Regulation of the hedgehog signaling by the mitogen‐activated protein kinase cascade in gastric cancer

The hedgehog and mitogen‐activated protein kinase (MAPK) signaling pathways regulate growth in many tumors, suggesting cooperation between these two pathways in the regulation of cell proliferation. However, interactions between these pathways have not been extensively studied. We assessed cross‐talk between hedgehog and MAPK signaling in the regulation of cell proliferation in gastric cancer. We showed that PTCH expression was significantly correlated with extracellular signal‐regulated kinase (ERK) 1/2 phosphorylation (P = 0.016) as well as SHH expression (P = 0.034) in the 35 gastric cancers assessed by immunohistochemistry. Indeed, MAPK signaling increased the GLI transcriptional activity and induced the expression of hedgehog target genes in gastric cancer cells. The inductive effect of activated KRAS and mitogen‐activated protein/extracellular signal‐regulated kinase kinase (MEK) 1 was blocked by the suppressor of fused (SUFU), indicating that MAPK signaling regulates GLI activity via a SUFU‐independent process. Moreover, the deletion of the NH2‐terminal domain of GLI1 gene resulted in reduced response to MEK1 stimulation. Our results suggest that the KRAS‐MEK‐ERK cascade has a positive regulatory role in GLI transcriptional activity in gastric cancer. © 2009 Wiley‐Liss, Inc.

[1]  M. Nakafuku,et al.  A binding site for Gli proteins is essential for HNF-3beta floor plate enhancer activity in transgenics and can respond to Shh in vitro. , 1997, Development.

[2]  Q. Gu,et al.  Activating Smoothened mutations in sporadic basal-cell carcinoma , 1998, Nature.

[3]  M. Yaffe,et al.  TAZ: a novel transcriptional co‐activator regulated by interactions with 14‐3‐3 and PDZ domain proteins , 2000, The EMBO journal.

[4]  C. Emerson,et al.  Protein kinase C-delta and mitogen-activated protein/extracellular signal-regulated kinase-1 control GLI activation in hedgehog signaling. , 2006, Cancer research.

[5]  F Kanai,et al.  Absence of PIK3CA hotspot mutations in hepatocellular carcinoma in Japanese patients , 2006, Oncogene.

[6]  P. Jackson,et al.  Dual degradation signals control Gli protein stability and tumor formation. , 2006, Genes & development.

[7]  Atsushi Ochiai,et al.  Interaction between epidermal growth factor and its receptor in progression of human gastric carcinoma , 1988, International journal of cancer.

[8]  D. Krause,et al.  Mammalian Suppressor-of-Fused modulates nuclear–cytoplasmic shuttling of GLI-1 , 1999, Nature Cell Biology.

[9]  P. Kogerman,et al.  Characterization of the Physical Interaction of Gli Proteins with SUFU Proteins* , 2003, The Journal of Biological Chemistry.

[10]  Y. Yamaji,et al.  CagA protein secreted by the intact type IV secretion system leads to gastric epithelial inflammation in the Mongolian gerbil model , 2006, The Journal of pathology.

[11]  M. Lewis,et al.  Hedgehog Signaling in Mouse Mammary Gland Development and Neoplasia , 2004, Journal of Mammary Gland Biology and Neoplasia.

[12]  Michael Dean,et al.  Mutations of the Human Homolog of Drosophila patched in the Nevoid Basal Cell Carcinoma Syndrome , 1996, Cell.

[13]  K. Kinzler,et al.  Tumorigenesis: RAF/RAS oncogenes and mismatch-repair status , 2002, Nature.

[14]  Yutaka Shimada,et al.  Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours , 2003, Nature.

[15]  Bert Vogelstein,et al.  The GLI gene is a member of the Kruppel family of zinc finger proteins , 1988, Nature.

[16]  J. Sebolt-Leopold,et al.  Targeting the mitogen-activated protein kinase cascade to treat cancer , 2004, Nature Reviews Cancer.

