Journal Article

Low mitochondrial DNA copy number induces chemotherapy resistance via epithelial-mesenchymal transition by DNA methylation in esophageal squamous cancer cells

Takahashi, Tsuyoshi, Kurokawa, Yukinori, Makino, Tomoki, Eguchi, Hidetoshi, Tanaka, Koji, Tsujimoto, Tomoyuki, Yamamoto, Kazuyoshi, Nakajima, Kiyokazu, Harino, Takashi, Masuike, Yasunori, Kubo, Yuto, Doki, Yuichiro, Saito, Takuro, Yamashita, Kotaro, Yamasaki, Makoto

2022

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Biomedical and Life Sciences / Biomedicine / Cancer / Cancer therapies / Carcinoma, Squamous Cell - drug therapy / Carcinoma, Squamous Cell - genetics / Carcinoma, Squamous Cell - metabolism / Cell Line, Tumor / Cell Proliferation - genetics / Chemoresistance / Chemotherapy / Complications and side effects / Copy number / Copy number variations / Depolarization / DNA Copy Number Variations - genetics / DNA methylation / DNA Methylation - genetics / DNA, Mitochondrial - genetics / DNA, Mitochondrial - metabolism / Drug resistance / Epithelial-mesenchymal transition / Epithelial-Mesenchymal Transition - genetics / Esophageal cancer / Esophageal diseases / Esophageal Neoplasms - drug therapy / Esophageal Neoplasms - genetics / Esophageal Neoplasms - metabolism / Esophageal Squamous Cell Carcinoma - drug therapy / Esophageal Squamous Cell Carcinoma - genetics / Gene expression / Gene Expression Regulation, Neoplastic / Genetic aspects / Health aspects / Humans / Medicine/Public Health / Membrane potential / Mesenchyme / Mitochondrial DNA / Mitochondrial membrane potential / Patients / Prognosis / Risk factors / Squamous cell carcinoma / Translational Cancer Biology