Department of Pathology, West China Second University Hospital, Sichuan University, Chengdu, China.
Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China.
Bioengineered. 2022 May;13(5):12211-12223. doi: 10.1080/21655979.2022.2074615.
Mitochondrial transcription factor B2 (TFB2M) is a protein modulating both mitochondrial DNA (mtDNA) transcription and compacting. In this study, we explored the expression profile of in ovarian cancer, its association with infiltration of tumor-associated macrophages (TAMs), and its influence on macrophage polarization. Serial sections of ovarian cancer tissue arrays were stained to detect TFB2M and CD163 expression. Epithelial ovarian cancer cell line OVISE and CAOV4 were used to assess the influence of TFB2M on IL-6 expression. THP-1 cells were utilized as an model for macrophage migration and polarization. Results showed that higher expression is associated with poor survival in ovarian cancer patients. IHC staining confirmed a moderately positive correlation between expression and the infiltration of CD163-positive cells in 68 primary ovarian cancer cases. overexpression was associated with increased mtDNA outside the mitochondria and elevated IL-6 expression in ovarian cancer cells. When cytosolic mtDNA was selectively inhibited by DNase I, -induced IL-6 upregulation was canceled. overexpression could activate the nuclear factor kappa-B (NF-κB) signaling pathway via promoting nucleus entry of p65 and p-p65, which was abrogated by inhibiting cytosolic mtDNA, TLR9, or NF-κB signaling pathway. Conditioned medium from OIVSE cells with overexpression could induce macrophage migration and M2 polarization. However, these inducing effects were abrogated by DNase I, TLR9 inhibitor, and anti-IL-6 R pretreatment. In conclusion, this study showed a novel role of TFB2M in the immunosuppressive tumor microenvironment. It promotes M2 macrophage infiltration via a cytosolic mtDNA/TLR9/NF-κB/IL-6 pathway in ovarian cancer.
线粒体转录因子 B2（TFB2M）是一种调节线粒体 DNA（mtDNA）转录和紧缩的蛋白质。在这项研究中，我们探索了 TFB2M 在卵巢癌中的表达谱、其与肿瘤相关巨噬细胞（TAMs）浸润的关联，以及对巨噬细胞极化的影响。对卵巢癌组织阵列的连续切片进行染色，以检测 TFB2M 和 CD163 的表达。使用上皮性卵巢癌细胞系 OVISE 和 CAOV4 评估 TFB2M 对 IL-6 表达的影响。THP-1 细胞被用作巨噬细胞迁移和极化的模型。结果表明，TFB2M 表达较高与卵巢癌患者生存不良相关。免疫组化染色证实了 68 例原发性卵巢癌中 TFB2M 表达与 CD163 阳性细胞浸润之间存在中度正相关。TFB2M 过表达与线粒体外 mtDNA 增加和卵巢癌细胞中 IL-6 表达升高相关。当通过 DNase I 选择性抑制胞质 mtDNA 时，-诱导的 IL-6 上调被取消。TFB2M 过表达可以通过促进 p65 和 p-p65 进入细胞核来激活核因子 kappa-B（NF-κB）信号通路，该通路被抑制胞质 mtDNA、TLR9 或 NF-κB 信号通路所阻断。过表达 TFB2M 的 OIVSE 细胞的条件培养基可诱导巨噬细胞迁移和 M2 极化。然而，这些诱导作用被 DNase I、TLR9 抑制剂和抗 IL-6R 预处理所阻断。总之，本研究表明 TFB2M 在免疫抑制性肿瘤微环境中具有新的作用。它通过卵巢癌细胞中的胞质 mtDNA/TLR9/NF-κB/IL-6 通路促进 M2 巨噬细胞浸润。
