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• W2045604306 abstract "The microRNA(miRNA)-34a is a key regulator of tumor suppression. It controls the expression of a plethora of target proteins involved in cell cycle, differentiation and apoptosis, and antagonizes processes that are necessary for basic cancer cell viability as well as cancer stemness, metastasis, and chemoresistance. In this review, we focus on the molecular mechanisms of miR-34a-mediated tumor suppression, giving emphasis on the main miR-34a targets, as well as on the principal regulators involved in the modulation of this miRNA. Moreover, we shed light on the miR-34a role in modulating responsiveness to chemotherapy and on the phytonutrients-mediated regulation of miR-34a expression and activity in cancer cells. Given the broad anti-oncogenic activity of miR-34a, we also discuss the substantial benefits of a new therapeutic concept based on nanotechnology delivery of miRNA mimics. In fact, the replacement of oncosuppressor miRNAs provides an effective strategy against tumor heterogeneity and the selective RNA-based delivery systems seems to be an excellent platform for a safe and effective targeting of the tumor. The microRNA(miRNA)-34a is a key regulator of tumor suppression. It controls the expression of a plethora of target proteins involved in cell cycle, differentiation and apoptosis, and antagonizes processes that are necessary for basic cancer cell viability as well as cancer stemness, metastasis, and chemoresistance. In this review, we focus on the molecular mechanisms of miR-34a-mediated tumor suppression, giving emphasis on the main miR-34a targets, as well as on the principal regulators involved in the modulation of this miRNA. Moreover, we shed light on the miR-34a role in modulating responsiveness to chemotherapy and on the phytonutrients-mediated regulation of miR-34a expression and activity in cancer cells. Given the broad anti-oncogenic activity of miR-34a, we also discuss the substantial benefits of a new therapeutic concept based on nanotechnology delivery of miRNA mimics. In fact, the replacement of oncosuppressor miRNAs provides an effective strategy against tumor heterogeneity and the selective RNA-based delivery systems seems to be an excellent platform for a safe and effective targeting of the tumor. MicroRNAs (miRNAs) are a class of small non-coding RNAs, which regulate gene expression at the post-transcriptional level and may conceivably play a key role in tumorigenesis. From the first demonstration in 2002.1Calin GA Dumitru CD Shimizu M Bichi R Zupo S Noch E et al.Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia.Proc Natl Acad Sci USA. 2002; 99: 15524-15529Crossref PubMed Scopus (2821) Google Scholar to the present, the involvement of miRNAs in human cancer has led to extensive research.2Volinia S Calin GA Liu CG Ambs S Cimmino A Petrocca F et al.A microRNA expression signature of human solid tumors defines cancer gene targets.Proc Natl Acad Sci USA. 2006; 103: 2257-2261Crossref PubMed Scopus (3447) Google Scholar,3Calin GA Croce CM MicroRNA signatures in human cancers.Nat Rev Cancer. 2006; 6: 857-866Crossref PubMed Scopus (3968) Google Scholar,4Croce CM Causes and consequences of microRNA dysregulation in cancer.Nat Rev Genet. 2009; 10: 704-714Crossref PubMed Scopus (1478) Google Scholar MiRNAs are dysregulated in almost all solid and hematological malignancies, and specific signatures allow the characterization of poorly differentiated tumors5Lu J Getz G Miska EA Alvarez-Saavedra E Lamb J Peck D et al.MicroRNA expression profiles classify human cancers.Nature. 