Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Department of Hepatobiliary Surgery, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Oncol Rep. 2018 Sep;40(3):1495-1502. doi: 10.3892/or.2018.6518. Epub 2018 Jun 22.
Pancreatic ductal adenocarcinoma (PDAC) is a highly invasive neoplasm with a 5‑year survival rate of <8%. Metformin, the most widely used antidiabetic drug in the world, has been shown to exert anticancer activities in epidemiological and animal studies. Our previous studies revealed that metformin suppressed desmoplasia in PDAC by reducing TGF‑β1 production in cancer cells. The aim of the present study was to investigate the effects of metformin on invasion and epithelial‑mesenchymal transition (EMT) in pancreatic cancer and to reveal the underlying mechanisms. In the present study, we revealed that metformin suppressed migration, invasion and EMT changes in pancreatic cancer cells. Furthermore, metformin reduced TGF‑β1 production and Smad2/3 phosphorylation in pancreatic cancer cells. In addition, treatment with recombinant TGF‑β1 recovered the metformin‑mediated invasion inhibition and EMT changes. Treatment with metformin also suppressed tumor growth, invasion and EMT in LSL‑KrasG12D/+, Trp53fl/+and Pdx1‑Cre (KPC) transgenic mice that harbor spontaneous pancreatic cancer. Collectively, our study revealed a new possible mechanism for the antitumor effects of metformin via autocrine TGF‑β1/Smad2/3 signaling in PDAC.
胰腺导管腺癌（PDAC）是一种具有高度侵袭性的肿瘤，其 5 年生存率<8%。二甲双胍是世界上应用最广泛的抗糖尿病药物，在流行病学和动物研究中已显示出抗癌活性。我们之前的研究表明，二甲双胍通过减少癌细胞中 TGF-β1 的产生来抑制 PDAC 的间质形成。本研究旨在探讨二甲双胍对胰腺癌侵袭和上皮间质转化（EMT）的影响，并揭示其潜在机制。在本研究中，我们发现二甲双胍抑制了胰腺癌细胞的迁移、侵袭和 EMT 变化。此外，二甲双胍降低了胰腺癌细胞中 TGF-β1 的产生和 Smad2/3 的磷酸化。此外，用重组 TGF-β1 处理可恢复二甲双胍介导的侵袭抑制和 EMT 变化。二甲双胍治疗还抑制了携带自发性胰腺癌的 LSL-KrasG12D/+, Trp53fl/+和 Pdx1-Cre（KPC）转基因小鼠的肿瘤生长、侵袭和 EMT。总之，我们的研究揭示了二甲双胍通过自分泌 TGF-β1/Smad2/3 信号通路在 PDAC 中发挥抗肿瘤作用的新可能机制。
