Genome-Wide Profiling of Cervical RNA-Binding Proteins Identifies Human Papillomavirus Regulation of RNASEH2A Expression by Viral E7 and E2F1
Genome-Wide Profiling of Cervical RNA-Binding Proteins Identifies Human Papillomavirus Regulation of RNASEH2A Expression by Viral E7 and E2F1
复制标题
宫颈 RNA 结合蛋白的全基因组分析鉴定了病毒 E7 和 E2F1 对 RNASEH2A 表达的人乳头瘤病毒调节
DOI：
10.1128/mbio.02687-18
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发表时间：
2019-01-01
期刊：
影响因子：
6.4
通讯作者：
Zheng，Zhi-Ming
中科院分区：
文献类型：
--
作者：
Xu，Junfen;Liu，Habin;Zheng，Zhi-Ming
宫颈癌的早期症状有哪些？本研究鉴定了HPV感染的宫颈组织样本和角质形成细胞中16个新基因（LY 6 K、FAM 83 A、CELSR 3、ASF 1B、IQGAP 3、SEMA 3F、CLDN 10、MSX 1、CXCL 5、ASRGL 1、ELAVL 2、GRB 7、KHSRP、NOVA 1、PTBP 1和RNASEH 2A）的差异表达。这些基因中的8个（CDKN 2A、ELAVL 2、GRB 7、HSPB 1、KHSRP、NOVA 1、PTBP 1和RNASEH 2A）编码RNA结合蛋白。进一步的研究表明，HPV 16和HPV 18感染均导致所选RBP编码基因的异常表达。我们发现病毒E6和E7降低NOVA 1表达，但E7通过E2 F1增加RNASEH 2A表达。这些基因的表达改变可用作高危（HR）-HPV致癌和进展的生物标志物。RNA结合蛋白（RBP）控制mRNA的加工、稳定性、转运、编辑和翻译。我们最近进行了转录组分析，健康）宫颈组织样品与人乳头瘤病毒（HPV）阳性宫颈癌组织样品的比较，并鉴定了614种差异表达的蛋白质编码转录物，这些转录物在癌症相关途径中富集，由95种已知的RBP组成。我们验证了26个基因的改变表达与一组72个宫颈样本，包括24个正常宫颈样本，25个宫颈上皮内瘤变2级（CIN 2）和CIN 3样本，和23个宫颈癌组织样本。LY 6 K（淋巴细胞抗原6复合物位点K）、FAM 83 A（具有序列相似性的家族成员83）、CELSR 3、ASF 1B、IQGAP 3、SEMA 3F、CLDN 10、MSX 1、CXCL 5、ASRGL 1、ELAVL 2、GRB 7、KHSRP、NOVA 1、PTBP 1和RNASEH 2A被鉴定为与宫颈病变进展和癌变相关的新候选基因。发现HPV 16或HPV 18感染改变人阴道和包皮角质形成细胞中8种RBP基因（CDKN 2A、ELAVL 2、GRB 7、HSPB 1、KHSRP、NOVA 1、PTBP 1和RNASEH 2A）的表达。病毒E6和E7均降低NOVA 1表达，但仅E7以E2 F1依赖性方式增加RNASEH 2A的表达。增殖细胞核抗原（PCNA）通过去除RNA引物来促进冈崎片段成熟，从而指导RNASEH 2在DNA复制方面的活性，并且两个因素与肿瘤进展密切相关。因此，我们预测通过病毒E7和E2 F1诱导RNASEH 2A的表达可能促进DNA复制和癌细胞增殖。宫颈癌的早期症状有哪些？本研究鉴定了HPV感染的宫颈组织样本和角质形成细胞中16个新基因（LY 6 K、FAM 83 A、CELSR 3、ASF 1B、IQGAP 3、SEMA 3F、CLDN 10、MSX 1、CXCL 5、ASRGL 1、ELAVL 2、GRB 7、KHSRP、NOVA 1、PTBP 1和RNASEH 2A）的差异表达。这些基因中的8个（CDKN 2A、ELAVL 2、GRB 7、HSPB 1、KHSRP、NOVA 1、PTBP 1和RNASEH 2A）编码RNA结合蛋白。进一步的研究表明，HPV 16和HPV 18感染均导致所选RBP编码基因的异常表达。我们发现病毒E6和E7降低NOVA 1表达，但E7通过E2 F1增加RNASEH 2A表达。这些基因的表达改变可用作高危（HR）-HPV致癌和进展的生物标志物。
High-risk HPV infections lead to development of cervical cancer. This study identified the differential expression of 16 novel genes (LY6K, FAM83A, CELSR3, ASF1B, IQGAP3, SEMA3F, CLDN10, MSX1, CXCL5, ASRGL1, ELAVL2, GRB7, KHSRP, NOVA1, PTBP1, and RNASEH2A) in HPV-infected cervical tissue samples and keratinocytes. Eight of these genes (CDKN2A, ELAVL2, GRB7, HSPB1, KHSRP, NOVA1, PTBP1, and RNASEH2A) encode RNA-binding proteins. Further studies indicated that both HPV16 and HPV18 infections lead to the aberrant expression of selected RBP-encoding genes. We found that viral E6 and E7 decrease NOVA1 expression but that E7 increases RNASEH2A expression via