Geminin, Ki67, and minichromosome maintenance 2 in gastric hyperplastic polyps, adenomas, and intestinal-type carcinomas: pathobiological significance.
BACKGROUND
Geminin negatively regulates Cdt1 and induces the formation of prereplicative complexes by loading mini-chromosome maintenance proteins (Mcm) onto chromatin and limiting DNA replication to once per cell cycle. Recent studies have suggested that geminin expression is a marker of the S/G2/M phase of the cell cycle and is associated with a poor prognosis in various human malignancies. This study aimed to clarify the pathobiological role of geminin in intestinal-type gastric carcinoma, and its relationships with minichromosome maintenance 2 (Mcm2) and Ki67 expression.


METHODS
We performed western blot analysis of seven human gastric cancer cell lines, and immunohistochemical analysis of 72 gastric mucosal lesions and 128 surgically removed advanced intestinal-type gastric carcinomas. Double-labeling immuno-fluorescence was performed to identify the coexpression of geminin and Ki67.


RESULTS
Geminin was detected in all cell lines. Geminin labeling indices (LIs) in hyperplastic polyps, low-grade adenomas, high-grade adenomas, and intestinal-type adenocarcinomas were 3.9%, 10.5%, 18.6%, and 27.2%, respectively. The equivalent LIs for Ki67 and Mcm2 were 17.7%, 42.2%, 52.6%, and 59.7%; and 26.7%, 70.0%, 67.8%, and 77.8%, respectively. Double-labeling immunofluorescence revealed coexpression of geminin and Ki67 in both normal and tumor cells. The LI for geminin was significantly correlated with N stage, International Union Against Cancer (UICC) stage, Mcm2 LI, and Ki67 LI. Patients in stages I-IV and stage III with higher LIs for geminin (>25%) had significantly worse prognoses (P < 0.05 and P < 0.04, respectively). Univariate Cox regression analysis indicated that the overall survival of stage I-IV tumors was significantly correlated with high geminin LIs (relative risk [RR] = 1.94; P = 0.04).


CONCLUSIONS
Geminin expression might reflect the biological nature of gastric intramucosal neoplasms and could be a possible prognostic marker in advanced intestinal-type gastric carcinomas.
Shomori
Kohei
K
Department of Microbiology and Pathology, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori, 683-8503, Japan.
Nishihara
Keisuke
K
Tamura
Takayuki
T
Tatebe
Shigeru
S
Horie
Yasushi
Y
Nosaka
Kanae
K
Haruki
Tomohiro
T
Hamamoto
Yuki
Y
Shiomi
Tatsushi
T
Nakabayashi
Motoki
M
Ito
Hisao
H
D000230:Adenocarcinoma / Q000401:mortality / Q000473:pathology; D000236:Adenoma / Q000401:mortality / Q000473:pathology; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000032:analysis* / Q000096:biosynthesis; D005260:Female; D005455:Fluorescent Antibody Technique; D064248:Geminin; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D007414:Intestinal Neoplasms / Q000401:mortality / Q000473:pathology; D007564:Japan; D053208:Kaplan-Meier Estimate; D019394:Ki-67 Antigen / Q000032:analysis* / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D064111:Minichromosome Maintenance Complex Component 2; D015999:Multivariate Analysis; D009687:Nuclear Proteins / Q000032:analysis* / Q000096:biosynthesis; D011127:Polyps / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D012044:Regression Analysis; D013223:Statistics as Topic; D013274:Stomach Neoplasms / Q000401:mortality / Q000473:pathology*
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C577995:GMNN protein, human; D064248:Geminin; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2
Clin Cancer Res. 2005 Apr 1;11(7):2510-7
15814627
Neoplasma. 2005;52(5):420-4
16151588
J Pathol. 2004 Oct;204(2):121-30
15376260
Am J Pathol. 2002 Jul;161(1):267-73
12107111
Science. 2000 Dec 22;290(5500):2309-12
11125146
Hum Pathol. 2009 Jul;40(7):975-81
19269009
Biophys J. 1963 Jan;3:11-33
13980635
Eur Surg Res. 1990;22(6):365-70
2079097
Biochem Biophys Res Commun. 2003 May 30;305(2):412-20
12745091
Semin Diagn Pathol. 2002 Feb;19(1):20-30
11936263
J Oral Pathol Med. 2010 Apr;39(4):328-34
20136698
J Cell Physiol. 2005 Jan;202(1):215-22
15389519
Cancer. 1982 Dec 1;50(11):2496-503
7139542
J Clin Oncol. 2007 Aug 1;25(22):3210-6
17664468
Acta Pathol Microbiol Scand. 1965;64:31-49
14320675
J Immunol. 1984 Oct;133(4):1710-5
6206131
Genes Cells. 2002 Jun;7(6):523-34
12059957
Cell. 1998 Jun 12;93(6):1043-53
9635433
Liver Int. 2006 May;26(4):424-32
16629645
J Clin Oncol. 2006 May 10;24(14):2137-50
16682732
Cancer. 2007 Mar 1;109(5):949-56
17262828
Br J Cancer. 2009 Mar 24;100(6):959-70
19240714
Br J Cancer. 2005 Nov 28;93(11):1295-300
16278669
Histopathology. 2003 Jun;42(6):566-74
12786892
Gastric Cancer. 2008;11(1):37-46
18373176
Gastrointest Endosc. 1992 Jul-Aug;38(4):481-4
1511825
Am J Pathol. 2002 Aug;161(2):611-8
12163385
N Engl J Med. 2006 Jul 6;355(1):11-20
16822992
Int J Biochem Cell Biol. 2006;38(7):1207-20
16487741
Tumori. 2008 Jul-Aug;94(4):531-8
18822690
Oncol Rep. 2009 May;21(5):1189-95
19360293
EMBO J. 1991 Apr;10(4):857-64
2009861
J Cell Sci. 2001 Jun;114(Pt 11):2027-41
11493639
Br J Cancer. 2003 Nov 3;89(9):1802-11
14583787