2005; 435: 834-838Crossref PubMed Scopus (5447) Google Scholar as well as harbor relevant clinical implications.6Garzon R Marcucci G Croce CM Targeting microRNAs in cancer: rationale, strategies and challenges.Nat Rev Drug Discov. 2010; 9: 775-789Crossref PubMed Scopus (702) Google Scholar,7Ling H Fabbri M Calin GA MicroRNAs and other non-coding RNAs as targets for anticancer drug development.Nat Rev Drug Discov. 2013; 12: 847-865Crossref PubMed Scopus (318) Google Scholar,8Lionetti M Musto P Di Martino MT Fabris S Agnelli L Todoerti K et al.Biological and clinical relevance of miRNA expression signatures in primary plasma cell leukemia.Clin Cancer Res. 2013; 19: 3130-3142Crossref PubMed Scopus (37) Google Scholar,9Negrini M Cutrona G Bassi C Fabris S Zagatti B Colombo M et al.microRNAome Expression in Chronic Lymphocytic Leukemia: Comparison with Normal B-cell Subsets and Correlations with Prognostic and Clinical Parameters.Clin Cancer Res. 2014; 20: 4141-4153Crossref PubMed Scopus (16) Google Scholar MiRNAs, which are upregulated in cancer cells and contribute to carcinogenesis by inhibiting tumor suppressor genes, are considered oncogenic miRNAs (OncomiRs),10Esquela-Kerscher A Slack FJ Oncomirs - microRNAs with a role in cancer.Nat Rev Cancer. 2006; 6: 259-269Crossref PubMed Scopus (4042) Google Scholar while downregulated miRNAs, that normally prevent cancer development by inhibiting the expression of proto-oncogenes, are known as tumor suppressor miRNAs.11Dimopoulos K Gimsing P Grønbæk K Aberrant microRNA expression in multiple myeloma.Eur J Haematol. 2013; 91: 95-105Crossref PubMed Scopus (0) Google Scholar Silencing Oncomirs with miRNA inhibitors or replacing tumor suppressor miRNAs with synthetic miRNA mimics is demonstrating a valuable experimental strategy for the treatment of solid and hematological malignancies.12Tagliaferri P Rossi M Di Martino MT Amodio N Leone E Gulla A et al.Promises and challenges of MicroRNA-based treatment of multiple myeloma.Curr Cancer Drug Targets. 2012; 12: 838-846Crossref PubMed Scopus (55) Google Scholar,13Amodio N Di Martino MT Neri A Tagliaferri P Tassone P Non-coding RNA: a novel opportunity for the personalized treatment of multiple myeloma.Expert Opin Biol Ther. 2013; 13 (suppl. 1): S125-S137Crossref PubMed Scopus (25) Google Scholar,14Rossi M Amodio N Di Martino MT Caracciolo D Tagliaferri P Tassone P From target therapy to miRNA therapeutics of human multiple myeloma: theoretical and technological issues in the evolving scenario.Curr Drug Targets. 2013; 14: 1144-1149Crossref PubMed Scopus (21) Google Scholar,15Rossi M Amodio N Di Martino MT Tagliaferri P Tassone P Cho WC MicroRNA and Multiple Myeloma: from Laboratory Findings to Translational Therapeutic Approaches.Curr Pharm Biotechnol. 2014; 15: 459-467Crossref PubMed Google Scholar,16Tutar L Tutar E Tutar Y MicroRNAs and Cancer; an Overview.Curr Pharm Biotechnol. 2014; 15: 430-437Crossref PubMed Google Scholar,17Rolfo C Fanale D Hong DS Tsimberidou AM Piha-Paul SA Pauwels P et al.Impact of MicroRNAs in Resistance to Chemotherapy and Novel Targeted Agents in Non-Small Cell Lung Cancer.Curr Pharm Biotechnol. 2014; 15: 475-485Crossref PubMed Google Scholar,18Thorsen SB Obad S Jensen NF Stenvang J Kauppinen S The therapeutic potential of microRNAs in cancer.Cancer J. 2012; 18: 275-284Crossref PubMed Scopus (59) Google Scholar,19Bader AG miR-34 - a microRNA replacement therapy is headed to the clinic.Front Genet. 2012; 3: 120Crossref PubMed Scopus (267) Google Scholar,20Bovell LC Putcha BD Samuel T Manne U Clinical implications of microRNAs in cancer.Biotech HistoChem. 