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01-06-2011 | Research

Identification of Signature Genes for Detecting Hedgehog Pathway Activation in Esophageal Cancer

Authors: Ling Yang, Yuehong Bian, Shuhong Huang, Xiaoli Ma, Chi Zhang, Xiulan Su, Zi-Jiang Chen, Jingwu Xie, Hongwei Zhang

Published in: Pathology & Oncology Research | Issue 2/2011

Abstract

The hedgehog signaling pathway plays an important role in cell growth and differentiation both in normal embryonic development and in tumors. Our previous work shows that hedgehog pathway is frequently activated in esophageal cancers. To further elucidate the role of hedgehog pathway in esophageal cancers we examined the expression of the target genes, hedgehog-interacting protein (HIP) and platelet derived growth factor receptor alpha (PDGFRα) and hedgehog signaling molecules, smoothened (SMO), suppressor of fused (Su(Fu)) in the specimens using in-situ hybridization and RT-PCR. We found that HIP, PDGFRα, SMO and Su(Fu) gene highly expressed in the primary esophageal squamous cell carcinomas but not in normal esophageal tissue. The transcripts of HIP, PDGFRα and SMO were expressed in 13 of 15 esophageal cancers. Su(Fu) expression was missing in 2 esophageal cancers. The results from in-situ hybridization were further confirmed by RT-PCR. Our results revealed a set of genes for detecting hedgehog signaling activation in esophageal cancer.

Xie J, Murone M, Luoh SM, Ryan A, Gu Q, Zhang C, Bonifas JM, Lam CW, Hynes M, Goddard A, Rosenthal A, Epstein EH Jr, de Sauvage FJ (1998) Activating Smoothened mutations in sporadic basal-cell carcinoma. Nature 391:90–2PubMedCrossRef

Lam CW, Xie J, To KF, Ng HK, Lee KC, Yuen NW, Lim PL, Chan LY, Tong SF, McCormick F (1999) A frequent activated smoothened mutation in sporadic basal cell carcinomas. Oncogene 18:833–6PubMedCrossRef

Kallassy M, Toftgard R, Ueda M, Nakazawa K, Vorechovsky I, Yamasaki H, Nakazawa H (1997) Patched (ptch)-associated preferential expression of smoothened (smoh) in human basal cell carcinoma of the skin. Cancer Res 57:4731–5PubMed

Oniscu A, James RM, Morris RG, Bader S, Malcomson RD, Harrison DJ (2004) Expression of Sonic hedgehog pathway genes is altered in colonic neoplasia. J Pathol 203:909–17PubMedCrossRef

Shao J, Zhang L, Gao J, Li Z, Chen Z (2006) Aberrant expression of PTCH (patched gene) and Smo (smoothened gene) in human pancreatic cancerous tissues and its association with hyperglycemia. Pancreas 33:38–44PubMedCrossRef

Martin ST, Sato N, Dhara S, Chang R, Hustinx SR, Abe T, Maitra A, Goggins M (2005) Aberrant methylation of the Human Hedgehog interacting protein (HHIP) gene in pancreatic neoplasms. Cancer Biol Ther 4:728–33PubMedCrossRef

Taniguchi H, Yamamoto H, Akutsu N, Nosho K, Adachi Y, Imai K, Shinomura Y (2007) Transcriptional silencing of hedgehog-interacting protein by CpG hypermethylation and chromatic structure in human gastrointestinal cancer. J Pathol 213:131–9PubMedCrossRef

Tada M, Kanai F, Tanaka Y, Tateishi K, Ohta M, Asaoka Y, Seto M, Muroyama R, Fukai K, Imazeki F, Kawabe T, Yokosuka O, Omata M (2008) Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma. Clin Cancer Res 14:3768–76PubMedCrossRef

Svard J, Heby-Henricson K, Persson-Lek M, Rozell B, Lauth M, Bergstrom A, Ericson J, Toftgard R, Teglund S (2006) Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. Dev Cell 10:187–97PubMedCrossRef

10.

Svard J, Rozell B, Toftgard R, Teglund S (2009) Tumor suppressor gene co-operativity in compound Patched1 and suppressor of fused heterozygous mutant mice. Mol Carcinog 48:408–19PubMedCrossRef

11.

Sheng T, Li C, Zhang X, Chi S, He N, Chen K, McCormick F, Gatalica Z, Xie J (2004) Activation of the hedgehog pathway in advanced prostate cancer. Mol Cancer 3:29PubMedCrossRef

12.

Chi S, Huang S, Li C, Zhang X, He N, Bhutani MS, Jones D, Castro CY, Logrono R, Haque A, Zwischenberger J, Tyring SK, Zhang H, Xie J (2006) Activation of the hedgehog pathway in a subset of lung cancers. Cancer Lett 244:53–60PubMedCrossRef

13.

Reifenberger J, Wolter M, Knobbe CB, Kohler B, Schonicke A, Scharwachter C, Kumar K, Blaschke B, Ruzicka T, Reifenberger G (2005) Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas. Br J Dermatol 152:43–51PubMedCrossRef

14.

Taylor MD, Liu L, Raffel C, Hui CC, Mainprize TG, Zhang X, Agatep R, Chiappa S, Gao L, Lowrance A, Hao A, Goldstein AM, Stavrou T, Scherer SW, Dura WT, Wainwright B, Squire JA, Rutka JT, Hogg D (2002) Mutations in SUFU predispose to medulloblastoma. Nat Genet 31:306–10PubMedCrossRef

15.

