title: Diabetes-associated angiotensin activation enhances liver metastasis of colon cancer.
abstract: We examined the effects of hyperglycemic conditions on liver metastasis of colorectal cancer (CRC). Angiotensin (A)-II increased growth, invasion, and anti-apoptotic survival in HT29 and CT26 cells. In contrast, angiotensinogen (ATG) increased these features in HT29 cells but not in CT26 cells. HT29 cells expressed A-II type 1 receptor, chymase, and rennin, whereas CT26 cells did not express renin. Renin expression and ATG-induced cell growth, invasion, and survival induced and increased as glucose concentration increased in HT29 cells and also CT26 cells. An inhibitor of renin or chymase abrogated A-II production in HT29 cells. Reduction of hepatic ATG production by cholesterol-conjugated antisense S-oligodeoxynucleotide suppressed liver metastasis of HT29 cells. An examination of 121 CRC patients showed that diabetes in CRC cases was associated with higher blood HbA1c, higher renin and A-II concentrations in the primary tumors, and higher incidence of liver metastasis than in nondiabetic cases. These results suggest that diabetes-associated angiotensin activation enhances liver metastasis of CRC and may therefore provide a possible target for antimetastatic therapy in CRC.
authors.affiliation: Department of Molecular Pathology, Nara Medical University, Shijo-cho, Kashihara, Nara, Japan.
authors.forename: Takasumi
authors.initials: T
authors.lastname: Shimomoto
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ohmori
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Chihara
authors.forename: Ayumi
authors.initials: A
authors.lastname: Denda
authors.forename: Tomonori
authors.initials: T
authors.lastname: Sasahira
authors.forename: Naokuni
authors.initials: N
authors.lastname: Tatsumoto
authors.forename: Kiyomu
authors.initials: K
authors.lastname: Fujii
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kuniyasu
mesh_terms: D000803:Angiotensin I / Q000096:biosynthesis / Q000378:metabolism; D000804:Angiotensin II / Q000096:biosynthesis / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D053818:Chymases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D003110:Colonic Neoplasms / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D048909:Diabetes Complications / Q000378:metabolism*; D003920:Diabetes Mellitus / Q000378:metabolism*; D005947:Glucose / Q000032:analysis; D006442:Glycated Hemoglobin / Q000032:analysis; D019073:HT29 Cells; D006801:Humans; D006943:Hyperglycemia; D008113:Liver Neoplasms / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D020320:Oligoribonucleotides, Antisense; D034622:RNA Interference; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D012083:Renin / Q000235:genetics / Q000378:metabolism
chemical_list: D000803:Angiotensin I; D000804:Angiotensin II; D047228:Angiotensin II Type 1 Receptor Blockers; D000808:Angiotensinogen; D053818:Chymases; D005947:Glucose; D006442:Glycated Hemoglobin; D020320:Oligoribonucleotides, Antisense; D034741:RNA, Small Interfering; D044140:Receptor, Angiotensin, Type 1; D012083:Renin; C517652:hemoglobin A1c protein, human