Microrna let-7: an emerging next-generation cancer therapeutic

In recent years, various rna-based technologies have been under evaluation as potential next-generation cancer therapeutics. Micrornas (mirnas), known to regulate the cell cycle and development, are deregulated in various cancers. Thus, they might serve as good targets or candidates in an exploration of anticancer therapeutics. One attractive candidate for this purpose is let-7 (“lethal-7”). Let-7 is underexpressed in various cancers, and restoration of its normal expression is found to inhibit cancer growth by targeting various oncogenes and inhibiting key regulators of several mitogenic pathways. In vivo, let-7 administration was found effective against mouse-model lung and breast cancers, and our computational prediction supports the possible effectiveness of let-7 in estrogen receptor (er)–positive metastatic breast cancer. Data also suggest that let-7 regulates apoptosis and cancer stem cell (csc) differentiation and can therefore be tested as a potential therapeutic in cancer treatment. However, the exact role of let-7 in cancer is not yet fully understood. There is a need to understand the causative molecular basis of let-7 alterations in cancer and to develop proper delivery systems before proceeding to therapeutic applications. This article attempts to highlight certain critical aspects of let-7’s therapeutic potential in cancer.

[1]  C. Croce,et al.  Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[2]  Sanghyuk Lee,et al.  miRGator: an integrated system for functional annotation of microRNAs , 2007, Nucleic Acids Res..

[3]  B. Ramratnam,et al.  Enhanced gene silencing of HIV-1 specific siRNA using microRNA designed hairpins. , 2004, Nucleic acids research.

[4]  Torsten Haferlach,et al.  Distinctive microRNA signature of acute myeloid leukemia bearing cytoplasmic mutated nucleophosmin , 2008, Proceedings of the National Academy of Sciences.

[5]  H. Horvitz,et al.  The let-7 MicroRNA family members mir-48, mir-84, and mir-241 function together to regulate developmental timing in Caenorhabditis elegans. , 2005, Developmental cell.

[6]  Y. Yatabe,et al.  Reduced Expression of the let-7 MicroRNAs in Human Lung Cancers in Association with Shortened Postoperative Survival , 2004, Cancer Research.

[7]  K. Taira,et al.  U6 promoter–driven siRNAs with four uridine 3′ overhangs efficiently suppress targeted gene expression in mammalian cells , 2002, Nature Biotechnology.

[8]  N. Rajewsky,et al.  Silencing of microRNAs in vivo with ‘antagomirs’ , 2005, Nature.

[9]  J. Yisraeli VICKZ proteins: a multi‐talented family of regulatory RNA‐binding proteins , 2005, Biology of the cell.

[10]  E. Miska,et al.  miRNAs in cancer: approaches, aetiology, diagnostics and therapy. , 2007, Human molecular genetics.

[11]  C. Joo,et al.  Lin28 mediates the terminal uridylation of let-7 precursor MicroRNA. , 2008, Molecular cell.

[12]  Guiliang Tang,et al.  The Expression of MicroRNA miR-107 Decreases Early in Alzheimer's Disease and May Accelerate Disease Progression through Regulation of β-Site Amyloid Precursor Protein-Cleaving Enzyme 1 , 2008, The Journal of Neuroscience.

[13]  M. Stoffel,et al.  Mechanisms and optimization of in vivo delivery of lipophilic siRNAs , 2007, Nature Biotechnology.

[14]  Izumi Horikawa,et al.  Nutlin-3a activates p53 to both down-regulate inhibitor of growth 2 and up-regulate mir-34a, mir-34b, and mir-34c expression, and induce senescence. , 2008, Cancer research.

[15]  Jennifer Taylor,et al.  Polycistronic RNA polymerase II expression vectors for RNA interference based on BIC/miR-155 , 2006, Nucleic acids research.

[16]  Michael F Clarke,et al.  The biology of cancer stem cells. , 2007, Annual review of cell and developmental biology.

[17]  S. Freier,et al.  Improved targeting of miRNA with antisense oligonucleotides , 2006, Nucleic acids research.

