2nd Area of Obstetrics, The People's Hospital of Pingyi County, No. 7, Jinhua Road, Pingyi Street, Linyi, 273300, China.
Department of Nursing, Yulin Traditional Chinese Medicine Hospital, No. 131 Xinjian South Road, Yuyang District, Yulin, 719000, China.
Biochem Biophys Res Commun. 2018 Dec 9;507(1-4):51-58. doi: 10.1016/j.bbrc.2018.10.146. Epub 2018 Nov 16.
Cervical cancer is one of the most lethal types of cancer among female. Microfibrillar-associated protein 5 (MFAP5) is an extracellular matrix (ECM) glycoprotein, and is confirmed to be involved in cell signaling during microfibril assembly, elastinogenesis and cell survival. However, the role of MFAP5 in cervical cancer development and progression remains poorly understood. In the study, MFAP5 was over-expressed in human cervical cancers, and in different cervical cancer cell lines. Patients suffering from cervical cancer with low MFAP5 expression exhibited better survival rate. Suppressing MFAP5 in cervical cancer cells markedly reduced the cell proliferation, migration and invasion by modulating epithelial-mesenchymal transition (EMT)-related signaling pathway. In addition, MFAP5 knockdown induced large number of cells distributed in G2/M phase, along with reduced Cyclin B1, Cyclin D1 and cyclin-dependent kinase 4 (CDK4) expressions, and enhanced p21 and p53 levels. Moreover, apoptosis was highly induced by MFAP5 silence through reducing Bcl-xl and Bcl-2 expressions, and promoting Bax, cleaved Caspase-3 and poly (ADP-Ribose) polymerase (PARP) expressions in cervical cancer cells. Reactive oxygen species (ROS) production levels were also higher in MFAP5-knockdown cells, along with Jun-N-terminal kinase (JNK) activation. Importantly, we found that MFAP5 knockdown-inhibited cervical cancer cell growth was dependent on ROS production. Finally, the depletion of MFAP5 prevented cervical cancer progression in vivo. In summary, our study identified a critical role played by MFAP5 in the progression of cervical cancer and the potential mechanisms by which exerted its effects, indicating that targeting MFAP5-related pathways could be conducive to the therapies for cervical cancer.
宫颈癌是女性中最致命的癌症类型之一。微纤维相关蛋白 5 (MFAP5) 是细胞外基质 (ECM) 糖蛋白，已被证实参与微纤维组装、弹性蛋白生成和细胞存活过程中的细胞信号转导。然而，MFAP5 在宫颈癌发展和进展中的作用仍知之甚少。在这项研究中，MFAP5 在人宫颈癌和不同的宫颈癌细胞系中过表达。MFAP5 低表达的宫颈癌患者的生存率更高。在宫颈癌细胞中抑制 MFAP5 通过调节上皮间质转化 (EMT) 相关信号通路，显著降低细胞增殖、迁移和侵袭。此外，MFAP5 敲低诱导大量细胞分布在 G2/M 期，同时降低细胞周期蛋白 B1、细胞周期蛋白 D1 和细胞周期蛋白依赖性激酶 4 (CDK4) 的表达，并增加 p21 和 p53 的水平。此外，MFAP5 沉默通过降低 Bcl-xl 和 Bcl-2 的表达，以及促进 Bax、裂解的 Caspase-3 和多聚 (ADP-核糖) 聚合酶 (PARP) 的表达，在宫颈癌细胞中高度诱导细胞凋亡。MFAP5 敲低细胞中的活性氧 (ROS) 产生水平也更高，同时 JNK 激活。重要的是，我们发现 MFAP5 敲低抑制宫颈癌细胞生长依赖于 ROS 产生。最后，MFAP5 的耗竭阻止了宫颈癌在体内的进展。总之，我们的研究确定了 MFAP5 在宫颈癌进展中的关键作用及其发挥作用的潜在机制，表明靶向 MFAP5 相关途径可能有利于宫颈癌的治疗。
