MicroRNA miR-155 Inhibits Bone Morphogenetic Protein (BMP) Signaling and BMP-Mediated Epstein-Barr Virus Reactivation

Abstract

Despite the limited genetic content of microRNAs, their pervasive role in controlling normal and pathology-associated cellular processes has become firmly established in recent years. The importance of microRNA dysregulation in cancer is well appreciated, and a number of oncomirs and tumor suppressor microRNAs have been identified (15). As a member of the oncomir class of microRNAs, miR-155 is implicated in lymphomagenesis and a wide array of nonlymphoid tumors including breast, colon, and lung (7,16,24,39,42,43). Despite strong evidence implicating miR-155 in cancer etiology, the mechanisms through which miR-155 supports the tumor phenotype are unclear, possibly due to limited knowledge of how predicted targets may be involved in the phenotypic properties of cancer. On the other hand, miR-155's roles in normal immune cell development and the adaptive immune response are much better understood (33, 41). These studies have demonstrated a critical role for miR-155 in immune cell activation and maturation. This evidence and other work (8, 40) have identified critical miR-155 targets whose downregulation is required for these processes.The Epstein-Barr virus (EBV) is a human DNA tumor virus that contributes to lymphoid and epithelial cell malignancies. As a herpesvirus, a unique aspect of the EBV infection cycle is the ability to exist in either a lytic replicative state or in a latent state in which no virus is produced. Depending in part on cell background, EBV utilizes multiple forms of latency gene expression programs. True latency and type I latency are defined by the expression of no protein coding genes or by expression of the episomal replication factor EBNA1 only. Type II latency is defined by the expression of EBNA1 and the latent membrane proteins, LMP1 and/or LMP2, and is the predominant form observed in epithelial tissues. Type III latency refers to expression of the full repertoire of latency genes, which are highly tumorigenic and are capable of growth-transforming naïve resting B cells. While this form of latency is not well tolerated in immunocompetent individuals except during early stages of infection (prior to the development of adaptive immunity to these proteins), type III latency-associated lymphoid malignancies are common in immunocompromised individuals. Expression of type III latency genes in B cells mimics antigen-dependent B-cell activation, and accompanying this activation is a substantial induction of miR-155 expression (17,20,23,29,44). While it is reasonable to assume that induction of miR-155 by the type III latency program plays a role in EBV-mediated B-cell activation and oncogenesis, little is known regarding the role of miR-155 in the virus life cycle or its tumorpromoting activities.Originally identified as cytokines critically involved in the regulation of osteogenic differentiation, bone morphogenetic proteins (BMPs) are now appreciated as having critical functions in a vast number of developmental processes. Dysregulation of BMP signaling is also implicated in disease states ...

Transcriptome and targetome analysis in MIR155 expressing cells using RNA-seq

“…(Yin et al 2010). Quantitative PCR analysis of all three of these genes and Western blot analysis of SMAD1 and SMAD5 showed inhibition by MIR155 in Mutu I cells (Yin et al 2010). The targeting of the MYO10 regulators, SMAD1 and SMAD5, in addition to the targeting of the MYO10 39 UTR, illustrates a reinforcing mechanism that leads to greater suppression of MYO10 function.…”

“…Both scenarios may explain discordant 39 UTR reporter/ NGS data that cannot be explained by altered transcript structure. KLRA1 and HAL (this study), and SMAD1 and MYO10 (see below) (Yin et al 2010; this study), are examples of genes showing relative expression of 0.6 or less in 39 UTR assays but whose relative expression at the endogenous RNA level was found to be z50% of their 39 UTR relative expression levels. These genes appear to be true targets of MIR155, but the greater observed regulation at the transcript level suggests a reinforcing component to the regulation of these genes.…”

“…These genes appear to be true targets of MIR155, but the greater observed regulation at the transcript level suggests a reinforcing component to the regulation of these genes. (Yin et al 2010). Quantitative PCR analysis of all three of these genes and Western blot analysis of SMAD1 and SMAD5 showed inhibition by MIR155 in Mutu I cells (Yin et al 2010).…”

Epstein–Barr Virus Infection as an Epigenetic Driver of Tumorigenesis

“…Depletion of miR-155 suppressed S-phase progression and induced apoptosis. miR-155 was also reported to target components of the BMP signaling cascade, including SMAD1, SMAD5, HIVEP2, CEBPB, RUNX2, and MYO10 (24). Antitumor effects of BMP signaling (25) could be inhibited by miR-155 through downregulation of these mediators.…”

Identification of Lung Cancer Related Function Modules Based on Co-Expression Network

“…联：Nomori H.和 Mori T.等人 [38] 经过四年，对 212 个 肺癌患者的跟踪研究发现， HTLV-I 病毒可能是与验证 或者免疫反应有关的细支气管肺泡癌的致病风险。此 外，对于模块 351 中包含的基因 SMAD5 和 PPCS，现 有研究 [39,40] 发现它们是与 Epstein-Barr(EB)病毒相关 的，而 Guertler A.等人 [41] 又发现 EB 病毒可以从年轻的 肺癌患者身上发现放射性敏感性。而模块中的另一个 基因 FUT6，Norden R.等人 [42] 发现疱疹病毒可以通过 基于共表达网络挖掘肺癌相关模块 Copyright © 2013 Hanspub …”