Abstract
Purpose
Pim-3, a member of the proto-oncogene Pim family with serine/threonine kinase activity was aberrantly expressed in cancerous lesions of endoderm-derived organs such as liver, pancreas, and colon. The aim of this study was to clarify the role of Pim-3 expression in the tumorigenesis and the development of gastric carcinomas.
Methods
Pim-3 expression was immunohistochemically examined on the tissue microarrays containing primary (n = 285) and metastastic (n = 37) sites of gastric carcinomas, in comparison with adenoma (n = 48) and non-cancerous mucosa (n = 84). It was also compared with the clinicopathological parameters of gastric carcinomas.
Results
Pim-3 expression was enhanced in adenoma (64.6%) and metastasis sites of gastric carcinoma (73.0%), to a lesser degree in primary sites of gastric carcinoma (39.3%) when compared to non-cancerous mucosa (13.1%, p < 0.0001). Pim-3 expression levels were higher in intestinal-type than diffuse-type gastric carcinoma (p = 0.018). Pim-3 expression was closely correlated with sex (p = 0.047), lymphatic (p = 0.019) and venous invasion (p = 0.014). Pim-3 expression was correlated significantly with vascular endothelial growth factor (VEGF, p = 0.009) and extracellular matrix metalloproteinase inducer (EMMPRIN, p = 0.032), both of which are presumed to be involved in neovascularization, a crucial step for metastasis. On the contrary, phosphatase and tensin homology deleted from human chromosome 10 (Pten) negative gastric carcinomas exhibited higher Pim-3 expression than Pten positive ones (p = 0.042). There was no relationship between Pim-3 expression and MVD in gastric carcinomas (p = 0.715). Furthermore, patients with Pim-3 positive gastric cancer, showed a lower cumulative survival rate than those with Pim-3 negative gastric cancer (p = 0.014) and Pim-3 positive was also identified as an independent prognostic factor for gastric carcinoma patients (p = 0.006).
Conclusions
Aberrant Pim-3 expression was involved in gastric adenoma–adenocarcinoma sequence and subsequent invasion and metastasis process in gastric cancer. Moreover, Pim-3 may be employed to predict the prognosis of gastric cancer patients. Distinct Pim-3 expression underlies the molecular mechanisms for the differentiation of intestinal-type and diffuse-type carcinomas.
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References
Amaravadi R, Thompson CB (2005) The survival kinases Akt and Pim as potential pharmacological targets. J Clin Invest 115:2618–2624
Bindukumar B, Schwartz SA, Nair MP, Aalinkeel R, Kawinski E, Chadha KC (2005) Prostate-specific antigen modulates the expression of genes involved in prostate tumor growth. Neoplasia 7:241–252
Celen O, Yildirim E, Berberoglu U (2007) Prognostic impact of positive lymph node ratio in gastric carcinoma. J Surg Oncol 96:95–101
Chang JG, Chen YJ, Perng LI, Wang NM, Kao MC, Yang TY, Chang CP, Tsai CH (1999) Mutation analysis of the PTEN/MMAC1 gene in cancers of the digestive tract. Eur J Cancer 35:647–651
Chang YT, Wu MS, Chang YJ, Chen CC, Lin YS, Hsieh T, Yang PC, Lin JT (2006) Distinct gene expression profiles in gastric epithelial cells induced by different clinical isolates of Helicobacter pylori-implication of bacteria and host interaction in gastric carcinogenesis. Hepatogastroenterology 53:484–490
Deneen B, Welford SM, Ho T, Hernandez F, Kurland I, Denny CT (2003) PIM3 proto-oncogene kinase is a common transcriptional target of divergent EWS/ETS oncoproteins. Mol Cell Biol 23:3897–3908
Faraji EI, Frank BB (2002) Multifocal atrophic gastritis and gastric carcinoma. Gastroenterol Clin North Am 31:499–516
Feldman JD, Vician L, Crispino M, Tocco G, Marcheselli VL, Bazan NG, Baudry M, Herschman HR (1998) KID-1, a protein kinase induced by depolarization in brain. J Biol Chem 273:16535–16543
Fujii C, Nakamoto Y, Lu P, Tsuneyama K, Popivanova BK, Kaneko S, Mukaida N (2005) Aberrant expression of serine/threonine kinase Pim-3 in hepatocellular carcinoma development and its role in the proliferation of human hepatoma cell lines. Int J Cancer 114:209–218
Juvan R, Hudler P, Gazvoda B, Repse S, Bracko M, Komel R (2007) Significance of genetic abnormalities of p53 protein in Slovenian patients with gastric carcinoma. Croat Med J 48:207–217
Knobbe CB, Reifenberger G (2003) Genetic alterations and aberrant expression of genes related to the phosphatidyl-inositol-3′-kinase/protein kinase B (Akt) signal transduction pathway in glioblastomas. Brain Pathol 13:507–518
Konietzko U, Kauselmann G, Scafidi J, Staubli U, Mikkers H, Berns A, Schweizer M, Waltereit R, Kuhl D (1999) Pim kinase expression is induced by LTP stimulation and required for the consolidation of enduring LTP. EMBO J 18:3359–3369
