Data_Sheet_1_Dysregulation of miR-375/AEG-1 Axis by Human Papillomavirus 16/18-E6/E7 Promotes Cellular Proliferation, Migration, and Invasion in Cervical Cancer.docx

Cervical Cancer (CC) is a highly aggressive tumor and is one of the leading causes of cancer-related deaths in women. miR-375 was shown to be significantly down-regulated in cervical cancer cells. However, the precise biological functions of miR-375 and the molecular mechanisms underlying its action in CC are largely unknown. miR-375 targets were predicted by bioinformatics target prediction tools and validated using luciferase reporter assay. Herein, we investigated the functional significance of miR-375 and its target gene in CC to identify potential new therapeutic targets. We found that miR-375 expression was significantly downregulated in CC, and astrocyte elevated gene-1 (AEG-1) was identified as a target of miR-375. Our results also showed that ectopic expression of miR-375 suppressed CC cell proliferation, migration, invasion and angiogenesis, and increased the 5-fluorouracil-induced apoptosis and cell cycle arrest in vitro. In contrast, inhibition of miR-375 expression significantly enhanced these functions. Furthermore, HPV - 16 E6/E7 and HPV - 18 E6/E7 significantly down-regulates miR-375 expression in CC. HPV 16/18-E6/E7/miR-375/AEG-1 axis plays an important role in the regulation of cell proliferation, migration, and invasion in CC. Therefore, targeting miR-375/AEG-1 mediated axis could serve as a potential therapeutic target for CC.

宫颈癌（Cervical Cancer，CC）是一种高侵袭性肿瘤，也是女性癌症相关死亡的主要诱因之一。已有研究表明miR-375在宫颈癌细胞中表达显著下调，但目前对于miR-375在宫颈癌中的确切生物学功能及其作用的分子机制仍不甚明晰。研究人员通过生物信息学靶标预测工具预测了miR-375的靶基因，并借助荧光素酶报告基因实验对其进行了验证。本研究旨在探究miR-375及其靶基因在宫颈癌中的功能意义，以筛选潜在的新型治疗靶点。研究发现，miR-375在宫颈癌组织或细胞中表达显著下调，且星形胶质细胞上调基因-1（astrocyte elevated gene-1，AEG-1）被鉴定为miR-375的靶基因。体外实验结果显示，过表达miR-375可抑制宫颈癌细胞的增殖、迁移、侵袭及血管生成，并增强5-氟尿嘧啶（5-fluorouracil）诱导的细胞凋亡与细胞周期阻滞；反之，抑制miR-375的表达则显著增强上述细胞功能。此外，HPV-16 E6/E7与HPV-18 E6/E7可显著下调宫颈癌中的miR-375表达。HPV 16/18-E6/E7/miR-375/AEG-1调控轴在宫颈癌细胞增殖、迁移及侵袭的调控过程中发挥关键作用。因此，靶向miR-375/AEG-1介导的调控轴有望成为宫颈癌潜在的治疗靶点。