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Erschienen in: Pathology & Oncology Research 2/2011

01.06.2011 | Research

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

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

Erschienen in: Pathology & Oncology Research | Ausgabe 2/2011

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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.
Literatur
1.
Zurück zum Zitat 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 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
2.
Zurück zum Zitat 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 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
3.
Zurück zum Zitat 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 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
4.
Zurück zum Zitat 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 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
5.
Zurück zum Zitat 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 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
6.
Zurück zum Zitat 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 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
7.
Zurück zum Zitat 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 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
8.
Zurück zum Zitat 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 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
9.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat Sarbia M, Becker KF, Hofler H (2004) Pathology of upper gastrointestinal malignancies. Semin Oncol 31:465–75PubMedCrossRef Sarbia M, Becker KF, Hofler H (2004) Pathology of upper gastrointestinal malignancies. Semin Oncol 31:465–75PubMedCrossRef
25.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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.
Zurück zum Zitat 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 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
Metadaten
Titel
Identification of Signature Genes for Detecting Hedgehog Pathway Activation in Esophageal Cancer
verfasst von
Ling Yang
Yuehong Bian
Shuhong Huang
Xiaoli Ma
Chi Zhang
Xiulan Su
Zi-Jiang Chen
Jingwu Xie
Hongwei Zhang
Publikationsdatum
01.06.2011
Verlag
Springer Netherlands
Erschienen in
Pathology & Oncology Research / Ausgabe 2/2011
Print ISSN: 1219-4956
Elektronische ISSN: 1532-2807
DOI
https://doi.org/10.1007/s12253-010-9337-8

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