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Metformin Increases E-cadherin in Tumors of Diabetic Patients With Endometrial Cancer and Suppresses Epithelial-Mesenchymal Transition in Endometrial Cancer Cell Lines
  1. Ido Laskov, MD*,,
  2. Paul Abou-Nader, PhD*,,
  3. Oreekha Amin, MBBS, MSc*,,
  4. Charles-Andre Philip, MD*,,
  5. Marie-Claude Beauchamp, PhD*,,
  6. Amber Yasmeen, PhD*,, and
  7. Walter H. Gotlieb, MD, PhD*,,
  1. *Division of Gynecologic Oncology, Jewish General Hospital;
  2. Segal Cancer Center, Lady Davis Institute of Medical Research; and
  3. Department of Oncology, McGill University, Montreal, Quebec, Canada.
  1. Address correspondence and reprint requests to Amber Yasmeen, PhD, Segal Cancer Center, Lady Davis Institute of Medical Research, McGill University, 3755 Cote Ste, Catherine Rd, Montreal, QC, Canada H3T 1E2. E-mail: amber.yasmeen@mail.mcgill.ca.

Abstract

Purpose Epithelial-mesenchymal transition (EMT) is a critical process for cancer metastasis and recurrence. Metformin, an effective oral antidiabetic drug, has been associated with decreased cancer risk and mortality. In this pilot study, we started to evaluate the effect of metformin on EMT in vivo and in vitro in endometrial cancer (EC).

Methods Endometrial cancer cell lines and freshly isolated EC tumor specimens were used to assess EMT after metformin treatment. Cell lines were subjected to wound healing and AlamarBlue assays to determine cell migration and cell proliferation; messenger RNA levels were measured by real-time reverse transcriptase (RT) quantitative polymerase chain reaction (PCR), and protein levels were measured by Western blots to detect EMT marker expression.

Results Protein expression and messenger RNA of E-cadherin was found to be increased (P = 0.02 and 0.04, respectively) in 30 EC tumor specimens of diabetic patients treated with metformin compared with 20 EC tumor specimens of diabetic patients treated with other antidiabetic agents. In vitro, metformin reduced cell migration at 5 mM for 48 hours, as determined by the wound healing assay in EC cell lines (Ishikawa, 45% reduction; HEC50, 40% reduction), whereas more than 90% of the cells remained viable on the AlamarBlue assay. Metformin reduced EMT in the cell lines and regulated the expression of the EMT-related epithelial markers, E-cadherin and Pan-keratin; the mesenchymal markers, N-cadherin, fibronectin, and vimentin; and the EMT drivers, Twist-1, snail-1, and ZEB-1.

Conclusions Tumors of patients on metformin have increased E-cadherin expression, and metformin decreases EMT in EC cell lines in vitro, suggesting clinical biological relevance of metformin in women with EC.

  • Metformin
  • Endometrial cancer
  • EMT
  • E-cadherin
  • Cell migration

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Footnotes

  • The authors declare no conflicts of interest.

  • Ethical statement: This study was approved by the ethic committee of Jewish General Hospital (JGH), Montreal, Quebec, Canada and all patients participating in this study gave informed consent in accordance with the JGH ethics committee regulations (protocol#03-041).

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