期刊论文详细信息
BMC Cancer
Activation of pro-oncogenic pathways in colorectal hyperplastic polyps
Catherine Do1  Claudine Bertrand1  Julien Palasse1  Marie-Bernadette Delisle2  Elizabeth Cohen-Jonathan-Moyal3  Catherine Seva1 
[1] INSERM UMR.1037-Cancer Research Center of Toulouse (CRCT), Université Paul Sabatier, 31052 Toulouse cedex III, Toulouse, France
[2] Service d’Anatomie Pathologique et Histologie Cytologie, CHU Rangueil and Faculté de Médecine Rangueil, Toulouse, France
[3] Institut Claudius Regaud, Toulouse, France
关键词: Pro-oncogenic pathways;    STAT3;    ERK;    Progastrin;    Colorectal;    Hyperplastic polyps;   
Others  :  1079462
DOI  :  10.1186/1471-2407-13-531
 received in 2013-05-16, accepted in 2013-11-05,  发布年份 2013
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【 摘 要 】

Background

In contrast to sessile serrated adenomas and traditional serrated adenomas which are associated with a significant cancer risk, the role of hyperplastic polyps (HP) in colorectal carcinogenesis as well as the molecular mechanisms underlying their development remain controversial and still need to be clarified. Several reports suggest that a subset of HP may represent precursor lesions of some colorectal cancers. However, biomarkers are needed to identify the subset of HP that may have a malignant potential. The hormone precursor, progastrin (PG) has been involved in colon carcinogenesis and is known to activate pro-oncogenic pathways such as the ERK or the STAT3 pathway. We therefore analyzed PG expression and the activation of these signaling factors in HP.

Methods

We retrospectively analyzed PG expression as well as the phosphorylation of ERK and STAT3 by immunohistochemistry in HP from 48 patients.

Results

Mean percentages of epithelial cells positive for PG or phospho-ERK were respectively, 31% and 33% in HP and were significantly higher in these lesions compared to normal colon (3%, p = 0.0021 and 7%, p = 0.0008, respectively). We found a significant correlation between PG and phospho-ERK expression in HP with ERK activation significantly stronger in lesions with high progastrin expression (p = 0.015). In contrast, STAT3 was not significantly activated in HP compared to normal colon and we did not observe a significant correlation with PG expression.

Conclusions

HP overexpressing PG that have the highest activation of the ERK pathway might reflect less latent lesions that might have a malignant potential.

