Abstract 1392: Mechanism of chemoresistance in esophageal squamous cell carcinoma based on mitochondrial DNA copy number

Abstract Epithelial-to-mesenchymal transition (EMT) has been reported to be associated with metastasis and resistance to therapy in various carcinomas. However, the mechanism of EMT induction and its regulation remain unresolved. Esophageal cancer is one of the most difficult-to-treat cancers that metastasize and are refractory to therapy. In this study, we focused on mitochondrial DNA to elucidate the mechanism of EMT induction in esophageal cancer and to search for therapeutic targets. We established a resistant strain (TE11-R) by long-term exposure of an esophageal cancer cell line (TE11) to chemotherapy (CDDP), and found that TE11-R acquired mesenchymal characteristics. We also observed that the mtDNA copy number was decreased in TE11-R. Next, we established ESCC with reduced mtDNA copy number (TE11-shT) by knockdown of mitochondrial transcription factor A (sh-TFAM). First, mtDNA copy number was reduced to 60% in TE11-shT. Complex IV activity and membrane potential (MMP) were reduced in TE11-shT compared to control TE11. Next, exposure of TE11 to depolarizing agents (CCCP) decreased expression of epithelial markers (CDH1) and increased expression of mesenchymal markers (CDH2, Vimentin, ZEB1) by qPCR and WB. Exposure of TE11-shT and CCCP to DNMT inhibitors increased expression of E-cadherin, decreased expression of N-cadherin and Vimentin, and improved CDDP sensitivity. and CDDP sensitivity were observed. Decreased mtDNA copy number in esophageal squamous cell carcinoma induced EMT via increased DNMT expression, suggesting that DNMT inhibitors may be therapeutic targets for treatment-resistant esophageal cancer cells. Citation Format: Koji Tanaka, Yuto Kubo, Kotaro Yamashita, Tomoki Makino, Tsuyoshi Takahashi, Yukinori Kurokawa, Kiyokazu Nakajima, Hidetoshi Eguchi, Yuichiro Doki. Mechanism of chemoresistance in esophageal squamous cell carcinoma based on mitochondrial DNA copy number [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1392.