Long noncoding RNAs (lncRNAs) play diverse roles in biological processes, but their expression profiles and functions in cervical carcinogenesis remain unknown. By RNA-sequencing (RNA-seq) analyses of 18 clinical specimens and selective validation by RT-qPCR analyses of 72 clinical samples, we provide evidence that, relative to normal cervical tissues, 194 lncRNAs are differentially regulated in high-risk (HR)-HPV infection along with cervical lesion progression. One such lncRNA, lnc-FANCI-2, is extensively characterized because it is expressed from a genomic locus adjacent to the FANCI gene encoding an important DNA repair factor. Both genes are up-regulated in HPV lesions and in in vitro model systems of HR-HPV18 infection. We observe a moderate reciprocal regulation of lnc-FANCI-2 and FANCI in cervical cancer CaSki cells. In these cells, lnc-FANCI-2 is transcribed from two alternative promoters, alternatively spliced, and polyadenylated at one of two alternative poly(A) sites. About 10 copies of lnc-FANCI-2 per cell are detected preferentially in the cytoplasm. Mechanistically, HR-HPVs, but not low-risk (LR)-HPV oncogenes induce lnc-FANCI-2 in primary and immortalized human keratinocytes. The induction is mediated primarily by E7, and to a lesser extent by E6, mostly independent of p53/E6AP and pRb/E2F. We show that YY1 interacts with an E7 CR3 core motif and transactivates the promoter of lnc-FANCI-2 by binding to two critical YY1-binding motifs. Moreover, HPV18 increases YY1 expression by reducing miR-29a, which targets the 3′ untranslated region of YY1 mRNA. These data have provided insights into the mechanisms of how HR-HPV infections contribute to cervical carcinogenesis.

长链非编码 RNA (lncRNA) 在生物过程中发挥着不同的作用，但它们在宫颈癌发生中的表达谱和功能仍然未知。通过对 18 个临床样本的 RNA 测序 (RNA-seq) 分析和通过对 72 个临床样本的 RT-qPCR 分析进行选择性验证，我们提供的证据表明，相对于正常宫颈组织，194 个 lncRNA 在高风险 (HR) 中受到差异调节-HPV感染伴随宫颈病变进展。一种这样的 lncRNA，lnc -FANCI-2 ，被广泛表征，因为它是从与编码重要 DNA 修复因子的FANCI基因相邻的基因组基因座表达的。这两个基因在 HPV 病变和 HR-HPV18 感染的体外模型系统中均上调。我们观察到适度的相互调节宫颈癌 CaSki 细胞中的 lnc-FANCI-2和FANCI 。在这些细胞中，lnc-FANCI-2从两个替代启动子转录，选择性剪接，并在两个替代多聚 (A) 位点之一进行多聚腺苷酸化。在细胞质中优先检测到每个细胞约 10 个lnc-FANCI-2拷贝。从机制上讲，HR-HPVs 而不是低风险 (LR)-HPV 致癌基因在原代和永生化人类角质形成细胞中诱导 lnc -FANCI-2 。诱导主要由 E7 介导，在较小程度上由 E6 介导，主要独立于 p53/E6AP 和 pRb/E2F。我们表明 YY1 与 E7 CR3 核心基序相互作用并反式激活lnc-FANCI-2的启动子通过与两个关键的 YY1 结合基序结合。此外，HPV18 通过减少 miR-29a 增加 YY1 的表达，miR-29a 靶向 YY1 mRNA 的 3' 非翻译区。这些数据提供了对 HR-HPV 感染如何促进宫颈癌发生机制的见解。