Therapeutic targeting of microRNAs: current status and future challenges

Li, Zhonghan; Rana, Tariq M.

doi:10.1038/nrd4359

Cited by 899 publications

(775 citation statements)

References 176 publications

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“…3B) and inversely correlates with beta‐catenin mRNA in CTNNB1 ‐deleted HBL tumors. These results suggest that the genetic status and transcriptional activity of beta‐catenin is linked to miRNA deregulation in cancer 11, 18, 34. Surprisingly, no inverse correlation was observed between the four decreased miRNAs and the level of total beta‐catenin mRNA in HBL tissues (Supporting Fig.…”

Section: Discussionmentioning

confidence: 89%

“…Because of their small size, easy manufacturing, biodisponibility, and pleiotropic effects, miRNAs are promising therapeutic molecules in clinical oncology 11, 12. Moreover, small noncoding RNA therapeutics are well tolerated in patients with manageable side effects 37.…”

Section: Discussionmentioning

confidence: 99%

“…Two miRNA replacement therapies are already involved in phase I clinical trials: MRX34 in patients with advanced liver cancer and TargomiR (miR‐26 mimic) in patients with malignant pleural mesothelioma and nonsmall‐cell lung cancer 11, 12. Given the rapid progress of siRNA and miRNA replacement therapy in cancer,11, 12 the identification of beta‐catenin‐regulating miRNAs provides new options to control the expression of this gene 10. Thus, miR‐624‐5p replacement therapy is a good option for the treatment of patients with HBL.…”

Section: Discussionmentioning

confidence: 99%

“…They guide the association of the RNA‐induced silencing complex with target messenger RNAs (mRNAs), mostly through interactions with the 3′‐untranslated region (UTR), resulting in translational repression and/or mRNA destabilization 11, 12. Deregulation of miRNA biogenesis and expression is a hallmark of cancer12 and has been reported in HBL 13, 14, 15.…”

Section: Introductionmentioning

confidence: 99%

“…Unlike small interfering RNAs (siRNAs), miRNAs can simultaneously target multiple genes involved in the same cellular pathways. This characteristic of miRNAs is an advantage for cancer therapy since tumors display specific signaling pathway alterations that can be controlled by single miRNAs 11, 12. Many miRNAs have been reported to target beta‐catenin: mature miRNA (miR)‐200a in human meningioma,16 members of the miR‐34 family in lung and breast carcinomas,17 miR‐483‐3p in breast and colon cancers,18 and miR‐214 in HCC 19.…”

Section: Introductionmentioning

confidence: 99%

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MicroRNA therapy inhibits hepatoblastoma growth in vivo by targeting β‐catenin and Wnt signaling

Indersie

Lesjean

Hooks

et al. 2017

Hepatology Communications

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Hepatoblastoma (HBL) is the most common pediatric liver cancer. In this malignant neoplasm, beta‐catenin protein accumulates and increases Wnt signaling due to recurrent activating mutations in the catenin‐beta 1 (CTNNB1) gene. Therefore, beta‐catenin is a key therapeutic target in HBL. However, controlling beta‐catenin production with therapeutic molecules has been challenging. New biological studies could provide alternative therapeutic solutions for the treatment of HBL, especially for advanced tumors and metastatic disease. In this study, we identified microRNAs (miRNAs) that target beta‐catenin and block HBL cell proliferation in vitro and tumor growth in vivo. Using our dual‐fluorescence‐FunREG system, we screened a library of 1,712 miRNA mimics and selected candidates inhibiting CTNNB1 expression through interaction with its untranslated regions. After validating the regulatory effect of nine miRNAs on beta‐catenin in HBL cells, we measured their expression in patient samples. Let‐7i‐3p, miR‐449b‐3p, miR‐624‐5p, and miR‐885‐5p were decreased in tumors compared to normal livers. Moreover, they inhibited HBL cell growth and Wnt signaling activity in vitro partly through beta‐catenin down‐regulation. Additionally, miR‐624‐5p induced cell senescence in vitro, blocked experimental HBL growth in vivo, and directly targeted the beta‐catenin 3′‐untranslated region. Conclusion: Our results shed light on how beta‐catenin‐regulating miRNAs control HBL progression through Wnt signaling inactivation. In particular, miR‐624‐5p may constitute a promising candidate for miRNA replacement therapy for HBL patients. (Hepatology Communications 2017;1:168‐183)

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

MicroRNA therapy inhibits hepatoblastoma growth in vivo by targeting β‐catenin and Wnt signaling

Indersie

Lesjean

Hooks

et al. 2017

Hepatology Communications

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Toward a structural understanding of nucleic acid‐sensing Toll‐like receptors in the innate immune system

2017

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The history of mankind has been plagued by the tug of war with viral infections. Toll-like receptors (TLRs) and other receptors of the innate immune system constitute an early defense system against invading viruses by recognizing the viral genetic material, the nucleic acids (NAs). Agonistic ligands of NA-sensing TLRs play an emerging role in the treatment of viral diseases, demonstrating a crucial role of these receptors. Recently, crystal structures have afforded new insights into TLR recognition of NAs. An aberrant activation by self-NAs, which leads to the inflammation and autoimmunity, is avoided by strict regulation of NA-TLR interaction at multiple check-points. This Review summarizes the novel structural understanding of NA-sensing by TLRs and regulatory mechanisms of these receptors.

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EMT‐ and MET‐related processes in nonepithelial tumors: importance for disease progression, prognosis, and therapeutic opportunities

2017

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The epithelial‐to mesenchymal (EMT) process is increasingly recognized for playing a key role in the progression, dissemination, and therapy resistance of epithelial tumors. Accumulating evidence suggests that EMT inducers also lead to a gain in mesenchymal properties and promote malignancy of nonepithelial tumors. In this review, we present and discuss current findings, illustrating the importance of EMT inducers in tumors originating from nonepithelial/mesenchymal tissues, including brain tumors, hematopoietic malignancies, and sarcomas. Among these tumors, the involvement of mesenchymal transition has been most extensively investigated in glioblastoma, providing proof for cell autonomous and microenvironment‐derived stimuli that provoke EMT‐like processes that regulate stem cell, invasive, and immunogenic properties as well as therapy resistance. The involvement of prominent EMT transcription factor families, such as TWIST, SNAI, and ZEB, in promoting therapy resistance and tumor aggressiveness has also been reported in lymphomas, leukemias, and sarcomas. A reverse process, resembling mesenchymal‐to‐epithelial transition (MET), seems particularly relevant for sarcomas, where (partial) epithelial differentiation is linked to less aggressive tumors and a better patient prognosis. Overall, a hybrid model in which more stable epithelial and mesenchymal intermediates exist likely extends to the biology of tumors originating from sources other than the epithelium. Deeper investigation and understanding of the EMT/MET machinery in nonepithelial tumors will shed light on the pathogenesis of these tumors, potentially paving the way toward the identification of clinically relevant biomarkers for prognosis and future therapeutic targets.

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Therapeutic targeting of microRNAs: current status and future challenges

Cited by 899 publications

References 176 publications

MicroRNA therapy inhibits hepatoblastoma growth in vivo by targeting β‐catenin and Wnt signaling

MicroRNA therapy inhibits hepatoblastoma growth in vivo by targeting β‐catenin and Wnt signaling

Toward a structural understanding of nucleic acid‐sensing Toll‐like receptors in the innate immune system

EMT‐ and MET‐related processes in nonepithelial tumors: importance for disease progression, prognosis, and therapeutic opportunities

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