【 授权许可】

   
2013 Do et al.; licensee BioMed Central Ltd.

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【 参考文献 】
  • [1]Longacre TA, Fenoglio-Preiser CM: Mixed hyperplastic adenomatous polyps/serrated adenomas. A distinct form of colorectal neoplasia. Am J Surg Pathol 1990, 14(6):524-537.
  • [2]Noffsinger AE, Hart J: Serrated adenoma: a distinct form of non-polypoid colorectal neoplasia? Gastrointest Endosc Clin N Am 2010, 20(3):543-563.
  • [3]Gurzu S, Jung I: Aberrant pattern of the cytokeratin 7/cytokeratin 20 immunophenotype in colorectal adenocarcinomas with BRAF mutations. Pathol Res Pract 2012, 208(3):163-166.
  • [4]Gurzu S, Szentirmay Z, Toth E, Bara T, Bara T Jr, Jung I: Serrated pathway adenocarcinomas: molecular and immunohistochemical insights into their recognition. PLoS One 2013, 8(3):e57699.
  • [5]Noffsinger AE: Serrated polyps and colorectal cancer: new pathway to malignancy. Annu Rev Pathol 2009, 4:343-364.
  • [6]Huang CS, O'Brien MJ, Yang S, Farraye FA: Hyperplastic polyps, serrated adenomas, and the serrated polyp neoplasia pathway. Am J Gastroenterol 2004, 99(11):2242-2255.
  • [7]Jeevaratnam P, Cottier DS, Browett PJ, Van De Water NS, Pokos V, Jass JR: Familial giant hyperplastic polyposis predisposing to colorectal cancer: a new hereditary bowel cancer syndrome. J Pathol 1996, 179(1):20-25.
  • [8]Renaut AJ, Douglas PR, Newstead GL: Hyperplastic polyposis of the colon and rectum. Colorectal Dis 2002, 4(3):213-215.
  • [9]Torlakovic E, Snover DC: Serrated adenomatous polyposis in humans. Gastroenterology 1996, 110(3):748-755.
  • [10]Warner AS, Glick ME, Fogt F: Multiple large hyperplastic polyps of the colon coincident with adenocarcinoma. Am J Gastroenterol 1994, 89(1):123-125.
  • [11]Huang EH, Whelan RL, Gleason NR, Maeda JS, Terry MB, Lee SW, Neugut AI, Forde KA: Increased incidence of colorectal adenomas in follow-up evaluation of patients with newly diagnosed hyperplastic polyps. Surg Endosc 2001, 15(7):646-648.
  • [12]Do C, Bertrand C, Palasse J, Delisle MB, Shulkes A, Cohen-Jonathan-Moyal E, Ferrand A, Seva C: A new biomarker that predicts colonic neoplasia outcome in patients with hyperplastic colonic polyps. Cancer Prev Res (Phila) 2012, 5(4):675-684.
  • [13]Dockray GJ, Varro A, Dimaline R, Wang T: The gastrins: their production and biological activities. Annu Rev Physiol 2001, 63:119-139.
  • [14]Finley GG, Koski RA, Melhem MF, Pipas JM, Meisler AI: Expression of the gastrin gene in the normal human colon and colorectal adenocarcinoma. Cancer Res 1993, 53(12):2919-2926.
  • [15]Nemeth J, Taylor B, Pauwels S, Varro A, Dockray GJ: Identification of progastrin derived peptides in colorectal carcinoma extracts. Gut 1993, 34(1):90-95.
  • [16]Siddheshwar RK, Gray JC, Kelly SB: Plasma levels of progastrin but not amidated gastrin or glycine extended gastrin are elevated in patients with colorectal carcinoma. Gut 2001, 48(1):47-52.
  • [17]Van Solinge WW, Nielsen FC, Friis-Hansen L, Falkmer UG, Rehfeld JF: Expression but incomplete maturation of progastrin in colorectal carcinomas. Gastroenterology 1993, 104(4):1099-1107.
  • [18]Baldwin GS, Hollande F, Yang Z, Karelina Y, Paterson A, Strang R, Fourmy D, Neumann G, Shulkes A: Biologically active recombinant human progastrin(6–80) contains a tightly bound calcium ion. J Biol Chem 2001, 276(11):7791-7796.
  • [19]Brown D, Yallampalli U, Owlia A, Owlia P: pp60c-Src Kinase mediates growth effects of the full-length precursor progastrin1–80 peptide on rat intestinal epithelial cells, in vitro. Endocrinology 2003, 144(1):201-211.
  • [20]Ferrand A, Bertrand C, Portolan G, Cui G, Carlson J, Pradayrol L, Fourmy D, Dufresne M, Wang TC, Seva C: Signaling pathways associated with colonic mucosa hyperproliferation in mice overexpressing gastrin precursors. Cancer Res 2005, 65(7):2770-2777.
  • [21]Umar S, Sarkar S, Cowey S, Singh P: Activation of NF-kappaB is required for mediating proliferative and antiapoptotic effects of progastrin on proximal colonic crypts of mice, in vivo. Oncogene 2008, 27(42):5599-5611.
  • [22]Wang TC, Koh TJ, Varro A, Cahill RJ, Dangler CA, Fox JG, Dockray GJ: Processing and proliferative effects of human progastrin in transgenic mice. J Clin Invest 1996, 98(8):1918-1929.
  • [23]Pannequin J, Delaunay N, Buchert M, Surrel F, Bourgaux JF, Ryan J, Boireau S, Coelho J, Pelegrin A, Singh P, et al.: Beta-catenin/Tcf-4 inhibition after progastrin targeting reduces growth and drives differentiation of intestinal tumors. Gastroenterology 2007, 133(5):1554-1568.
  • [24]Singh P, Lu X, Cobb S, Miller BT, Tarasova N, Varro A, Owlia A: Progastrin1-80 stimulates growth of intestinal epithelial cells in vitro via high-affinity binding sites. Am J Physiol Gastrointest Liver Physiol 2003, 284(2):G328-G339.
