Harino Takashi, Tanaka Koji, Motooka Daisuke, Masuike Yasunori, Takahashi Tsuyoshi, Yamashita Kotaro, Saito Takuro, Yamamoto Kazuyoshi, Makino Tomoki, Kurokawa Yukinori, Nakajima Kiyokazu, Eguchi Hidetoshi, Doki Yuichiro
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2-E2, Yamada-Oka, Suita, Osaka, 565-0871, Japan.
Genome Information Research Center, Research Institute for Microbial Diseases, Osaka University, Suita, Japan.
Sci Rep. 2024 Dec 30;14(1):31653. doi: 10.1038/s41598-024-80226-3.
Esophageal cancer is a highly aggressive disease, and acquired resistance to chemotherapy remains a significant hurdle in its treatment. mtDNA, crucial for cellular energy production, is prone to mutations at a higher rate than nuclear DNA. These mutations can accumulate and disrupt cellular function; however, mtDNA mutations induced by chemotherapy in esophageal cancer remain unexplored. We aimed to identify such mutations in esophageal cancer, pre- and post-chemotherapy, and explore the relationship between them and clinicopathological factors associated with chemotherapy resistance. We investigated mtDNA mutations in Human esophageal squamous cell carcinoma (ESCC) cancer cell lines (TE8 and TE11) and patient samples (27 pre- and post-chemotherapy, and 96 post-chemotherapy) using next-generation sequencing. Our analysis revealed a rise in mtDNA mutations following chemotherapy, particularly within the D-loop region. Moreover, mutations in a specific D-loop segment (hypervariable segment 1; HVS1) were associated with lower mtDNA copy number, poorer response to chemotherapy, and decreased five-year survival rates. These findings suggest that HVS1 mutations in mtDNA acquired after chemotherapy may contribute to treatment resistance and poorer clinical outcomes in patients with esophageal cancer. This study sheds light on the mechanisms of chemotherapy resistance and provides valuable insights for future research to overcome this challenge.
食管癌是一种侵袭性很强的疾病，对化疗产生获得性耐药仍然是其治疗中的一个重大障碍。线粒体DNA（mtDNA）对细胞能量产生至关重要，其突变率高于核DNA。这些突变会积累并破坏细胞功能；然而，化疗在食管癌中诱导的mtDNA突变仍未得到探索。我们旨在识别食管癌化疗前后的此类突变，并探讨它们与化疗耐药相关的临床病理因素之间的关系。我们使用下一代测序技术研究了人食管鳞状细胞癌（ESCC）癌细胞系（TE8和TE11）以及患者样本（27例化疗前后样本和96例化疗后样本）中的mtDNA突变。我们的分析显示化疗后mtDNA突变增加，尤其是在D环区域内。此外，特定D环片段（高变区1；HVS1）中的突变与较低的mtDNA拷贝数、较差的化疗反应以及降低的五年生存率相关。这些发现表明化疗后获得的mtDNA中的HVS1突变可能导致食管癌患者的治疗耐药和较差的临床结果。这项研究揭示了化疗耐药的机制，并为未来克服这一挑战的研究提供了有价值的见解。