[17]  M. Lauth,et al.  Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway. , 2006, Developmental cell.

[18]  D. Roberts,et al.  Sonic hedgehog expression correlates with fundic gland differentiation in the adult gastrointestinal tract , 2002, Gut.

[19]  Ximing J. Yang,et al.  Epidermal Growth Factor Receptor Protein Expression and Gene Amplification in Small Cell Carcinoma of the Urinary Bladder , 2007, Clinical Cancer Research.

[20]  Nicoletta Kessaris,et al.  Cooperation between sonic hedgehog and fibroblast growth factor/MAPK signalling pathways in neocortical precursors , 2004, Development.

[21]  H. Rubinfeld,et al.  Nuclear translocation of mitogen-activated protein kinase kinase (MEK1) in response to mitogenic stimulation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[22]  A. Maitra,et al.  Urological Survey UROLOGICAL ONCOLOGY: PROSTATE CANCER Hedgehog Signalling in Prostate Regeneration, Neoplasia and Metastasis , 2005 .

[23]  S. O’Brien,et al.  The GLI-Kruppel family of human genes , 1988, Molecular and cellular biology.

[24]  C. James,et al.  PTEN/MMAC1 mutations and EGFR amplification in glioblastomas. , 1997, Cancer research.

[25]  Jingwu Xie,et al.  Oncogenic KRAS Activates Hedgehog Signaling Pathway in Pancreatic Cancer Cells* , 2007, Journal of Biological Chemistry.

[26]  D. Shibata,et al.  Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes , 1988, Cell.

[27]  Gregory Y. Lauwers,et al.  Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis , 2003, Nature.

[28]  N. Altorki,et al.  Infrequent point mutations of ras oncogenes in gastric cancers. , 1990, Gastroenterology.

[29]  T. Kawabe,et al.  p53-Independent negative regulation of p21/cyclin-dependent kinase-interacting protein 1 by the sonic hedgehog-glioma-associated oncogene 1 pathway in gastric carcinoma cells. , 2005, Cancer research.

[30]  J. Taipale,et al.  Patched acts catalytically to suppress the activity of Smoothened , 2002, Nature.

[31]  T. Kawabe,et al.  Functional analysis of mutations within the kinase activation segment of B-Raf in human colorectal tumors. , 2003, Cancer research.

[32]  Maria Kasper,et al.  Selective Modulation of Hedgehog/GLI Target Gene Expression by Epidermal Growth Factor Signaling in Human Keratinocytes , 2006, Molecular and Cellular Biology.

[33]  Stephen B. Baylin,et al.  Hedgehog signalling within airway epithelial progenitors and in small-cell lung cancer , 2003, Nature.

[34]  Marina Pasca di Magliano,et al.  Hedgehog signalling in cancer formation and maintenance , 2003, Nature Reviews Cancer.

[35]  M. Hebrok,et al.  Hedgehog/Ras interactions regulate early stages of pancreatic cancer. , 2006, Genes & development.

[36]  T. McDonnell,et al.  Sonic hedgehog induces epidermal growth factor dependent matrix infiltration in HaCaT keratinocytes. , 2005, The Journal of investigative dermatology.

[37]  David Hogg,et al.  Mutations in SUFU predispose to medulloblastoma , 2002, Nature Genetics.

[38]  D. Melton,et al.  Hedgehog signals regulate multiple aspects of gastrointestinal development. , 2000, Development.

[39]  A. Gurney,et al.  Gli regulation by the opposing activities of Fused and Suppressor of Fused , 2000, Nature Cell Biology.

[40]  Shan Wang,et al.  Increased expression of mitogen-activated protein kinase and its upstream regulating signal in human gastric cancer. , 2005, World journal of gastroenterology.

[41]  Masatoshi Nomura,et al.  Hedgehog Signaling Pathway is a New Therapeutic Target for Patients with Breast Cancer , 2004, Cancer Research.

[42]  Barbara Stecca,et al.  Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways , 2007, Proceedings of the National Academy of Sciences.