Cellular MicroRNA Let-7a Suppresses KSHV Replication through Targeting MAP4K4 Signaling Pathways

Tan, Xiaohua; Gao, Yuan; Nan, Yuemin; Zhang, Jinxia; Chen, Di; Wang, Xiaobo; Lian, Fuzhi; Cao, Yang; Hu, Yu; Xu, Liangwen; Ma, Haiyan; Yu, Hong; Liu, Tingjie; Wu, Yinyin; Xu, Xianrong; Yan, Yutao; Yang, Lei

doi:10.1371/journal.pone.0132148

Cited by 20 publications

(14 citation statements)

References 43 publications

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“…Tumors from both groups showed similar histology ( Figure 1—figure supplement 1 ) and MYC expression ( Figure 1I ). Gene-expression within tumors showed that previously validated let-7 targets involved in proliferation and growth including Cdc25a ( Johnson et al, 2007), Cdc34 ( Legesse-Miller et al, 2009 ), E2f2 ( Dong et al, 2010 ), E2f5 ( Kropp et al, 2015 ), and Map4k4 ( Tan et al, 2015 ) were upregulated in MYC -tumors, but suppressed back down to normal levels in the context of let-7 overexpression ( Figure 1J–L ), suggesting that the repression of these targets restrains MYC -dependent tumorigenesis. These data indicated that let-7g has potent tumor suppressor activity in the context of MYC -driven hepatoblastoma.…”

Section: Resultsmentioning

confidence: 90%

Precise let-7 expression levels balance organ regeneration against tumor suppression

Nguyen

Zhou

et al. 2015

eLife

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The in vivo roles for even the most intensely studied microRNAs remain poorly defined. Here, analysis of mouse models revealed that let-7, a large and ancient microRNA family, performs tumor suppressive roles at the expense of regeneration. Too little or too much let-7 resulted in compromised protection against cancer or tissue damage, respectively. Modest let-7 overexpression abrogated MYC-driven liver cancer by antagonizing multiple let-7 sensitive oncogenes. However, the same level of overexpression blocked liver regeneration, while let-7 deletion enhanced it, demonstrating that distinct let-7 levels can mediate desirable phenotypes. let-7 dependent regeneration phenotypes resulted from influences on the insulin-PI3K-mTOR pathway. We found that chronic high-dose let-7 overexpression caused liver damage and degeneration, paradoxically leading to tumorigenesis. These dose-dependent roles for let-7 in tissue repair and tumorigenesis rationalize the tight regulation of this microRNA in development, and have important implications for let-7 based therapeutics.DOI: http://dx.doi.org/10.7554/eLife.09431.001

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Section: Resultsmentioning

confidence: 90%

Precise let-7 expression levels balance organ regeneration against tumor suppression

Nguyen

Zhou

et al. 2015

eLife

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“…Furthermore, MAP4K4 is the upstream regulator of the ERK, JNK, and p38 MAPK signaling pathways. MAP4K4 contains a let - 7 target site in its 3′-UTR, indicating that let-7 family can regulate MAPK pathways by altering MAP4K4 expression levels 39 , 40 . Hsa-let-7c-5p can facilitate human enterovirus 71 replication by inhibiting MAP4K4 expression; this mechanism might explain the virus’s ability to subvert the JNK pathway 41 .…”

Section: Discussionmentioning

confidence: 99%

Hsa-let-7c controls the committed differentiation of IGF-1-treated mesenchymal stem cells derived from dental pulps by targeting IGF-1R via the MAPK pathways

Liu

et al. 2018

Exp Mol Med

102

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The putative tumor suppressor microRNA let-7c is extensively associated with the biological properties of cancer cells. However, the potential involvement of let-7c in the differentiation of mesenchymal stem cells has not been fully explored. In this study, we investigated the influence of hsa-let-7c (let-7c) on the proliferation and differentiation of human dental pulp-derived mesenchymal stem cells (DPMSCs) treated with insulin-like growth factor 1 (IGF-1) via flow cytometry, CCK-8 assays, alizarin red staining, real-time RT-PCR, and western blotting. In general, the proliferative capabilities and cell viability of DPMSCs were not significantly affected by the overexpression or deletion of let-7c. However, overexpression of let-7c significantly inhibited the expression of IGF-1 receptor (IGF-1R) and downregulated the osteo/odontogenic differentiation of DPMSCs, as indicated by decreased levels of several osteo/odontogenic markers (osteocalcin, osterix, runt-related transcription factor 2, dentin sialophosphoprotein, dentin sialoprotein, alkaline phosphatase, type 1 collagen, and dentin matrix protein 1) in IGF-1-treated DPMSCs. Inversely, deletion of let-7c resulted in increased IGF-1R levels and enhanced osteo/odontogenic differentiation. Furthermore, the ERK, JNK, and P38 MAPK pathways were significantly inhibited following the overexpression of let-7c in DPMSCs. Deletion of let-7c promoted the activation of the JNK and P38 MAPK pathways. Our cumulative findings indicate that Let-7c can inhibit the osteo/odontogenic differentiation of IGF-1-treated DPMSCs by targeting IGF-1R via the JNK/P38 MAPK signaling pathways.

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“…For example, let-7b have been reported to inhibit hepatitis C virus (HCV) infectivity by interacting with the HCV genome 37 . Let-7a suppresses Kaposi’s sarcoma-associated herpesvirus (KSHV) replication through targeting of MAP4K4 signaling pathways 38 . Let-7g inhibits hepatitis B virus (HBV) preS2 protein expression and generation of viral products 39 .…”

Section: Discussionmentioning

confidence: 99%

MicroRNA let-7f-5p Inhibits Porcine Reproductive and Respiratory Syndrome Virus by Targeting MYH9

Yan

et al. 2016

Sci Rep

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Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important viral pathogens in the swine industry. Current antiviral strategies do not effectively prevent and control PRRSV. Recent reports show that microRNAs (miRNAs) play vital roles in viral infections by post transcriptionally regulating the expression of viral or host genes. Our previous research showed that non-muscle myosin heavy chain 9 (MYH9) is an essential factor for PRRSV infection. Using bioinformatic prediction and experimental verification, we demonstrate that MYH9 expression is regulated by the miRNA let-7f-5p, which binds to the MYH9 mRNA 3′UTR and may play an important role during PRRSV infection. To understand how let-7f-5p regulates PRRSV infection, we analyzed the expression pattern of both let-7f-5p and MYH9 in porcine alveolar macrophages (PAMs) after infection with either highly pathogenic PRRSV (HP-PRRSV) or classical type PRRSV (N-PRRSV) using a deep sequencing approach with quantitative real-time PCR validation. Our results showed that both HP-PRRSV and N-PRRSV infection reduced let-7f-5p expression while also inducing MYH9 expression. Furthermore, let-7f-5p significantly inhibited PRRSV replication through suppression of MYH9 expression. These findings not only provide new insights into the pathogenesis of PRRSV, but also suggest potential new antiviral strategies against PRRSV infection.

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Cellular MicroRNA Let-7a Suppresses KSHV Replication through Targeting MAP4K4 Signaling Pathways

Cited by 20 publications

References 43 publications

Precise let-7 expression levels balance organ regeneration against tumor suppression

Precise let-7 expression levels balance organ regeneration against tumor suppression

Hsa-let-7c controls the committed differentiation of IGF-1-treated mesenchymal stem cells derived from dental pulps by targeting IGF-1R via the MAPK pathways

MicroRNA let-7f-5p Inhibits Porcine Reproductive and Respiratory Syndrome Virus by Targeting MYH9

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