Fujihara Shintaro, Kato Kiyohito, Morishita Asahiro, Iwama Hisakazu, Nishioka Tomoko, Chiyo Taiga, Nishiyama Noriko, Miyoshi Hisaaki, Kobayashi Mitsuyoshi, Kobara Hideki, Mori Hirohito, Okano Keiichi, Suzuki Yasuyuki, Masaki Tsutomu
Department of Gastroenterology and Neurology, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Life Science Resarch Center, Faculty of Medicine, Kagawa University, Miki-cho, Kita-gun, Kagawa 761-0793, Japan.
Int J Oncol. 2015 May;46(5):2172-80. doi: 10.3892/ijo.2015.2903. Epub 2015 Feb 24.
Esophageal carcinoma is the eighth most common cancer worldwide and the sixth leading cause of cancer-related deaths, with one of the worst prognoses of any form of cancer. Treatment with the anti-diabetic drug metformin has been associated with reduced cancer incidence in patients with type 2 diabetes. This study therefore evaluated the effects of metformin on the proliferation, in vitro and in vivo, of human esophageal adenocarcinoma cells, as well as the microRNAs associated with the antitumor effects of metformin. Metformin inhibited the proliferation of the esophageal adenocarcinoma cell lines OE19, OE33, SK-GT4 and OACM 5.1C, blocking the G0 to G1 transition in the cell cycle. This was accompanied by strong reductions in G1 cyclins, especially cyclin D1, cyclin-dependent kinase (Cdk)4, and Cdk6, and decreases in retinoblastoma protein phosphorylation. In addition, metformin reduced the phosphorylation of epidermal growth factor receptor and insulin-like growth factor and insulin-like growth factor-1 receptor, as well as angiogenesis-related proteins, such as vascular endothelial growth factor, tissue inhibitor of metalloproteinases (TIMP)-1, and TIMP-2. Metformin also markedly altered microRNA expression. Treatment with metformin of athymic nude mice bearing xenograft tumors reduced tumor proliferation. These findings suggest that metformin may have clinical use in the treatment of esophageal adenocarcinoma.
食管癌是全球第八大常见癌症，也是癌症相关死亡的第六大主要原因，其预后是所有癌症形式中最差的之一。使用抗糖尿病药物二甲双胍进行治疗与2型糖尿病患者癌症发病率降低有关。因此，本研究评估了二甲双胍对人食管腺癌细胞体内外增殖的影响，以及与二甲双胍抗肿瘤作用相关的微小RNA。二甲双胍抑制食管腺癌细胞系OE19、OE33、SK-GT4和OACM 5.1C的增殖，阻断细胞周期中从G0到G1的转变。这伴随着G1期细胞周期蛋白的显著减少，尤其是细胞周期蛋白D1、细胞周期蛋白依赖性激酶（Cdk）4和Cdk6，以及视网膜母细胞瘤蛋白磷酸化的降低。此外，二甲双胍降低了表皮生长因子受体、胰岛素样生长因子和胰岛素样生长因子-1受体的磷酸化，以及血管生成相关蛋白，如血管内皮生长因子、金属蛋白酶组织抑制剂（TIMP）-1和TIMP-2的磷酸化。二甲双胍还显著改变了微小RNA的表达。用二甲双胍治疗携带异种移植肿瘤 的无胸腺裸鼠可降低肿瘤增殖。这些发现表明二甲双胍可能在食管腺癌的治疗中具有临床应用价值。
