Abstract
Gastric cardia adenocarcinoma (GCA) is distinct from adenocarcinoma of the distal stomach because of its different etiological factors, tumor characteristics, and biological behavior. However, its pathogenesis is not fully understood. The purpose of this study is to characterize the role of Pim-3, c-Myc, and p-p27 in the tumorigenesis and progression of different sites of gastric adenocarcinoma by determining its pathogenetic significance. The expression of Pim-3, c-Myc, and p-p27 proteins was evaluated by immunohistochemistry in 140 resection specimens of gastric adenocarcinomas (78 GCAs , 62 DGAs and 20 normal gastric tissues). The level of expression of Pim-3, c-Myc, and p-p27 and the co-expression of all three markers (Pim-3+/c-Myc+/p-p27+) in GCA were significantly lower than that in DGA tumors (P < 0.05). Detailed analysis of the immunoreactivity patterns showed that in DGA, Pim-3 immunoreactivity was associated significantly with poor tumor differentiation, advanced tumor stage, and presence of lymph node metastasis. In addition, c-Myc overexpression correlated with tumor stage and lymph node metastasis, and positive p-p27 expression correlated with poor differentiation and tumor stage. The phenotype of Pim-3+/c-Myc+/p-p27+ co-expression was closely correlated with tumor stage and lymph node metastasis (P < 0.05). In contrast, GCA only demonstrated a close correlation of Pim-3 overexpression with poor tumor differentiation and tumor stage (P < 0.05). Our results demonstrate the presence of different expression patterns of Pim-3, c-Myc, p-p27, and Pim-3+/c-Myc+/p-p27+ and their clinicopathologic significance in GCA and DGA tumors. Our results add support to the notion that distinct molecular mechanisms may be involved in the development and progression of adenocarcinomas from the gastric cardia and distal portion of stomach.
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References
Varadhachary G, Ajani JA. Gastric cancer. Clin Adv Hematol Oncol. 2005;3:118–24.
Pera M. Epidemiology of esophageal cancer, especially adenocarcinoma of the esophagus and esophagogastric junction. Recent Results Cancer Res. 2000;155:1–14.
Richards DA, Boehm KA, Anthony SP. Systemic therapy for gastric cancer and adenocarcinoma of the gastroesophageal junction: present status and future directions. Expert Opin Investig Drugs. 2007;16:1059–68.
Zhao C, Zhang X, Xue L, Xing L, Wang J, Li X. Analysis of the changing trends of frequency and localization of gastric cancers arising fromdifferent sites of the stomach in population of the high incidence area of esophageal and gastriccancers in Hebei Province. Zhonghua Zhong Liu Za Zhi. 2008;30:817–20.
Ichikura T, Ogawa T, Kawabata T, Chochi K, Sugasawa H, Mochizuki H. Is adenocarcinoma of the gastric cardia a distinct entity independent of subcardial carcinoma? World J Surg. 2003;27:334–8.
MacDonald WC, MacDonald JB. Adenocarcinoma of the esophagus and/or gastric cardia. Cancer. 1987;60:1094–8.
Gray JR, Coldman AJ, MacDonald WC. Cigarette and alcohol use in patients with adenocarcinoma of the gastric cardia or lower esophagus. Cancer. 1992;69:2227–31.
Yao D, Wang Y, Xue L, Wang H, Zhang J, Zhang X. Different expression pattern and significance of p14ARF-Mdm2-p53 pathway and Bmi-1 exist between gastric cardia and distal gastric adenocarcinoma. Hum Pathol. 2013;44:844–51.
Xue L, Zhang X, Li Y, Yang H, Li X, Mi J, et al. Differences of immunophenotypic markers and signaling molecules between adenocarcinomas of gastric cardia and distal stomach. Hum Pathol. 2011;42:594–601.
Mukaida N, Wang YY, Li YY. Roles of Pim-3, a novel survival kinase, in tumorigenesis. Cancer Sci. 2011;102:1437–42.
Zheng HC, Tsuneyama K, Takahashi H, Miwa S, Sugiyama T, Popivanova BK, et al. Aberrant Pim-3 expression is involved in gastric adenoma-adenocarcinoma sequence and cancer progression. J Cancer Res Clin Oncol. 2008;134:481–8.
Forshell LP, Li Y, Forshell TZ, Rudelius M, Nilsson L, Keller U, et al. The direct Myc target Pim3 cooperates with other pim kinases in supporting viability of Myc-induced B-cell lymphomas. Oncotarget. 2011;2:448–60.
