Oncogenic KSHV-encoded interferon regulatory factor upregulates HMGB2 and CMPK1 expression to promote cell invasion by disrupting a complex lncRNA-OIP5-AS1/miR-218-5p network
Oncogenic KSHV-encoded interferon regulatory factor upregulates HMGB2 and CMPK1 expression to promote cell invasion by disrupting a complex lncRNA-OIP5-AS1/miR-218-5p network
复制标题
致癌 KSHV 编码的干扰素调节因子上调 HMGB2 和 CMPK1 表达，通过破坏复杂的 lncRNA-OIP5-AS1/miR-218-5p 网络促进细胞侵袭
DOI：
10.1371/journal.ppat.1007578
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发表时间：
2019-01-01
期刊：
影响因子：
6.7
通讯作者：
Lu, Chun
中科院分区：
文献类型：
--
作者：
Li, Wan;Wang, Qingxia;Lu, Chun
卡波西肉瘤（KS）是一种高度播散性的梭形内皮细胞过度增殖性肿瘤，是由卡波西肉瘤相关疱疹病毒（KSHV）感染引起的最常见的艾滋病相关恶性肿瘤。 KSHV 编码的病毒干扰素调节因子 1 (vIRF1) 是一种病毒癌基因，但其在 KSHV 诱导的肿瘤侵袭性和运动性中的作用仍不清楚。在此，我们报道vIRF1通过下调miR-218-5p以减轻其对下游靶标高迁移率族蛋白2（HMGB2）和胞苷/尿苷单磷酸激酶1（CMPK1）的抑制来促进内皮细胞迁移、侵袭和增殖。从机制上讲，vIRF1 抑制 p53 功能，增加 DNA 甲基转移酶 1 (DNMT1) 的表达和 pre-miR-218-1（miR-218-5p 的前体）启动子的 DNA 甲基化，并增加长非编码 RNA OIP5 反义 RNA 1 (lnc-OIP5-AS1) 的表达，该长链非编码 RNA OIP5 反义 RNA 1 (lnc-OIP5-AS1) 充当 miR-218-5p 的竞争性内源 RNA (ceRNA)抑制其功能并降低其稳定性。此外，lnc-OIP5-AS1 会增加 pre-miR-218-1 启动子的 DNA 甲基化。最后，从 KSHV 基因组中删除 vIRF1 会降低 lnc-OIP5-AS1 的水平，增加 miR-218-5p 的水平，并抑制 KSHV 诱导的入侵。总之，这些结果定义了一种新型复杂的 lnc-OIP5-AS1/miR-218-5p 网络，该网络被 vIRF1 劫持，以促进 KSHV 诱导的肿瘤的侵袭性和运动性。 KSHV 编码的病毒干扰素调节因子 1 (vIRF1) 是一种致癌蛋白，已被证明在 KSHV 逃避先天抗病毒反应和诱导肿瘤发生中至关重要，但其在 KS 肿瘤侵袭性和运动性中的作用仍不清楚。越来越多的文献提出lncRNA可以作为肿瘤抑制基因或癌基因，并且许多lncRNA可能作为竞争性内源RNA（ceRNA）竞争性地结合microRNA（miRNA），从而对转录后调控产生影响。然而，细胞lncRNA是否参与KS的进展仍不清楚。在这里，我们揭示了 vIRF1 在细胞运动和增殖中先前未定义的作用，并描述了参与 KS 发病机制的细胞 lncRNA 和 miRNA 的交叉调节网络。我们发现 miR-218-5p 和 lnc-OIP5-AS1 之间的串扰通过增加 HMGB2 和 CMPK1 表达来促进 vIRF1 诱导的细胞运动和增殖。总之，这项研究构成了与 KS 发病机制相关的重要发现，特别是在 KS 肿瘤的侵袭性和运动性方面。
Kaposi's sarcoma (KS), a highly disseminated tumor of hyperproliferative spindle endothelial cells, is the most common AIDS-associated malignancy caused by infection of Kaposi's sarcoma-associated herpesvirus (KSHV). KSHV-encoded viral interferon regulatory factor 1 (vIRF1) is a viral oncogene but its role in KSHV-induced tumor invasiveness and motility remains unknown. Here, we report that vIRF1 promotes endothelial cell migration, invasion and proliferation by down-regulating miR-218-5p to relieve its suppression of downstream targets high mobility group box 2 (HMGB2) and cytidine/uridine monophosphate kinase 1 (CMPK1). Mechanistically, vIRF1 inhibits p53 function to increase the expression of DNA methyltransferase 1 (DNMT1) and DNA methylation of the promoter of pre-miR-218-1, a precursor of miR-218-5p, and increases the expression of a long non-coding RNA OIP5 antisense RNA 1 (lnc-OIP5-AS1), which acts as a competing endogenous RNA (ceRNA) of miR-218-5p to inhibit its function and reduce its stability. Moreover, lnc-OIP5-AS1 increases DNA methylation of the pre-miR-218-1 promoter. Finally, deletion of vIRF1 from the KSHV genome reduces the level of lnc-OIP5-AS1, increases the level of miR-218-5p, and inhibits KSHV-induced invasion. Together, these results define a novel complex lnc-OIP5-AS1/miR-218-5p network hijacked by vIRF1 to promote invasiveness and motility of KSHV-induced tumors.Author summary Kaposi's sarcoma-associated herpesvirus (KSHV) infection caused Kaposi's sarcoma (KS), a highly disseminated tumor that frequently occurs in patients with AIDS. KSHV-encoded viral interferon regulatory factor 1 (vIRF1) is an oncogenic protein, which has been shown to be vital in KSHV evasion of innate antiviral response and induction of tumorigenesis but its role in KS tumor invasiveness and motility remains unclear. A growing volume of literatures has proposed that lncRNAs could function as tumor suppressors or oncogenes, and numerous lncRNAs might act as competing endogenous RNAs (ceRNAs) that competitively bind to microRNAs (miRNAs), hence exerting influence on posttranscriptional regulation. However, whether cellular lncRNAs are involved in the progression of KS is still unknown. Here, we revealed a previously undefined role of vIRF1 in cell motility and proliferation, and described the cross-regulatory network of cellular lncRNAs and miRNAs involved in the pathogenesis of KS. We found that the crosstalk between miR-218-5p and lnc-OIP5-AS1 contributed to vIRF1-induced cell motility and proliferation via increasing HMGB2 and CMPK1 expression. In summary, this study constitutes an important discovery related to KS pathogenesis, particularly in the invasiveness and motility of KS tumors.