2013; 88: 388-396Crossref PubMed Scopus (9) Google Scholar MiRNAs with epigenetic or antiangiogenetic or modulatory activity within the microenvironment as well as with synergistic activity with chemotherapeutic agents are particularly promising in translational therapeutic approaches.21Amodio N Leotta M Bellizzi D Di Martino MT D'Aquila P Lionetti M et al.DNA-demethylating and anti-tumor activity of synthetic miR-29b mimics in multiple myeloma.Oncotarget. 2012; 3: 1246-1258Crossref PubMed Google Scholar,22Amodio N Di Martino MT Foresta U Leone E Lionetti M Leotta M et al.miR-29b sensitizes multiple myeloma cells to bortezomib-induced apoptosis through the activation of a feedback loop with the transcription factor Sp1.Cell Death Dis. 2012; 3: e436Crossref PubMed Scopus (71) Google Scholar,23Rossi M Pitari MR Amodio N Di Martino MT Conforti F Leone E et al.miR-29b negatively regulates human osteoclastic cell differentiation and function: implications for the treatment of multiple myeloma-related bone disease.J Cell Physiol. 2013; 228: 1506-1515Crossref PubMed Scopus (0) Google Scholar,24Leone E Morelli E Di Martino MT Amodio N Foresta U Gullà A et al.Targeting miR-21 inhibits in vitro and in vivo multiple myeloma cell growth.Clin Cancer Res. 2013; 19: 2096-2106Crossref PubMed Scopus (63) Google Scholar,25Di Martino MT Gullà A Cantafio ME Lionetti M Leone E Amodio N et al.In vitro and in vivo anti-tumor activity of miR-221/222 inhibitors in multiple myeloma.Oncotarget. 2013; 4: 242-255Crossref PubMed Google Scholar,26Amodio N Bellizzi D Leotta M Raimondi L Biamonte L D'Aquila P et al.miR-29b induces SOCS-1 expression by promoter demethylation and negatively regulates migration of multiple myeloma and endothelial cells.Cell Cycle. 2013; 12: 3650-3662Crossref PubMed Scopus (47) Google Scholar,27Leotta M Biamonte L Raimondi L Ronchetti D Martino MT Botta C et al.A p53-dependent tumor suppressor network is induced by selective miR-125a-5p inhibition in multiple myeloma cells in vitro.J Cell Physiol. 2014; 229: 2106-2116Crossref PubMed Scopus (29) Google Scholar,28Raimondi L Amodio N Di Martino MT Altomare E Leotta M Caracciolo D et al.Targeting of multiple myeloma-related angiogenesis by miR-199a-5p mimics: in vitro and in vivo anti-tumor activity.Oncotarget. 2014; 5: 3039-3054Crossref PubMed Google Scholar,29Suzuki H Maruyama R Yamamoto E Kai M DNA methylation and microRNA dysregulation in cancer.Mol Oncol. 2012; 6: 567-578Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar The miR-34 family consists of three members: miR-34a, miR-34b, and miR-34c; miR-34a is encoded by its own transcript, whereas miR-34b and miR-34c share a common primary transcript. In mice, miR-34a is ubiquitously expressed with the highest expression in brain, whereas miR-34b/c is mainly expressed in lung tissues. Moreover, miR-34a is expressed at higher levels than miR-34b/c, with the exception of the lung.30Hermeking H The miR-34 family in cancer and apoptosis.Cell Death Differ. 2010; 17: 193-199Crossref PubMed Scopus (585) Google Scholar Therefore, the two miR-34 genes have presumably tissue-specific functions, even though they are anyway direct transcriptional targets of the onco-suppressor p53, whose expression is greatly affected by DNA damage and oncogenic stress. miR-34 family, thus, contributes to p53 downstream effects on proliferation arrest and induction of apoptosis, by targeting c-MYC, CDK6, and c-MET.30Hermeking H The miR-34 family in cancer and apoptosis.Cell Death Differ. 