  • [25]Umar S, Sarkar S, Wang Y, Singh P: Functional cross-talk between beta-catenin and NFkappaB signaling pathways in colonic crypts of mice in response to progastrin. J Biol Chem 2009, 284(33):22274-22284.
  • [26]Kusaba T, Nakayama T, Yamazumi K, Yakata Y, Yoshizaki A, Inoue K, Nagayasu T, Sekine I: Activation of STAT3 is a marker of poor prognosis in human colorectal cancer. Oncol Rep 2006, 15(6):1445-1451.
  • [27]Kusaba T, Nakayama T, Yamazumi K, Yakata Y, Yoshizaki A, Nagayasu T, Sekine I: Expression of p-STAT3 in human colorectal adenocarcinoma and adenoma; correlation with clinicopathological factors. J Clin Pathol 2005, 58(8):833-838.
  • [28]Corvinus FM, Orth C, Moriggl R, Tsareva SA, Wagner S, Pfitzner EB, Baus D, Kaufmann R, Huber LA, Zatloukal K, et al.: Persistent STAT3 activation in colon cancer is associated with enhanced cell proliferation and tumor growth. Neoplasia 2005, 7(6):545-555.
  • [29]Hoshino R, Chatani Y, Yamori T, Tsuruo T, Oka H, Yoshida O, Shimada Y, Ari-i S, Wada H, Fujimoto J, et al.: Constitutive activation of the 41-/43-kDa mitogen-activated protein kinase signaling pathway in human tumors. Oncogene 1999, 18(3):813-822.
  • [30]Lee SH, Lee JW, Soung YH, Kim SY, Nam SW, Park WS, Kim SH, Yoo NJ, Lee JY: Colorectal tumors frequently express phosphorylated mitogen-activated protein kinase. APMIS 2004, 112(4–5):233-238.
  • [31]Torlakovic E, Skovlund E, Snover DC, Torlakovic G, Nesland JM: Morphologic reappraisal of serrated colorectal polyps. Am J Surg Pathol 2003, 27(1):65-81.
  • [32]Ciccotosto GD, McLeish A, Hardy KJ, Shulkes A: Expression, processing, and secretion of gastrin in patients with colorectal carcinoma. Gastroenterology 1995, 109(4):1142-1153.
  • [33]Lin LI: A concordance correlation coefficient to evaluate reproducibility. Biometrics 1989, 45(1):255-268.
  • [34]Binquet C, Verret C, Chene G, Salmi LR, Letenneur L, Palmer G, Hajjar M, Salamon R: Major statistical software usable in epidemiology. Rev Epidemiol Sante Publique 1998, 46(4):329-336.
  • [35]Chakladar A, Dubeykovskiy A, Wojtukiewicz LJ, Pratap J, Lei S, Wang TC: Synergistic activation of the murine gastrin promoter by oncogenic Ras and beta-catenin involves SMAD recruitment. Biochem Biophys Res Commun 2005, 336(1):190-196.
  • [36]Koh TJ, Bulitta CJ, Fleming JV, Dockray GJ, Varro A, Wang TC: Gastrin is a target of the beta-catenin/TCF-4 growth-signaling pathway in a model of intestinal polyposis. J Clin Invest 2000, 106(4):533-539.
  • [37]Nakata H, Wang SL, Chung DC, Westwick JK, Tillotson LG: Oncogenic ras induces gastrin gene expression in colon cancer. Gastroenterology 1998, 115(5):1144-1153.
  • [38]Bongers G, Muniz LR, Pacer ME, Iuga AC, Thirunarayanan N, Slinger E, Smit MJ, Reddy EP, Mayer L, Furtado GC, et al.: A role for the epidermal growth factor receptor signaling in development of intestinal serrated polyps in mice and humans. Gastroenterology 2012, 143(3):730-740.
  • [39]Ford MG, Valle JD, Soroka CJ, Merchant JL: EGF receptor activation stimulates endogenous gastrin gene expression in canine G cells and human gastric cell cultures. J Clin Invest 1997, 99(11):2762-2771.
  • [40]Merchant JL, Demediuk B, Brand SJ: A GC-rich element confers epidermal growth factor responsiveness to transcription from the gastrin promoter. Mol Cell Biol 1991, 11(5):2686-2696.
  • [41]Singh P, Owlia A, Varro A, Dai B, Rajaraman S, Wood T: Gastrin gene expression is required for the proliferation and tumorigenicity of human colon cancer cells. Cancer Res 1996, 56(18):4111-4115.
  • [42]Grabowska AM, Hughes J, Watson SA: Use of interfering RNA to investigate the role of endogenous gastrin in the survival of gastrointestinal cancer cells. Br J Cancer 2007, 96(3):464-473.
  • [43]Duckworth CA, Clyde D, Worthley DL, Wang TC, Varro A, Pritchard DM: Progastrin-induced secretion of insulin-like growth factor 2 from colonic myofibroblasts stimulates colonic epithelial proliferation in mice. Gastroenterology 2013, 145(1):197-208.
  • [44]Hollande F, Imdahl A, Mantamadiotis T, Ciccotosto GD, Shulkes A, Baldwin GS: Glycine-extended gastrin acts as an autocrine growth factor in a nontransformed colon cell line. Gastroenterology 1997, 113(5):1576-1588.
  • [45]Jin G, Ramanathan V, Quante M, Baik GH, Yang X, Wang SS, Tu S, Gordon SA, Pritchard DM, Varro A, et al.: Inactivating cholecystokinin-2 receptor inhibits progastrin-dependent colonic crypt fission, proliferation, and colorectal cancer in mice. J Clin Invest 2009, 119(9):2691-2701.
  • [46]Dubeykovskiy A, Nguyen T, Dubeykovskaya Z, Lei S, Wang TC: Flow cytometric detection of progastrin interaction with gastrointestinal cells. Regul Pept 2008, 151(1–3):106-114.
  • [47]Sarkar S, Swiercz R, Kantara C, Hajjar KA, Singh P: Annexin A2 mediates up-regulation of NF-kappaB, beta-catenin, and stem cell in response to progastrin in mice and HEK-293 cells. Gastroenterology 2011, 140(2):583-595.
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