Gutin G (2002) Digraphs: Theory, Algorithms and Applications. ISBN/ASIN: 1852332689, Springer, 2-4.
93. Batagelj V, Mrvar A (2003) Pajek - Analysis and Visualization of Large Networks. In J̈unger, M., Mutzel, P. (Eds.): Graph Drawing Software. Springer (series Mathematics and Visualization), Berlin. 77-103. ISBN 3-540-00881-0. Springer, Amazon, preprint.
94. Bastian M, Heymann S, Jacomy M (2009) Gephi: an open source software for exploring and manipulating networks. International AAAI Conference on Weblogs and Social Media.
95. Csardi G, Nepusz T (2006) The igraph software package for complex network research, InterJournal, Complex Systems 1695. Available at: http://igraph.sf.net.
96. Hornik K (2012) The R FAQ. ISBN 3-900051-08-9. Available: http://CRAN.R-project.org/doc/FAQ/R-FAQ.html via the Internet. Accessed 12 Nov 2012.
97. Newman MEJ, (2004) Analysis of weighted networks. Physical Review E 70: 056131 DOI:10.1103/PhysRevE.70.056131.
98. Parkinson H, Sarkans U, Kolesnikov N, Abeygunawardena N, Burdett T, et al. (2010) ArrayExpress update-an archive of microarray and high-throughput sequencing-based functional genomics experiments. Nucl Acid Res DOI: 10.1093/nar/gkq1040.
99. Sun L, Hui AM, Su Q, Vortmeyer A, Kotliarov Y, et al. (2006) Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell 9: 287-300; DOI 10.1016/j.ccr.2006.03.003.
100. Pei H, Li L, Fridley BL, Jenkins GD, Kalari KR, et al. (2009) FKBP51 Affects Cancer Cell Response to Chemotherapy by Negatively Regulating Akt. Cancer Cell 16: 259-266; DOI 10.1016/j.ccr.2009.07.016.
101. Bian YH, Huang SH, Yang L, Ma XL, Xie JW, et al. (2007) Sonic hedgehog-Gli1 pathway in colorectal adenocarcinomas. World J Gastroenterol 13(11): 1659-166.