2010; 17: 193-199Crossref PubMed Scopus (585) Google Scholar MiRNAs are originally transcribed as long hairpin molecules (pri-miRNAs) that are subsequently processed over several steps until DICER cuts them intoduplexes of their final 22–23 nt length. RNase III, human DROSHA, is the core nuclease that executes the initiation step of pri-miRNAs processing into stem-loop precursors of approximately 70 nucleotides (pre-miRNAs). DICER, a member of the RNase III superfamily of bidentate nucleases, mediates the cytoplasmic processing of pre-miRNAs into mature miRNAs. Thus, the two RNase III proteins, DROSHA and DICER, have key roles in miRNA-mediated gene regulation in processes such as development and differentiation. As a last step, one strand of the miRNA duplex (“mature strand”) is incorporated into the RNA-induced silencing complex (RISC) while the other is supposedly degraded. Once integrated into the RISC, miRNAs guide this protein complex to partially complementary binding sites located in the 3′ untranslated region (UTR) of target mRNAs and inhibit their expression either by interfering with translation or by destabilizing the target mRNA.31Di Martino MT Campani V Misso G Gallo Cantafio ME Gullà A Foresta U et al.In vivo activity of miR-34a mimics delivered by stable nucleic acid lipid particles (SNALPs) against multiple myeloma.PLoS ONE. 2014; 9: e90005Crossref PubMed Scopus (33) Google Scholar BRCA1 triggers miRNA biogenesis in collaboration with DROSHA microprocessor and SMADs/p53. In details, BRCA1 has been shown to trigger expression of let-7a-1, miR-16-1, miR-145, and miR-34a.32Di Martino MT Leone E Amodio N Foresta U Lionetti M Pitari MR et al.Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: in vitro and in vivo evidence.Clin Cancer Res. 2012; 18: 6260-6270Crossref PubMed Scopus (91) Google Scholar It has lately been shown that DICER1 depleted colorectal cancer cells revealed a notably higher expression of cancer stem cell markers such as Sox9, Sox2, Lgr5, CD44, and Nanog. Moreover, ectopic re-expression of miR-34a in both primary and tumor-derived cell lines was put in correlation with cycle arrest, apoptosis and cell growth inhibition.11Dimopoulos K Gimsing P Grønbæk K Aberrant microRNA expression in multiple myeloma.Eur J Haematol. 2013; 91: 95-105Crossref PubMed Scopus (0) Google Scholar Di Martino et al. have recently explored the molecular effects induced by enforced expression of miR-34a on multiple myeloma (MM) cells, showing a time-dependent modulation of several signaling pathways involved in the control of cell proliferation and apoptosis. The last group was the first one to have demonstrated a role of miR-34a in the pathogenesis of MM finding it downregulated in a wide series of MM samples.31Di Martino MT Campani V Misso G Gallo Cantafio ME Gullà A Foresta U et al.In vivo activity of miR-34a mimics delivered by stable nucleic acid lipid particles (SNALPs) against multiple myeloma.PLoS ONE. 2014; 9: e90005Crossref PubMed Scopus (33) Google Scholar,32Di Martino MT Leone E Amodio N Foresta U Lionetti M Pitari MR et al.Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: in vitro and in vivo evidence.Clin Cancer Res. 2012; 18: 6260-6270Crossref PubMed Scopus (91) Google Scholar The involvement of miR-34a in this haematological neoplasia can open a new scenario in understanding the molecular pathways involved in the generation of this disease from preneoplastic lesions such as monoclonal gammopathy. One of the most affected was the Erk/Akt-dependent pathway.31Di Martino MT Campani V Misso G Gallo Cantafio ME Gullà A Foresta U et al.In vivo activity of miR-34a mimics delivered by stable nucleic acid lipid particles (SNALPs) against multiple myeloma.PLoS ONE. 2014; 9: e90005Crossref PubMed Scopus (33) Google Scholar The authors demonstrated that miR-34a induces sequential down modulation of both Erk and Akt activity, which is followed by pro-caspase-6 and -3 cleavage and apoptosis induction in MM cells. Previously, the same authors have also showed the potential of miR-34a treatment in downregulating both Bcl-2 and NOTCH1 and in the