Department of Medical Genetics, School of Basic Medical Sciences, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, Jiangsu, People's Republic of China.
Department of General Surgery, The Affiliated Yixing Hospital of Jiangsu University, Yixing, 214200, Jiangsu, People's Republic of China.
Genes Genomics. 2022 Jul;44(7):801-812. doi: 10.1007/s13258-022-01258-5. Epub 2022 May 14.
Tissue factor pathway inhibitor-1 (TFPI) is a serine protease inhibitor, which is responsible for inactivating TF-induced coagulation. Recently, increasing studies revealed that TFPI was lowly expressed in tumor cells and exhibited the antitumor activity.
The aim of this study was to explore the role and underlying molecular mechanisms of TFPI in breast cancer.
The expression and prognostic value of TFPI were analyzed using UALCAN and Kaplan-Meier plotter website. The expression level of TFPI in breast cancer tissues and cells was examined by immunohistochemistry (IHC) and western blot analysis, respectively. Cellular proliferation was evaluated by CCK-8 and colony formation assays. Cell migration and invasion were determined by transwell assay. The methylation level of TFPI promoter was determined by methylation-specific PCR.
TFPI expression was significantly lower in breast cancer tissues and cells compared to normal breast tissues and normal breast cells. Patients with low TFPI levels showed worse overall survival (OS). Furthermore, overexpression of TFPI significantly inhibited the proliferation, migration and invasion of breast cancer cells. Conversely, knockdown of TFPI promoted the proliferation, migration and invasion of breast cancer cells. Mechanistically, TFPI inhibited the ERK/p38 MAPK signaling pathway in breast cancer. Moreover, DNA hypermethylation of TFPI promoter was responsible for the downregulation of TFPI in breast cancer cells.
TFPI inhibited breast cancer cell proliferation, migration and invasion through inhibition of the ERK/p38 MAPK signaling pathway, suggesting that TFPI may serve as a novel prognostic biomarker and therapeutic target for breast cancer.
组织因子途径抑制物-1（TFPI）是一种丝氨酸蛋白酶抑制剂，负责使 TF 诱导的凝血失活。最近，越来越多的研究表明 TFPI 在肿瘤细胞中低表达，并具有抗肿瘤活性。
本研究旨在探讨 TFPI 在乳腺癌中的作用及其潜在的分子机制。
使用 UALCAN 和 Kaplan-Meier plotter 网站分析 TFPI 的表达和预后价值。通过免疫组织化学（IHC）和 Western blot 分析分别检测乳腺癌组织和细胞中 TFPI 的表达水平。通过 CCK-8 和集落形成实验评估细胞增殖。通过 Transwell 测定法测定细胞迁移和侵袭。通过甲基化特异性 PCR 测定 TFPI 启动子的甲基化水平。
与正常乳腺组织和正常乳腺细胞相比，乳腺癌组织和细胞中 TFPI 的表达明显降低。TFPI 水平低的患者总生存期（OS）较差。此外，TFPI 的过表达显著抑制乳腺癌细胞的增殖、迁移和侵袭。相反，TFPI 的敲低促进了乳腺癌细胞的增殖、迁移和侵袭。机制上，TFPI 抑制了乳腺癌中的 ERK/p38 MAPK 信号通路。此外，TFPI 启动子的 DNA 高甲基化是乳腺癌细胞中 TFPI 下调的原因。
TFPI 通过抑制 ERK/p38 MAPK 信号通路抑制乳腺癌细胞的增殖、迁移和侵袭，提示 TFPI 可能作为乳腺癌的一种新的预后生物标志物和治疗靶点。