Kumada T, Tsuneyama K, Hatta H, Ishizawa S, Takano Y (2004) Improved 1–h rapid immunostaining method using intermittent microwave irradiation: practicability based on 5 years application in Toyama Medical and Pharmaceutical University Hospital. Mod Pathol 17:1141–1149
Li D, Xie K, Wolff R, Abbruzzese JL (2004) Pancreatic cancer. Lancet 363:1049–1057
Li YY, Popivanova BK, Nagai Y, Ishikura H, Fujii C, Mukaida N (2006) 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 66:6741–6747
Oki E, Baba H, Tokunaga E, Nakamura T, Ueda N, Futatsugi M, Mashino K, Yamamoto M, Ikebe M, Kakeji Y, Maehara Y (2005) Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer 117:376–380
Pedrero JM, Carracedo DG, Pinto CM, Zapatero AH, Rodrigo JP, Nieto CS, Gonzalez MV (2005) Frequent genetic and biochemical alterations of the PI 3-K/AKT/PTEN pathway in head and neck squamous cell carcinoma. Int J Cancer 114:242–248
Popivanova BK, Li YY, Zheng H, Fuji C, Tsuneyama K, Mukaida N (2007) A proto-oncogene, Pim-3 with serine/threonin kinase activity, is aberrantly expressed in human colon cancer cells, accompanied with Bad phosphorylation. Cancer Sci 98:321–328
Roy HK, Olusola BF, Clemens DL, Karolski WJ, Ratashak A, Lynch HT, Smyrk TC (2002) AKT proto-oncogene overexpression is an early event during sporadic colon carcinogenesis. Carcinogenesis 23:201–205
Shirabe K, Shimada M, Matsumata T, Higashi H, Yakeishi Y, Wakiyama S, Ikeda Y, Ezaki T, Fukuzawa S, Takenaka K, Kishikawa K, Ikeda T, Taguchi K, Maehara Y, Sugimachi K (2003) Analysis of the prognostic factors for liver metastasis of gastric cancer after hepatic resection: a multi-institutional study of the indications for resection. Hepatogastroenterology 50:1560–1563
Sobin LH, Wittekind CH (2002) TNM Classification of Malignant Tumors, 6th edn. Wiley, New Jersey
Tang JM, He QY, Guo RX, Chang XJ (2006) Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung Cancer 51:181–191
Weidner N (1995) Current pathologic methods for measuring intratumoral microvessel density within breast carcinoma and other solid tumors. Breast Cancer Res Treat 36:169–180
Xia HH, Talley NJ (2001) Apoptosis in gastric epithelium induced by Helicobacter pylori infection: implications in gastric carcinogenesis. Am J Gastroenterol 96:16–26
Yang XY, Ren CP, Wang L, Li H, Jiang CJ, Zhang HB, Zhao M, Yao KT (2005) Identification of differentially expressed genes in metastatic and non-metastatic nasopharyngeal carcinoma cells by suppression subtractive hybridization. Cell Oncol 27:215–223
Zheng HC, Sun JM, Li XH, Yang XF, Zhang YC, Xin Y (2003) Role of PTEN and MMP-7 expression in growth, invasion, metastasis and angiogenesis of gastric carcinoma. Pathol Int 53:659–666
Zheng H, Takahashi H, Murai Y, Cui Z, Nomoto K, Niwa H, Tsuneyama K, Takano Y (2006a) Expressions of MMP-2, MMP-9, and VEGF were closely linked to growth, invasion, metastasis, angiogenesis of gastric carcinoma. Anticancer Res 26:3579–3584
Zheng H, Takahashi H, Nakajima T, Murai Y, Cui Z, Nomoto K, Tsuneyama K, Takano Y (2006b) MUC6 down-regulation correlates with gastric carcinoma progression and a poor prognosis: an immunohistochemical study with tissue microarrays. J Cancer Res Clin Oncol 132:817–823
Zheng HC, Takahashi H, Murai Y, Cui ZG, Nomoto K, Miwa S, Tsuneyama K, Takano Y (2006c) EMMPRIN expression contributes to growth and angiogenesis of gastric carcinoma: a good marker to indicate local invasion and prognosis. Br J cancer 95:1371–1378
Zheng H, Takahashi H, Murai Y, Cui Z, Nomoto K, Tsuneyama K, Takano Y (2007a) Low expression of FHIT and PTEN correlates with ma- lignancy of gastric carcinoma: tissue- array findings. Appl Immunohistochem Mol Morphol (in press)
Zheng H, Takahashi H, Murai Y, Cui Z, Nomoto K, Miwa S, Tsuneyama K, Takano Y (2007b) Pathobiological characteristics of intestinal- and diffuse-type gastric carcinoma in Japan: An immunostaining study on the tissue microarray. J Clin Pathol 60:273–277
Zippo A, De Robertis A, Bardelli M, Galvagni F, Oliviero S (2004) Identification of Flk-1 target genes in vasculogenesis: Pim-1 is required for endothelial and mural cell differentiation in vitro. Blood 103:4536–4544
Acknowledgments
We particularly thank Kanako Yasuyoshi, Tokimasa Kumada and Hideki Hatta for their technical help and Yukari Inoue for her secretarial assistance. This work was partially supported by the Japanese Ministry of Education, Science, Sports and Culture, Grant-in-Aid for Scientific Research 14770072, 18590324 and Japanese Smoking Foundation.
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Zheng, HC., Tsuneyama, K., Takahashi, H. et al. Aberrant Pim-3 expression is involved in gastric adenoma–adenocarcinoma sequence and cancer progression. J Cancer Res Clin Oncol 134, 481–488 (2008). https://doi.org/10.1007/s00432-007-0310-1
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DOI: https://doi.org/10.1007/s00432-007-0310-1