induction of apoptosis both in vitro and in a xenograft mouse model.32Di Martino MT Leone E Amodio N Foresta U Lionetti M Pitari MR et al.Synthetic miR-34a mimics as a novel therapeutic agent for multiple myeloma: in vitro and in vivo evidence.Clin Cancer Res. 2012; 18: 6260-6270Crossref PubMed Scopus (91) Google Scholar In addition, downregulation of DICER in cancer cells was found to correlate with the promotion of metastasis. Intriguingly, DICER1 deficient colon cancer cells showed lower expression of EpCAM, indicating invasive potential, and significant over-expression of CD44 and other cancer stem cell markers. Increased metastatic potential in DICER1-impaired cells associated with the defective production of the miRNAs that regulate the pathways involved in this process, such as miR-34a, miR-126, and the miR-200 family.33Iliou MS da Silva-Diz V Carmona FJ Ramalho-Carvalho J Heyn H Villanueva A et al.Impaired DICER1 function promotes stemness and metastasis in colon cancer.Oncogene. 2014; 33: 4003-4015Crossref PubMed Scopus (0) Google Scholar MiR-34a has been also associated with regulation of cancer stem cells function in various cancer types such as prostate cancer,34Liu C Kelnar K Liu B Chen X Calhoun-Davis T Li H et al.The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44.Nat Med. 2011; 17: 211-215Crossref PubMed Scopus (657) Google Scholar pancreatic cancer,35Nalls D Tang SN Rodova M Srivastava RK Shankar S Targeting epigenetic regulation of miR-34a for treatment of pancreatic cancer by inhibition of pancreatic cancer stem cells.PLoS ONE. 2011; 6: e24099Crossref PubMed Scopus (129) Google Scholar medulloblastoma,36Stankevicins L Almeida da Silva AP Ventura Dos Passos F Dos Santos Ferreira E Menks Ribeiro MC David MG et al.MiR-34a is up-regulated in response to low dose, low energy X-ray induced DNA damage in breast cells.Radiat Oncol. 2013; 8: 231Crossref PubMed Scopus (0) Google Scholar glioblastoma.37Guessous F Zhang Y Kofman A Catania A Li Y Schiff D et al.microRNA-34a is tumor suppressive in brain tumors and glioma stem cells.Cell Cycle. 2010; 9: 1031-1036Crossref PubMed Google Scholar Furthermore, miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44, indicating the direct role of CD44 and miR-34a in cancer development and progression.34Liu C Kelnar K Liu B Chen X Calhoun-Davis T Li H et al.The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44.Nat Med. 2011; 17: 211-215Crossref PubMed Scopus (657) Google Scholar Consistently, Shi et al. described that overexpression of miR-34a inhibited CD44hi NSCLC cell growth in vitro and in xenograft tumors, demonstrating that miR-34a impairs tumors regeneration by negatively regulation of stem-like NSCLC.38Li Z Branham WS Dial SL Wang Y Guo L Shi L et al.Genomic analysis of microRNA time-course expression in liver of mice treated with genotoxic carcinogen N-ethyl-N-nitrosourea.BMC Genomics. 2010; 11: 609Crossref PubMed Scopus (24) Google Scholar In lung cancers, miR-34a has been evaluated as a replacement therapy candidate; in fact, exogenous miR-34a-mimics delivery was found to substantially reduce the tumor growth.39Yamakuchi M Lowenstein CJ MiR-34, SIRT1 and p53: the feedback loop.Cell Cycle. 