Morishita D, Katayama R, Sekimizu K, Tsuruo T, Fujita N. Pim kinases promote cell cycle progression by phosphorylating and down-regulating p27Kip1 at the transcriptional and posttranscriptional levels. Cancer Res. 2008;68:5076–85.
Zhang L, Hou Y, Ashktorab H, Gao L, Xu Y, Wu K, et al. The impact of C-MYC gene expression on gastric cancer cell. Mol Cell Biochem. 2010;344:125–35.
Lee KH, Lee HE, Cho SJ, Cho YJ, Lee HS, Kim JH, et al. Immunohistochemical analysis of cell cycle-related molecules in gastric carcinoma: prognostic significance, correlation with clinicopathological parameters, proliferation and apoptosis. Pathobiology. 2008;75:364–72.
Siewert JR, Holscher AH, Becker K, Gossner W. Cardia cancer: attempt at a therapeutically relevant classification. Chirurg. 1987;58:25–32.
Siewert JR, Feith M, Stein HJ. Biologic and clinical variations of adenocarcinoma at the esophago-gastric junction: relevance of a topographic-anatomic subclassification. J Surg Oncol. 2005;90:139–46. discussion 146.
Flejou JF. WHO classification of digestive tumors: the fourth edition. Ann Pathol. 2011;31:S27–31.
Kwon SJ. Evaluation of the 7th UICC TNM staging system of gastric cancer. J Gastric Cancer. 2011;11:78–85.
Zhu S, Sun P, Zhang Y, Yan L, Luo B. Expression of c-myc and PCNA in epstein-barr virus-associated gastric carcinoma. Exp Ther Med. 2013;5:1030–4.
He SM, Zhao ZW, Wang Y, Zhao JP, Wang L, Hou F, et al. Potential role of Jun activation domain-binding protein 1 and phosphorylated p27 expression in prognosis of glioma. Brain Tumor Pathol. 2012;29:3–9.
Hammerman PS, Fox CJ, Birnbaum MJ, Thompson CB. Pim and akt oncogenes are independent regulators of hematopoietic cell growth and survival. Blood. 2005;105:4477–83.
Li YY, Popivanova BK, Nagai Y, Ishikura H, Fujii C, Mukaida N. Pim-3, a proto-oncogene with serine/threonine kinase activity, is aberrantly expressed in human pancreatic cancer and phosphorylates bad to block bad-mediated apoptosis in human pancreatic cancer cell lines. Cancer Res. 2006;66:6741–7.
Popivanova BK, Li YY, Zheng H, Omura K, Fujii C, Tsuneyama K, et al. Proto-oncogene, Pim-3 with serine/threonine kinase activity, is aberrantly expressed in human colon cancer cells and can prevent bad-mediated apoptosis. Cancer Sci. 2007;98:321–8.
Brault L, Gasser C, Bracher F, Huber K, Knapp S, Schwaller J. Pim serine/threonine kinases in the pathogenesis and therapy of hematologic malignancies and solid cancers. Haematologica. 2010;95:1004–15.
Wu Y, Wang YY, Nakamoto Y, Li YY, Baba T, Kaneko S, et al. Accelerated hepatocellular carcinoma development in mice expressing the Pim-3 transgene selectively in the liver. Oncogene. 2010;29:2228–37.
ZF H, Y H, Q Z, J J: Significance of Pim-3 expression in gastric carcinoma. Shijie Huaren Xiaohua Zazhi 2008;16:3515-18.
Zhang Y, Wang Z, Li X, Magnuson NS. Pim kinase-dependent inhibition of c-Myc degradation. Oncogene. 2008;27:4809–19.
Beharry Z, Mahajan S, Zemskova M, Lin YW, Tholanikunnel BG, Xia Z, et al. The Pim protein kinases regulate energy metabolism and cell growth. Proc Natl Acad Sci U S A. 2011;108:528–33.
Zhang Y, Wang Z, Magnuson NS. Pim-1 kinase-dependent phosphorylation of p21cip1/WAF1 regulates its stability and cellular localization in H1299 cells. Mol Cancer Res. 2007;5:909–22.
Tan P, Cady B, Wanner M, Worland P, Cukor B, Magi-Galluzzi C, et al. The cell cycle inhibitor p27 is an independent prognostic marker in small (t1a, b) invasive breast carcinomas. Cancer Res. 1997;57:1259–63.
Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, et al. Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nat Med. 1997;3:227–30.
