Transferrin facilitates the formation of DNA double-strand breaks via transferrin receptor 1:the possible involvement of transferrin in carcinogenesis of high-grade serous ovarian cancer.
Transferrin facilitates the formation of DNA double-strand breaks via transferrin receptor 1:the possible involvement of transferrin in carcinogenesis of high-grade serous ovarian cancer.
复制标题
转铁蛋白通过转铁蛋白受体1促进DNA双链断裂的形成：转铁蛋白可能参与高级别浆液性卵巢癌的致癌过程。
作者：
Shigeta S;Toyoshima M* (*corresponding author);Ishibashi M;Usui T;Kitatani K*;Yaegashi N
输卵管上皮是高级别浆液性卵巢癌起源的候选者。含有转铁蛋白的卵泡液和/或逆行经血可能是致癌的危险因素。输卵管上皮中 DNA 双链断裂 (DNA-DSB) 的积累被认为在癌症的发展中发挥着重要作用。然而，DNA-DSB 积累的机制尚未完全阐明。铁离子催化的芬顿反应中产生的羟基自由基作为有效的 DNA-DSB 诱导分子，提高了转铁蛋白铁离子转运蛋白在 DNA-DSB 形成中的潜力。我们研究了转铁蛋白在 DNA 损伤和卵巢癌发展中的潜在作用。在人输卵管分泌上皮细胞和 A2780 卵巢癌细胞中，转铁蛋白治疗促进了丝氨酸 139 处磷酸化的组蛋白 2AX (γH2AX) 的形成，该组蛋白被称为 DNA-DSB 标记。转铁蛋白受体 1 (TfR1) 的敲低（而非转铁蛋白受体 2）抑制了转铁蛋白的摄取以及随后的 γH2AX 的形成。由于活性氧 (ROS) 中的羟基自由基参与 DNA-DSB，因此确定了 ROS 的形成。使用 TfR1 特异性小干扰 RNA 处理可显着减少转铁蛋白诱导的 ROS 形成。此外，在过氧化氢存在的情况下，TfR1 依赖性转铁蛋白的摄取可增强 DNA-DSB 的形成，过氧化氢可作为芬顿反应的底物。一项针对小鼠输卵管的离体研究进一步证明，转铁蛋白治疗在输卵管上皮中引入了 DNA-DSB。总的来说，这些数据表明转铁蛋白-TfR1 轴负责诱导 DNA-DSB，从而可能导致 DNA 损伤/基因组不稳定。这些发现还表明，暴露于转铁蛋白可促进输卵管上皮细胞中 DNA-DSB 的积累，从而引发并促进卵巢癌的发展。
Fallopian tubal epithelium is a candidate for the origin of high-grade serous ovarian cancer. Transferrin-containing follicular fluid and/or retrograde menstrual blood are possible risk factors for carcinogenesis. Accumulation of DNA double-strand breaks (DNA-DSBs) in the fallopian tubal epithelium is considered to play an important role in the development of cancer. However, the mechanisms by which DNA-DSBs accumulate have not yet been fully elucidated. The hydroxyl radical, which is produced in a Fenton reaction catalyzed by an iron ion, serves as a potent DNA-DSB-inducing molecule, raising the potential of an iron ion transporter of transferrin in the formation of DNA-DSBs. We studied the potential involvement of transferrin in DNA damage and the development of ovarian cancer. Treatment with transferrin facilitated the formation of histone 2AX phosphorylated at Serine 139 (γH2AX), which is known as a DNA-DSB marker, in human fallopian tube secretory epithelial cells and A2780 ovarian cancer cells. Knockdown of transferrin receptor 1 (TfR1), but not transferrin receptor 2, suppressed the transferrin uptake and consequent formation of γH2AX. As hydroxyl radicals in reactive oxygen species (ROS) are involved in DNA-DSBs, the formation of ROS was determined. Treatment with TfR1-specific small interference RNAs significantly diminished transferrin-induced formation of ROS. Moreover, TfR1-dependent uptake of transferrin was revealed to augment the formation of DNA-DSBs in the presence of hydrogen peroxide, which served as a substrate for the Fenton reaction. An ex vivo study with murine fallopian tubes further demonstrated that transferrin treatment introduced DNA-DSBs in the fallopian tubal epithelium. Collectively, these data suggested that the transferrin-TfR1 axis accounts for the induction of DNA-DSBs that potentially lead to DNA damage/genome instability. These findings also suggested that exposure to transferrin initiates and promotes the development of ovarian cancer by aiding the accumulation of DNA-DSBs in the fallopian tubal epithelium.