2009; 8: 712-715Crossref PubMed Google Scholar In addition, a relative loss of miR-34a expression was considered a key etiologic factor in contributing to the aggressive behavior of lung cancer stem cells (CSC), and thus those features were mitigated by exogenous delivery and restoration of miR-34a activity.40Basak SK Veena MS Oh S Lai C Vangala S Elashoff D et al.The CD44(high) tumorigenic subsets in lung cancer biospecimens are enriched for low miR-34a expression.PLoS ONE. 2013; 8: e73195Crossref PubMed Scopus (0) Google Scholar MiRNAs are actively involved in the regulation of genes that are related to DNA damage and repair; therefore, changes in miRNA biogenesis and maturation processes are often associated with the response to these mechanisms. Recent studies show that transcription of miRNA can be directly affected by DNA damage. We have already underlined the critical role played by the p53 gene in this regulation and the p53-dependent modulation of miR-34a in response to DNA injury.30Hermeking H The miR-34 family in cancer and apoptosis.Cell Death Differ. 2010; 17: 193-199Crossref PubMed Scopus (585) Google Scholar Several studies have found that DNA damage-induced miR-34a expression was dependent on p53, and that this was followed by induction of cell cycle arrest, promotion of apoptosis, and DNA repair.36Stankevicins L Almeida da Silva AP Ventura Dos Passos F Dos Santos Ferreira E Menks Ribeiro MC David MG et al.MiR-34a is up-regulated in response to low dose, low energy X-ray induced DNA damage in breast cells.Radiat Oncol. 2013; 8: 231Crossref PubMed Scopus (0) Google Scholar Wild-type p53 expressing glioblastoma cell lines have been shown to respond to radiation and there was significantly higher DNA damage in post-irradiated cancer cells. Mechanistically, it has been shown that miR-34a-mediated negative regulation of p53-binding protein 1(53BP1) resulted in suppression of genomic instability in tumor cells.41Kofman AV Kim J Park SY Dupart E Letson C Bao Y et al.microRNA-34a promotes DNA damage and mitotic catastrophe.Cell Cycle. 2013; 12: 3500-3511Crossref PubMed Scopus (14) Google Scholar p53 can induce expression of miR-34a also in irradiated mice. Moreover, upregulation of miR-34a in response to genotoxic agent exposure is observed in different biological systems.38Li Z Branham WS Dial SL Wang Y Guo L Shi L et al.Genomic analysis of microRNA time-course expression in liver of mice treated with genotoxic carcinogen N-ethyl-N-nitrosourea.BMC Genomics. 2010; 11: 609Crossref PubMed Scopus (24) Google Scholar When DNA damage activates the p53 gene, p53 protein binds to the promoter of miR-34a and upregulates miRNA expression (Figure 1). MiR-34a is, in fact, a direct transcriptional target of p53 because the promoter region of miR-34a contains a canonical p53 binding site.39Yamakuchi M Lowenstein CJ MiR-34, SIRT1 and p53: the feedback loop.Cell Cycle. 2009; 8: 712-715Crossref PubMed Google Scholar The p53 network suppresses tumor formation through the coordinated activation of multiple transcriptional targets, and miR-34 may act in concert with other effectors to inhibit inappropriate cell proliferation. DNA damage signaling also affects the miRNA maturation biogenesis processes through the activation of the p53 gene. In fact, p53 binding to DROSHA facilitates the processing of pri-miRNAs in pre-miRNAs and mutation in the DNA-binding domain of p53 negatively affects this processing, thus reducing the expression of the related miRNAs. Moreover, in silico analyses, reveal that all three components of the p53 tumor suppressor, p53, p63, and p73, can regulate the major components of miRNA processing, such as DROSHA-DGCR8, DICER-TRBP2, and Argonaute proteins. In addition to being a direct transcriptional target of p53, miR-34a indirectly upregulates p53-dependent apoptosis through another intermediate protein, SIRT1,39Yamakuchi M Lowenstein CJ MiR-34, SIRT1 and p53: the feedback loop.Cell Cycle. 