Rikova K, Guo A, Zeng Q, Possemato A, Yu J, Haack H, Nardone J, Lee K, Reeves C, Li Y, Hu Y, Tan Z, Stokes M, Sullivan L, Mitchell J, Wetzel R, Macneill J, Ren JM, Yuan J, Bakalarski CE, Villen J, Kornhauser JM, Smith B, Li D, Zhou X, Gygi SP, Gu TL, Polakiewicz RD, Rush J, Comb MJ (2007) Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer. Cell 131:1190–203PubMedCrossRef

16.

Taja-Chayeb L, Chavez-Blanco A, Martinez-Tlahuel J, Gonzalez-Fierro A, Candelaria M, Chanona-Vilchis J, Robles E, Duenas-Gonzalez A (2006) Expression of platelet derived growth factor family members and the potential role of imatinib mesylate for cervical cancer. Cancer Cell Int 6:22PubMedCrossRef

17.

Zhang T, Sun HC, Xu Y, Zhang KZ, Wang L, Qin LX, Wu WZ, Liu YK, Ye SL, Tang ZY (2005) Overexpression of platelet-derived growth factor receptor alpha in endothelial cells of hepatocellular carcinoma associated with high metastatic potential. Clin Cancer Res 11:8557–63PubMedCrossRef

18.

Matei D, Emerson RE, Lai YC, Baldridge LA, Rao J, Yiannoutsos C, Donner DD (2006) Autocrine activation of PDGFRalpha promotes the progression of ovarian cancer. Oncogene 25:2060–9PubMedCrossRef

19.

Jechlinger M, Sommer A, Moriggl R, Seither P, Kraut N, Capodiecci P, Donovan M, Cordon-Cardo C, Beug H, Grunert S (2006) Autocrine PDGFR signaling promotes mammary cancer metastasis. J Clin Invest 116:1561–70PubMedCrossRef

20.

Lev DC, Kim SJ, Onn A, Stone V, Nam DH, Yazici S, Fidler IJ, Price JE (2005) Inhibition of platelet-derived growth factor receptor signaling restricts the growth of human breast cancer in the bone of nude mice. Clin Cancer Res 11:306–14PubMed

21.

Russell MR, Jamieson WL, Dolloff NG, Fatatis A (2009) The alpha-receptor for platelet-derived growth factor as a target for antibody-mediated inhibition of skeletal metastases from prostate cancer cells. Oncogene 28:412–21PubMedCrossRef

22.

Wehler TC, Frerichs K, Graf C, Drescher D, Schimanski K, Biesterfeld S, Berger MR, Kanzler S, Junginger T, Galle PR, Moehler M, Gockel I, Schimanski CC (2008) PDGFRalpha/beta expression correlates with the metastatic behavior of human colorectal cancer: a possible rationale for a molecular targeting strategy. Oncol Rep 19:697–704PubMed

23.

Ma X, Sheng T, Zhang Y, Zhang X, He J, Huang S, Chen K, Sultz J, Adegboyega PA, Zhang H, Xie J (2006) Hedgehog signaling is activated in subsets of esophageal cancers. Int J Cancer 118:139–48PubMedCrossRef

24.

Sarbia M, Becker KF, Hofler H (2004) Pathology of upper gastrointestinal malignancies. Semin Oncol 31:465–75PubMedCrossRef

25.

Bonifas JM, Pennypacker S, Chuang PT, McMahon AP, Williams M, Rosenthal A, De Sauvage FJ, Epstein EH Jr (2001) Activation of expression of hedgehog target genes in basal cell carcinomas. J Invest Dermatol 116:739–42PubMedCrossRef

26.

Xie J, Aszterbaum M, Zhang X, Bonifas JM, Zachary C, Epstein E, McCormick F (2001) A role of PDGFRalpha in basal cell carcinoma proliferation. Proc Natl Acad Sci USA 98:9255–9PubMedCrossRef

27.

Heinrich MC, Corless CL, Demetri GD, Blanke CD, von Mehren M, Joensuu H, McGreevey LS, Chen CJ, Van den Abbeele AD, Druker BJ, Kiese B, Eisenberg B, Roberts PJ, Singer S, Fletcher CD, Silberman S, Dimitrijevic S, Fletcher JA (2003) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342–9PubMedCrossRef

28.

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 73:397–405PubMedCrossRef

29.

Karhadkar SS, Bova GS, Abdallah N, Dhara S, Gardner D, Maitra A, Isaacs JT, Berman DM, Beachy PA (2004) Hedgehog signalling in prostate regeneration, neoplasia and metastasis. Nature 431:707–12PubMedCrossRef

30.

Yang L, Huang SH, Bian YH, Ma XL, Zhang HW, Xie JW (2010) Indentification of signature genes for detecting hedgehog signaling activation in gastric cancer. Mol Med Rep 3:473–478

Title: Identification of Signature Genes for Detecting Hedgehog Pathway Activation in Esophageal Cancer
Authors: Ling Yang
Yuehong Bian
Shuhong Huang
Xiaoli Ma
Chi Zhang
Xiulan Su
Zi-Jiang Chen
Jingwu Xie
Hongwei Zhang
Publication date: 01-06-2011
Publisher: Springer Netherlands
Published in: Pathology & Oncology Research / Issue 2/2011
Print ISSN: 1219-4956
Electronic ISSN: 1532-2807
DOI: https://doi.org/10.1007/s12253-010-9337-8

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