Department of Molecular Pathology, Nara Medical University, Shijo-cho, Kashihara, Nara, Japan.
Clin Exp Metastasis. 2012 Dec;29(8):915-25. doi: 10.1007/s10585-012-9480-6. Epub 2012 May 3.
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.
我们研究了高血糖条件对结直肠癌（CRC）肝转移的影响。血管紧张素（A）-II 增加了 HT29 和 CT26 细胞的生长、侵袭和抗凋亡存活。相比之下，血管紧张素原（ATG）增加了 HT29 细胞的这些特征，但不增加 CT26 细胞的这些特征。HT29 细胞表达 A-II 型 1 受体、糜酶和肾素，而 CT26 细胞不表达肾素。肾素表达和 ATG 诱导的细胞生长、侵袭和存活随着 HT29 细胞和 CT26 细胞中葡萄糖浓度的增加而增加。在 HT29 细胞中，肾素或糜酶抑制剂可消除 A-II 的产生。胆固醇缀合反义 S-寡脱氧核苷酸减少肝内 ATG 产生可抑制 HT29 细胞的肝转移。对 121 例 CRC 患者的检查表明，CRC 病例中的糖尿病与原发性肿瘤中更高的 HbA1c、更高的肾素和 A-II 浓度以及更高的肝转移发生率相关，高于非糖尿病病例。这些结果表明，糖尿病相关的血管紧张素激活增强了结直肠癌的肝转移，因此可能为结直肠癌的抗转移治疗提供了一个可能的靶点。
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