2009; 8: 712-715Crossref PubMed Google Scholar which has a well-conserved NAD-dependent sirtuin core domain, and catalyzes NAD-dependent deacetylation of several targets. Once activated, SIRT1 deacetylates also a variety of non-histone target proteins, such as p53, the retinoblastoma protein (Rb), FoxO transcription factors, Ku70, NFκB and PGC-1alpha. SIRT1-mediated deacetylation of p53 decreases the transcriptional activation and consequent protein expression of p53 downstream targets, such as p21 and PUMA.39Yamakuchi M Lowenstein CJ MiR-34, SIRT1 and p53: the feedback loop.Cell Cycle. 2009; 8: 712-715Crossref PubMed Google Scholar Therefore, SIRT1 mediates the survival of cells during periods of severe stress through the inhibition of apoptosis. MiR-34 inhibition of SIRT1 leads to an increase in p53 acetylation and p53 activity. As a result, miR-34 suppression of SIRT1 strengthens p53-mediated apoptosis. Simultaneously, increased p53, heightens miR-34a production, thus enhancing p53 stabilization and completing a positive feedback loop that protects cells from cellular oxidative stress and DNA damage. Bioinformatic approaches and cellular experiments have allowed identifying several mRNAs as direct miR-34a targets (Table 1). Most of them encode factors required for G1/S transition (c-MYC, E2F, CDK4, CDK6), anti-apoptotic proteins (Bcl2, SIRT1), and proteins involved in invasion (c-MET).30Hermeking H The miR-34 family in cancer and apoptosis.Cell Death Differ. 2010; 17: 193-199Crossref PubMed Scopus (585) Google Scholar MiRNAs regulate their targets via association of a 7 nucleotide stretch, the so-called seed-sequence, located in their 5′-portion with a complementary sequence in the 3′-UTR of the target mRNA.31Di Martino MT Campani V Misso G Gallo Cantafio ME Gullà A Foresta U et al.In vivo activity of miR-34a mimics delivered by stable nucleic acid lipid particles (SNALPs) against multiple myeloma.PLoS ONE. 2014; 9: e90005Crossref PubMed Scopus (33) Google Scholar Additional base pairing may occur via nucleotides in the middle and 3′-portion of the miRNA. Since the relatively short seed region is the primary determinant of target recognition, a single miRNA presumably regulates dozens or even hundreds of target mRNAs. Bioinformatic predictions suggest that several hundred mRNAs contain matches to the miR-34a seed sequence. Recently, proteomics analysis revealed early targets of miR-34a involved in neuroblastoma tumorigenesis.42De Antonellis P Carotenuto M Vandenbussche J De Vita G Ferrucci V Medaglia C et al.Early Targets of miR-34a in Neuroblastoma.Mol Cell Proteomics. 2014; 13: 2114-2131Crossref PubMed Scopus (5) Google Scholar,43Rothe K Lin H Lin KB Leung A Wang HM Malekesmaeili M et al.The core autophagy protein ATG4B is a potential biomarker and therapeutic target in CML stem/progenitor cells.Blood. 2014; 123: 3622-3634Crossref PubMed Scopus (0) Google Scholar However, the main miR-34a targets also confirmed by cellular experiments are summarized below and illustrated in the Figure 2.Table 1Main miR-34a targets. Sequence alignment based on bioinformatic predictions. Open table in a new tab Notch signaling pathway participates in a variety of cellular processes, including cell fate specification, differentiation, proliferation, apoptosis, adhesion, epithelial-mesenchymal transition, migration, and angiogenesis. Activation of Notch signaling contributes to the pathogenesis of several human neoplasms and its inhibition may be an effective therapeutic approach. Li et al., put for the first time in relation the augmented levels of Notch with the miR-34a downregulation in glioblastoma and medulloblastoma, showing that miR-34a targeted both Notch-1 and Notch-2.44Li Y Guessous F Zhang Y Dipierro C Kefas B Johnson E et al.MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes.Cancer Res. 2009; 69: 7569-7576Crossref PubMed Scopus (338) Google Scholar Furthermore, in cervical cancer and trophoblast cell lines, miR-34a was found to regulate the expression of Jagged-1 and its receptor Notch-1; enforced expression of miR-34a was related with the reduction of the invasion capacity Jagged-1 and Notch-1–mediated.45Pang RT Leung CO Ye TM Liu W Chiu PC Lam KK et al.MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells.Carcinogenesis. 