Background: Esophageal squamous cell carcinoma (ESCC) is one of the most severe cancers and is characterized by chemotherapy resistance and poor prognosis associated with epithelial-mesenchymal transition (EMT). In a previous study, a low mitochondrial DNA (mtDNA) copy number was associated with poorer prognosis and induced EMT in ESCC. However, the detailed mechanism related to mtDNA copy number and EMT is unclear. The aim of this study was to clarify the mechanism by which a change in mtDNA copy number contributes to EMT and to examine treatment of chemotherapy resistance in ESCC. Methods: The association between low mtDNA copy number and chemotherapy resistance was investigated using specimens from 88 patients who underwent surgery after neoadjuvant chemotherapy. Then, the mtDNA content of human ESCC cell lines, TE8 and TE11, was depleted by knockdown of mitochondrial transcription factor A expression. The present study focused on modulation of mitochondrial membrane potential (MMP) and DNA methylation as the mechanisms by which mtDNA copy number affects EMT. mRNA and protein expression, chemotherapy sensitivity, proliferation, MMP and DNA methylation were evaluated, and in vitro and in vivo assays were conducted to clarify these mechanisms. Results: ESCC patients with decreased mtDNA copy number who underwent R0 resection after neoadjuvant chemotherapy had significantly worse pathological response and recurrence-free survival. Additionally, low mtDNA copy number was associated with resistance to chemotherapy in vitro and in vivo. mtDNA controlled MMP, and MMP depolarization induced EMT. Depletion of mtDNA and low MMP induced DNA methylation via a DNA methylation transcription factor (DNMT), and a DNMT inhibitor suppressed EMT and improved chemotherapy sensitivity in mtDNA-depleted ESCC cells, as shown by in vitro and in vivo assays. Conclusion: This study showed that decreased mtDNA copy number induced EMT via modulation of MMP and DNA methylation in ESCC. Therapeutic strategies increasing mtDNA copy number and DNMT inhibitors may be effective in preventing EMT and chemosensitivity resistance.

Background: Perioperative fluid balance is an important indicator in the management of esophageal cancer patients who undergo esophagectomy. However, the association between perioperative fluid balance and postoperative complications after minimally invasive esophagectomy (MIE) remains unclear. Methods: This study included 115 patients with thoracic esophageal squamous cell cancer who underwent MIE between January 2018 and January 2020. We retrospectively evaluated the association between perioperative fluid balance from during surgery to postoperative day (POD) 2, and postoperative complications. Results: The patients were divided into lower group and higher group based on the median fluid balance during surgery and at POD 1 and POD 2. We found that the higher group at POD 1 (≥3000 mL) was the most important indicator of postoperative complications, such as acute pneumonia within 7 days after surgery, and anastomotic leakage (p = 0.029, p = 0.024, respectively). Moreover, the higher group at POD 1 was a significant independent factor for acute postoperative pneumonia by multivariate analysis (OR: 3.270, 95% CI: 1.077–9.929, p = 0.037). Conclusion: This study showed that fluid overload at POD 1 had a negative influence on postoperative complications in patients with esophageal cancer. The fluid balance must be strictly controlled during the early postoperative management of patients undergoing esophageal cancer surgery.