Lab of Pathology, Hebei Medical University, Shijiazhuang, Hebei 050017, P.R. China.
Department of Pathology, The Second Hospital, Hebei Medical University, Shijiazhuang, Hebei 050000, P.R. China.
Oncol Rep. 2019 Oct;42(4):1497-1506. doi: 10.3892/or.2019.7252. Epub 2019 Jul 26.
Intrinsic and acquired resistance of cancer to radio‑and chemotherapy is one of the major challenges in the treatment of esophageal squamous cell carcinoma (ESCC). Elevated reactive oxygen species (ROS) play an important role in the resistance to cisplatin in ESCCs. Super dismutase [Mn], mitochondrial (SOD‑2), an important primary antioxidant enzyme located in mitochondria, could regulate ROS production. Our previous study showed that tumor necrosis factor‑α (TNF‑α)‑mediated SOD‑2 through NF‑κB was involved in epithelial‑mesenchymal transition and migration in A549 cells. Therefore, the present study aimed to identify if TNF‑α mediated SOD‑2 upregulation is involved in cisplatin resistance in ESCC. It was identified that a higher expression of SOD‑2 in human ESCC samples was associated with TNF‑α expression and poor overall survival in patients with ESCC, suggesting that SOD‑2 may act as an oncogene in ESCC. To further confirm if TNF‑α could upregulate SOD‑2 to contribute to cell proliferation, the human ESCC cell line Eca‑109 was treated with TNF‑α in vitro. TNF‑α could upregulate SOD‑2 and induce cell proliferation in Eca109 cells, while blocking SOD‑2 using small interfering RNA (siRNA) inhibited TNF‑α‑induced cell proliferation. Upregulation of SOD‑2 by TNF‑α was inhibited by blocking the NF‑κB pathway, which suggested that SOD‑2 by TNF‑α/NF‑κB contributes to cell proliferation in Eca109 cells. Furthermore, it was observed that TNF‑α could induce cisplatin resistance in Eca109 cells, while transfection with SOD‑2 siRNA could significantly increase the chemosensitivity of ESCC to cisplatin. Therefore, the present results suggested that SOD‑2 may serve as an oncogene, and the upregulation of SOD‑2 by TNF‑α/NF‑κB may contribute to cisplatin resistance in ESCC.
癌症对放化疗的内在和获得性耐药是食管鳞状细胞癌（ESCC）治疗的主要挑战之一。升高的活性氧（ROS）在 ESCC 对顺铂的耐药性中发挥重要作用。超氧化物歧化酶[Mn]，线粒体（SOD-2），一种位于线粒体中的重要初级抗氧化酶，可以调节 ROS 的产生。我们之前的研究表明，肿瘤坏死因子-α（TNF-α）通过 NF-κB 介导 SOD-2 参与 A549 细胞中的上皮-间充质转化和迁移。因此，本研究旨在确定 TNF-α 介导的 SOD-2 上调是否参与 ESCC 中的顺铂耐药。研究发现，人 ESCC 样本中 SOD-2 的高表达与 TNF-α 的表达和 ESCC 患者的总生存率降低相关，表明 SOD-2 可能在 ESCC 中作为癌基因发挥作用。为了进一步证实 TNF-α 是否可以上调 SOD-2 以促进细胞增殖，在体外用人 ESCC 细胞系 Eca-109 进行处理。TNF-α 可上调 SOD-2 并诱导 Eca109 细胞增殖，而使用小干扰 RNA（siRNA）阻断 SOD-2 可抑制 TNF-α诱导的细胞增殖。TNF-α 上调 SOD-2 被阻断 NF-κB 途径抑制，这表明 TNF-α/NF-κB 通过 SOD-2 促进 Eca109 细胞的增殖。此外，研究观察到 TNF-α 可诱导 Eca109 细胞对顺铂产生耐药性，而 SOD-2 siRNA 的转染可显著增加 ESCC 对顺铂的化疗敏感性。因此，本研究结果表明 SOD-2 可能作为癌基因，TNF-α/NF-κB 上调 SOD-2 可能导致 ESCC 对顺铂的耐药性。
