Laboratory for Advanced Interdisciplinary Research, Institutes of Translational Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Gynecology and Obstetrics, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
FASEB J. 2020 Oct;34(10):13211-13223. doi: 10.1096/fj.202000762R. Epub 2020 Aug 26.
Human papillomaviruses 16 (HPV16) is the primary causative agent of cervical cancer (CC). E6 oncoprotein plays a crucial role in cervical carcinogenesis and commonly cause the dysregulation of the long noncoding RNAs (lncRNAs) expression. However, the biological function of lncRNAs in HPV16-related CC remains largely unexplored. In the present study HPV16 E6-induced differential expression of lncRNAs, miRNA, and mRNA were identified using microarray-based analysis and verified in tumor r cell lines and tumor tissues, and the function of lncRNA in CC was investigated in vitro and in vivo. We found that an lncRNA, named GABPB1-AS1, was significantly upregulated in HPV16-positive CC tissues and cell lines. GABPB1-AS1 expression in HPV16-positive CC tissues was positively associated with tumor size, lymph node metastasis, and FIGO stage. High expression of GABPB1-AS1 was correlated with a poor prognosis for HPV16-positive CC patients. Functionally, E6-induced GABPB1-AS1 overexpression facilitated CC cells proliferation and invasion in vitro and in vivo. Mechanistically, GABPB1-AS1 acted as a competing endogenous RNA (ceRNA) by sponging miR-519e-5p, resulting in the de-repression of its target gene Notch2 which is well known as an oncogene. Therefore, GABPB1-AS1 functioned as a tumor activator in CC pathogenesis by binding to miR-519e-5p and destroying its tumor suppressive function. Collectively, current results demonstrate that GABPB1-AS1 is associated with CC progression, and may be a promising biomarker or target for the clinical management of CC.
人乳头瘤病毒 16（HPV16）是宫颈癌（CC）的主要致病因子。E6 癌蛋白在宫颈癌发生中起关键作用，通常导致长链非编码 RNA（lncRNAs）表达失调。然而，lncRNAs 在 HPV16 相关 CC 中的生物学功能仍在很大程度上未被探索。在本研究中，使用基于微阵列的分析鉴定了 HPV16 E6 诱导的 lncRNA、miRNA 和 mRNA 的差异表达，并在肿瘤细胞系和肿瘤组织中进行了验证，还在体外和体内研究了 lncRNA 在 CC 中的功能。我们发现，一种名为 GABPB1-AS1 的 lncRNA 在 HPV16 阳性 CC 组织和细胞系中显著上调。HPV16 阳性 CC 组织中 GABPB1-AS1 的表达与肿瘤大小、淋巴结转移和 FIGO 分期呈正相关。GABPB1-AS1 高表达与 HPV16 阳性 CC 患者的预后不良相关。功能上，E6 诱导的 GABPB1-AS1 过表达促进了 CC 细胞在体外和体内的增殖和侵袭。机制上，GABPB1-AS1 通过海绵吸附 miR-519e-5p 作为竞争性内源性 RNA（ceRNA），从而解除其靶基因 Notch2 的抑制， Notch2 是众所周知的癌基因。因此，GABPB1-AS1 通过与 miR-519e-5p 结合并破坏其肿瘤抑制功能，在 CC 发病机制中充当肿瘤激活物。总之，目前的结果表明，GABPB1-AS1 与 CC 进展相关，可能是 CC 临床管理有前途的生物标志物或靶标。