Loda M, Cukor B, Tam SW, Lavin P, Fiorentino M, Draetta GF, et al. Increased proteasome-dependent degradation of the cyclin-dependent kinase inhibitor p27 in aggressive colorectal carcinomas. Nat Med. 1997;3:231–4.
Esposito V, Baldi A, De Luca A, Groger AM, Loda M, Giordano GG, et al. Prognostic role of the cyclin-dependent kinase inhibitor p27 in non-small cell lung cancer. Cancer Res. 1997;57:3381–5.
Tsihlias J, Kapusta LR, DeBoer G, Morava-Protzner I, Zbieranowski I, Bhattacharya N, et al. Loss of cyclin-dependent kinase inhibitor p27Kip1 is a novel prognostic factor in localized human prostate adenocarcinoma. Cancer Res. 1998;58:542–8.
Ohtani M, Isozaki H, Fujii K, Nomura E, Niki M, Mabuchi H, et al. Impact of the expression of cyclin-dependent kinase inhibitor p27Kip1 and apoptosis in tumor cells on the overall survival of patients with non-early stage gastric carcinoma. Cancer. 1999;85:1711–8.
Bloom J, Pagano M. Deregulated degradation of the cdk inhibitor p27 and malignant transformation. Semin Cancer Biol. 2003;13:41–7.
Allen JD, Verhoeven E, Domen J, van der Valk M, Berns A. Pim-2 transgene induces lymphoid tumors, exhibiting potent synergy with c-myc. Oncogene. 1997;15:1133–41.
van Lohuizen M, Verbeek S, Krimpenfort P, Domen J, Saris C, Radaszkiewicz T, et al. Predisposition to lymphomagenesis in pim-1 transgenic mice: cooperation with c-myc and N-myc in murine leukemia virus-induced tumors. Cell. 1989;56:673–82.
Mikkers H, Allen J, Knipscheer P, Romeijn L, Hart A, Vink E, et al. High-throughput retroviral tagging to identify components of specific signaling pathways in cancer. Nat Genet. 2002;32:153–9.
Keller UB, Old JB, Dorsey FC, Nilsson JA, Nilsson L, MacLean KH, et al. Myc targets Cks1 to provoke the suppression of p27Kip1, proliferation and lymphomagenesis. EMBO J. 2007;26:2562–74.
Yang W, Shen J, Wu M, Arsura M, FitzGerald M, Suldan Z, et al. Repression of transcription of the p27(Kip1) cyclin-dependent kinase inhibitor gene by c-Myc. Oncogene. 2001;20:1688–702.
Vlach J, Hennecke S, Alevizopoulos K, Conti D, Amati B. Growth arrest by the cyclin-dependent kinase inhibitor p27Kip1 is abrogated by c-Myc. EMBO J. 1996;15:6595–604.
Muller D, Bouchard C, Rudolph B, Steiner P, Stuckmann I, Saffrich R, et al. Cdk2-dependent phosphorylation of p27 facilitates its myc-induced release from cyclin e/cdk2 complexes. Oncogene. 1997;15:2561–76.
Perez-Roger I, Kim SH, Griffiths B, Sewing A, Land H. Cyclins D1 and D2 mediate myc-induced proliferation via sequestration of p27(Kip1) and p21(Cip1). EMBO J. 1999;18:5310–20.
Bouchard C, Thieke K, Maier A, Saffrich R, Hanley-Hyde J, Ansorge W, et al. Direct induction of cyclin D2 by Myc contributes to cell cycle progression and sequestration of p27. EMBO J. 1999;18:5321–33.
Alves MK, Lima VP, Andre AR, Ferreira MV, Barros MA, Rabenhorst SH. p27KIP1 expression in gastric cancer: differential pathways in the histological subtypes associated with Helicobacter pylori infection. Scand J Gastroenterol. 2010;45:409–20.
Gulmann C, Hegarty H, Grace A, Leader M, Patchett S, Kay E. Differences in proximal (cardia) versus distal (antral) gastric carcinogenesis via the retinoblastoma pathway. World J Gastroenterol. 2004;10:17–21.
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This work was supported by the National natural Science Foundation of China (grant no. 81301696).
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Lou, L., Wang, Y., Cui, J. et al. Differential expression of Pim-3, c-Myc, and p-p27 proteins in adenocarcinomas of the gastric cardia and distal stomach. Tumor Biol. 35, 5029–5036 (2014). https://doi.org/10.1007/s13277-014-1664-z
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DOI: https://doi.org/10.1007/s13277-014-1664-z