miR-199a-3p Modulates MTOR and PAK4 Pathways and Inhibits Tumor Growth in a Hepatocellular Carcinoma Transgenic Mouse Model

Callegari, Elisa; D’Abundo, Lucilla; Guerriero, Paola; Simioni, Carolina; Elamin, Bahaeldin K.; Russo, Mara; Cani, Alice; Bassi, Cristian; Zagatti, Barbara; Giacomelli, Luciano; Blandamura, Stella; Moshiri, Farzaneh; Ultimo, Simona; Frassoldati, Antonio; Altavilla, Giuseppe; Gramantieri, Laura; Neri, Luca M.; Sabbioni, Silvia; Negrini, Massimo

doi:10.1016/j.omtn.2018.04.002

Cited by 83 publications

(88 citation statements)

References 51 publications

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“…In addition, AAV-mediated miR-199a/b-3p delivery by a single tail-vein injection in patient-derived orthotopic mice showed increased miRNA levels in tumor tissue, together with reduced tumor size, demonstrating the efficacy and nontoxicity of AAV8 vector system for potential HCC gene therapy [46]. Findings here obtained with miR-199a-3p-based therapeutics agree with those reported in the TG221 mice, proving the reliability of these animal models and suggesting miR-199a-3p replacement as a promising therapeutic option for human HCC [19].…”

Section: Patient-derived Xenograft Micesupporting

confidence: 80%

“…Since an miR-221 TG mouse also displays miR-199a-3p constitutive downregulation, miR-199a-3p mimics were adopted by using two experimental protocols: DEN priming in 10-day newborn mice followed by three IP injections per week for three weeks at three or five months of age. Both protocols showed a decreased number and size of nodules in miR-199a-3p mimics treated group with an anticancer effect similar to that observed in sorafenib-treated mice [19]. A decrease of mTOR and PAK4 protein expression was observed in HCC specimens from miRNA mimics treated animals, confirming similar mechanisms of action observed in other preclinical models, as well as in human HCCs [3,46].…”

Section: Mir-221 Tg Mousesupporting

confidence: 78%

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MicroRNAs in Animal Models of HCC

Fornari

Gramantieri

Callegari

et al. 2019

Cancers

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Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality. Molecular heterogeneity and absence of biomarkers for patient allocation to the best therapeutic option contribute to poor prognosis of advanced stages. Aberrant microRNA (miRNA) expression is associated with HCC development and progression and influences drug resistance. Therefore, miRNAs have been assayed as putative biomarkers and therapeutic targets. miRNA-based therapeutic approaches demonstrated safety profiles and antitumor efficacy in HCC animal models; nevertheless, caution should be used when transferring preclinical findings to the clinics, due to possible molecular inconsistency between animal models and the heterogeneous pattern of the human disease. In this context, models with defined genetic and molecular backgrounds might help to identify novel therapeutic options for specific HCC subgroups. In this review, we describe rodent models of HCC, emphasizing their representativeness with the human pathology and their usefulness as preclinical tools for assessing miRNA-based therapeutic strategies.

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Section: Patient-derived Xenograft Micesupporting

confidence: 80%

Section: Mir-221 Tg Mousesupporting

confidence: 78%

MicroRNAs in Animal Models of HCC

Fornari

Gramantieri

Callegari

et al. 2019

Cancers

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“…Because miR‐199a is the third most highly expressed miRNA in normal liver and its downregulation correlates with poor prognosis, Callegari et al investigated the tumor suppressive effects of miR‐199a using a transgenic mouse model of HCC. For their in vivo delivery experiments, they used lipid nanoparticles that were composed of 1,2‐dioleoyl‐sn‐glycero‐3‐phosphoethanolamine, 1,2‐dimyristoyl‐sn‐glycerol, methoxypolyethylene glycol, and linoleic acid at a ratio of 50:48:2, and demonstrated that miR‐199a exerted anti‐tumor activity against mouse HCC.…”

