Aberrant Pim-3 expression is involved in gastric adenoma-adenocarcinoma sequence and cancer progression.
OBJECTIVE
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.
Zheng
Hua-Chuan
HC
Department of Diagnostic Pathology, Graduate School of Medical and Pharmaceutical Sciences, University of Toyama, Toyama, 930-0194, Japan.
Tsuneyama
Koichi
K
Takahashi
Hiroyuki
H
Miwa
Shigeharu
S
Sugiyama
Toshiro
T
Popivanova
Boryana Konstantinova
BK
Fujii
Chifumi
C
Nomoto
Kazuhiro
K
Mukaida
Naofumi
N
Takano
Yasuo
Y
D000230:Adenocarcinoma / Q000098:blood supply / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D000236:Adenoma / Q000098:blood supply / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000032:analysis; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000032:analysis*; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000032:analysis*; D013274:Stomach Neoplasms / Q000098:blood supply / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D046888:Tissue Array Analysis; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D018952:Antigens, CD34; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; C499249:PIM3 protein, human; D017346:Protein Serine-Threonine Kinases