E2F1. The altered expression of these genes may be utilized as biomarkers for high-risk (HR)-HPV carcinogenesis and progression. ABSTRACT RNA-binding proteins (RBPs) control mRNA processing, stability, transport, editing, and translation. We recently conducted transcriptome analyses comparing normal (i.e., healthy) cervical tissue samples with human papillomavirus (HPV)-positive cervical cancer tissue samples and identified 614 differentially expressed protein-coding transcripts which are enriched in cancer-related pathways and consist of 95 known RBPs. We verified the altered expression of 26 genes with a cohort of 72 cervical samples, including 24 normal cervical samples, 25 cervical intraepithelial neoplasia grade 2 (CIN2) and CIN3 samples, and 23 cervical cancer tissue samples. LY6K (lymphocyte antigen 6 complex locus K), FAM83A (family member with sequence similarity 83), CELSR3, ASF1B, IQGAP3, SEMA3F, CLDN10, MSX1, CXCL5, ASRGL1, ELAVL2, GRB7, KHSRP, NOVA1, PTBP1, and RNASEH2A were identified as novel candidate genes associated with cervical lesion progression and carcinogenesis. HPV16 or HPV18 infection was found to alter the expression of 8 RBP genes (CDKN2A, ELAVL2, GRB7, HSPB1, KHSRP, NOVA1, PTBP1, and RNASEH2A) in human vaginal and foreskin keratinocytes. Both viral E6 and E7 decreased NOVA1 expression, but only E7 increased the expression of RNASEH2A in an E2F1-dependent manner. Proliferating cell nuclear antigen (PCNA) directs RNASEH2 activity with respect to DNA replication by removing the RNA primers to promote Okazaki fragment maturation, and two factors are closely associated with neoplasia progression. Therefore, we predict that the induction of expression of RNASEH2A via viral E7 and E2F1 may promote DNA replication and cancer cell proliferation. IMPORTANCE High-risk HPV infections lead to development of cervical cancer. This study identified the differential expression of 16 novel genes (LY6K, FAM83A, CELSR3, ASF1B, IQGAP3, SEMA3F, CLDN10, MSX1, CXCL5, ASRGL1, ELAVL2, GRB7, KHSRP, NOVA1, PTBP1, and RNASEH2A) in HPV-infected cervical tissue samples and keratinocytes. Eight of these genes (CDKN2A, ELAVL2, GRB7, HSPB1, KHSRP, NOVA1, PTBP1, and RNASEH2A) encode RNA-binding proteins. Further studies indicated that both HPV16 and HPV18 infections lead to the aberrant expression of selected RBP-encoding genes. We found that viral E6 and E7 decrease NOVA1 expression but that E7 increases RNASEH2A expression via E2F1. The altered expression of these genes may be utilized as biomarkers for high-risk (HR)-HPV carcinogenesis and progression.