Section: Therapeutic Approaches Based On Mirna Regulationmentioning

confidence: 99%

“…[70][71][72] In addition to LNA-mediated suppression of miRNA, TS-miRNA replacement has been attempted using miRNA mimics, viral vectors expressing miRNA, and small compounds that regulate the endogenous expression of miRNA. 14,73,74 Because miR-199a is the third most highly expressed miRNA in normal liver and its downregulation correlates with poor prognosis, 75 Callegari et al 76 inhibition is also effective against other diseases. For example, miR-122 is a liver-specific miRNA that stimulates translation of HCV by interacting with the 5′UTR of the HCV genome.…”

Section: Ther Apeuti C Approache S Ba S Ed On Mirna Reg Ul Ati Onmentioning

confidence: 99%

Development of miRNA‐based therapeutic approaches for cancer patients

Takahashi

Prieto‐Vila

Kohama³

et al. 2019

Cancer Science

108

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Over the past few decades, si RNA and mi RNA have attracted a great deal of attention from researchers and clinicians. These molecules have been extensively studied from the standpoint of developing biopharmaceuticals against various diseases, including heart disease, diabetes and cancers. si RNA suppresses only a single target, whereas each mi RNA regulates the expression of multiple target genes. More importantly, because mi RNA are also secreted from cancer cells, and their aberrant expression is associated with tumor development and progression, they represent not only therapeutic targets but also promising biomarkers for diagnosis and prognosis. Therefore, mi RNA may be more effective tools against cancers, in which multiple signal pathways are dysregulated. In this review, we summarize recent progress in the development of mi RNA therapeutics for the treatment of cancer patients, and describe delivery systems for oligonucleotide therapeutics.

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“…Previous studies have reported that dysregulation of PAK4 expression contributes to the development and progression of various tumors [28,29]. Several studies have reported that PAK4 could be regulated by many miRNAs in various cancers, including miR-485 and miR-199a-3p [30][31][32]. In OSCC, PAK4 serves as a super enhancer-associated candidate oncogene and promotes the proliferation of OSCC cells [33].…”

Section: Discussionmentioning

confidence: 99%

Linc01234 promotes cell proliferation and metastasis in oral squamous cell carcinoma via miR-433/PAK4 axis

Liu

Jian

et al. 2020

BMC Cancer

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Background: Increasing studies have demonstrated that long non-coding RNAs (lncRNAs) play an important role in tumor progression. However, the potential biological functions and clinical importance of Linc01234 in oral squamous cell carcinoma (OSCC) remain unclear. Methods: We evaluated the expression profile and prognostic value of Linc01234 in OSCC tissues by RT-qPCR. Then, functional in vitro experiments were performed to investigate the effects of Linc01234 on tumor growth, migration and invasion in OSCC. Mechanistically, RT-qPCR, bioinformatic analysis and dual luciferase reporter assays were performed to identify a competitive endogenous RNA (ceRNA) mechanism involving Linc01234, miR-433-3p and PAK4. Results: We found that Linc01234 was clearly upregulated in OSCC tissues and cell lines, and its level was positively associated with T stage, lymph node metastasis, differentiation and poor prognosis of patients with OSCC. Our results shown that Linc01234 inhibited cell proliferation and metastatic abilities in CAL27 and SCC25 cells following its knockdown. Mechanistic analysis indicated that Linc01234 may act as a ceRNA (competing endogenous RNA) of miR-433-3p to relieve the repressive effect of miR-433-3p on its target PAK4. Conclusions:Our results indicated that Linc01234 promotes OSCC progression through the Linc01234/miR-433/ PAK4 axis and might be a potential therapeutic target for OSCC.

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miR-199a-3p Modulates MTOR and PAK4 Pathways and Inhibits Tumor Growth in a Hepatocellular Carcinoma Transgenic Mouse Model

Cited by 83 publications

References 51 publications

MicroRNAs in Animal Models of HCC

MicroRNAs in Animal Models of HCC

Development of miRNA‐based therapeutic approaches for cancer patients

Linc01234 promotes cell proliferation and metastasis in oral squamous cell carcinoma via miR-433/PAK4 axis

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