2010; 31: 1037-1044Crossref PubMed Scopus (144) Google Scholar It is well acclaimed that Delta-like ligand-1 (Dll1) is a known ligand of the Notch-1 and Notch-2 receptors. It has been shown that Dll1 is negatively regulated by miR-34a. Medulloblastoma cells reconstituted with miR-34a displayed remarkably reduced expression of Dll1 that resulted in activation of Notch-1 mediated signaling, as evidenced by Notch-1 intracellular domain (NICD1) protein after 12 hours. Also, one of the target genes of Notch-1 signaling, HEY1 was noted to be increased. Interestingly, Notch-2 mediated signaling was inhibited in miR-34a reconstructed cancer cells, as evidenced by downregulation of NICD2 and of its known target: the Hairy and enhancer of split 1 (Hes1).46de Antonellis P Medaglia C Cusanelli E Andolfo I Liguori L De Vita G et al.MiR-34a targeting of Notch ligand delta-like 1 impairs CD15+/CD133+ tumor-propagating cells and supports neural differentiation in medulloblastoma.PLoS ONE. 2011; 6: e24584Crossref PubMed Scopus (0) Google Scholar Notably, since the Notch pathway is a critical regulator of asymmetric division of stem cells, Bu et al. described that well-differentiated colorectal cancer may perform either self-renewal or differentiated division depending on miR-34a levels. Specifically, low mir-34a levels upregulate notch signaling and promote symmetric division to produce colon cancer stem cells (CCSC), while asymmetric division and production of differentiated non-CCSC is controlled by high miR-34a levels that depress Notch signaling.47Bu P Chen KY Chen JH Wang L Walters J Shin YJ et al.A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells.Cell Stem Cell. 2013; 12: 602-615Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar,48Winton DJ miR-34a sets the “sweet spot” for notch in colorectal cancer stem cells.Cell Stem Cell. 2013; 12: 499-501Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar c-Myc is one of the major factors involved in tumor development. Thus, its inhibition by miR-34a binding in 3′ UTR region is thought to be a significant function of miR-34a. In primary renal cell carcinoma, miR-34a reduces the c-Myc–Miz–Skp2 transcriptional complex, which induces RhoA transcription and inhibits cell invasion. MiR-34a also directly suppresses formation of c-Myc–P-TEFb complex involved in the control of the elongation phase of transcription by Polymerase II. MiR-34a was also shown to strongly inhibit cell proliferation, in vivo xenograft tumor growth and cell invasion. Moreover, C-Myc resulted negatively regulated by miR-34a in kidney cancer cells and ChIP assay revealed that miR-34a suppressed the recruitment of c-Myc to the RhoA promoter.49Yamamura S Saini S Majid S Hirata H Ueno K Deng G et al.MicroRNA-34a modulates c-Myc transcriptional complexes to suppress malignancy in human prostate cancer cells.PLoS ONE. 2012; 7: e29722Crossref PubMed Scopus (0) Google Scholar A series of studies carried out in parallel with those about Notch, revealed that also c-Met is a known target of miR-34a and correlates to the metastasis potential of tumors. Enforced miR-34a expression downregulated c-Met oncogene and inhibited proliferation and metastasis of osteosarcoma cells,50Yan" @default.
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• W2045604306 title "Mir-34: A New Weapon Against Cancer?" @default.
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