Local angiotensin II-generation in human gastric cancer: correlation with tumor progression through the activation of ERK1/2, NF-kappaB and survivin.
Angiotensin II is a main effector peptide in renin-angiotensin system, acting as a growth promoter via angiotensin II type 1 (AT1) receptor. The present study examined intrinsic angiotensin II generating system in gastric cancer and potential roles of angiotensin II in cellular proliferation and survival. The expression of AT1 receptor was examined in gastric cancer cell lines and tissues. In addition, we measured angiotensin II concentration in tissues from twenty gastric cancer and corresponding normal region using the florisil method. In vitro, we investigated the potential roles of angiotensin II in cellular proliferation and cell survival in cultured human gastric cancer cell line. The effects of AT1 receptor blocker candesartan were evaluated in a mouse model of peritoneal carcinomatosis. AT1 receptor protein was expressed in gastric cancer cell lines and tissues. Angiotensin II concentration in tumor region (1447+/-624 pg/g wet) was significantly higher than those of normal region (775+/-320 pg/g wet) (p<0.05). Angiotensin II stimulates the cell proliferation in the AT1 receptor-positive OCUM2MD3 gastric cancer cell line and this proliferative effect of angiotensin II was inhibited by a specific AT1 receptor antagonist, candesartan. We also confirmed the angiotensin II stimulated ERK1/2, nuclear transcript factor-kappaB (NF-kappaB) and surviving activation, which are central molecules of cellular proliferation and survival in OCUM2MD3 cells. Candesartan significantly prolonged survival time in a mouse model of peritoneal carcinomatosis compared with control group (p=0.0.197, log-rank test). Our data provide in vivo evidence of intrinsic angiotensin II generating system in gastric cancer and indicate locally formed angiotensin II is involved in cellular proliferation and survival.
Gastroenterologic Surgery, Division of Cancer Medicine, Graduate School of Medical Scinece, Kanazawa University, Kanazawa, Ishikawa 920-8641, Japan. junkino0416@gmail.co.jp
Jun
J
Kinoshita
Sachio
S
Fushida
Shinichi
S
Harada
Yasumichi
Y
Yagi
Hideto
H
Fujita
Shinichi
S
Kinami
Itasu
I
Ninomiya
Takashi
T
Fujimura
Masato
M
Kayahara
Masakazu
M
Yashiro
Kosei
K
Hirakawa
Tetsuo
T
Ohta
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D018262:Adenocarcinoma, Clear Cell / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D002288:Adenocarcinoma, Mucinous / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D000328:Adult; D000368:Aged; D000804:Angiotensin II / Q000096:biosynthesis*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001562:Benzimidazoles / Q000494:pharmacology; D001713:Biphenyl Compounds; D015153:Blotting, Western; D018276:Carcinoma, Medullary / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D051034:Inhibitor of Apoptosis Proteins; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D010534:Peritoneal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D015996:Survival Rate; D000077022:Survivin; D013777:Tetrazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D047228:Angiotensin II Type 1 Receptor Blockers; C107489:BIRC5 protein, human; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D016328:NF-kappa B; D044140:Receptor, Angiotensin, Type 1; D000077022:Survivin; D013777:Tetrazoles; D000804:Angiotensin II; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C081643:candesartan