[18]  Eric J Wagner,et al.  Both natural and designed micro RNAs can inhibit the expression of cognate mRNAs when expressed in human cells. , 2002, Molecular cell.

[19]  P. Platzer,et al.  Differential expression of PTEN-targeting microRNAs miR-19a and miR-21 in Cowden syndrome. , 2008, American journal of human genetics.

[20]  A. Forge,et al.  MicroRNAs and regeneration: Let-7 members as potential regulators of dedifferentiation in lens and inner ear hair cell regeneration of the adult newt. , 2007, Biochemical and biophysical research communications.

[21]  S. Knuutila,et al.  Increased expression of high mobility group A proteins in lung cancer , 2006, The Journal of pathology.

[22]  I. Screpanti,et al.  Expression of the HMGI(Y) gene products in human neuroblastic tumours correlates with differentiation status , 2000, British Journal of Cancer.

[23]  L. Johnston,et al.  Temporal Regulation of Metamorphic Processes in Drosophila by the let-7 and miR-125 Heterochronic MicroRNAs , 2008, Current Biology.

[24]  W. Filipowicz,et al.  Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? , 2008, Nature Reviews Genetics.

[25]  Tsung-Cheng Chang,et al.  Widespread microRNA repression by Myc contributes to tumorigenesis , 2008, Nature Genetics.

[26]  Phillip A Sharp,et al.  Suppression of non-small cell lung tumor development by the let-7 microRNA family , 2008, Proceedings of the National Academy of Sciences.

[27]  M. Stoffel,et al.  Specificity, duplex degradation and subcellular localization of antagomirs , 2007, Nucleic acids research.

[28]  Michael Z Michael,et al.  Reduced accumulation of specific microRNAs in colorectal neoplasia. , 2003, Molecular cancer research : MCR.

[29]  G. Daley,et al.  Selective Blockade of MicroRNA Processing by Lin28 , 2008, Science.

[30]  Anton J. Enright,et al.  Requirement of bic/microRNA-155 for Normal Immune Function , 2007, Science.

[31]  Yuriy Gusev,et al.  Real-time expression profiling of microRNA precursors in human cancer cell lines , 2005, Nucleic acids research.

[32]  H. Horvitz,et al.  MicroRNA Expression in Zebrafish Embryonic Development , 2005, Science.

[33]  L. Smirnova,et al.  A feedback loop comprising lin-28 and let-7 controls pre-let-7 maturation during neural stem-cell commitment , 2008, Nature Cell Biology.

[34]  K. Morimura,et al.  Peroxisome Proliferator-Activated Receptor α Regulates a MicroRNA-Mediated Signaling Cascade Responsible for Hepatocellular Proliferation , 2007, Molecular and Cellular Biology.

[35]  T. Kwok,et al.  Let-7a microRNA suppresses therapeutics-induced cancer cell death by targeting caspase-3 , 2008, Apoptosis.

[36]  Thomas D. Schmittgen,et al.  Human chromosome 21-derived miRNAs are overexpressed in down syndrome brains and hearts. , 2008, Biochemical and biophysical research communications.

[37]  C. Burge,et al.  Identification of let-7-regulated oncofetal genes. , 2008, Cancer research.

[38]  B. Cullen,et al.  Use of RNA polymerase II to transcribe artificial microRNAs. , 2005, Methods in enzymology.

[39]  R. Sachidanandam,et al.  A role for microRNAs in maintenance of mouse mammary epithelial progenitor cells , 2007 .

[40]  Sean J. Morrison,et al.  Hmga2 Promotes Neural Stem Cell Self-Renewal in Young but Not Old Mice by Reducing p16Ink4a and p19Arf Expression , 2008, Cell.

[41]  B. Monia,et al.  Therapeutic potential for microRNAs. , 2007, Advanced drug delivery reviews.

[42]  J. Lieberman,et al.  let-7 Regulates Self Renewal and Tumorigenicity of Breast Cancer Cells , 2007, Cell.

[43]  A. Pasquinelli,et al.  Genes and Mechanisms Related to RNA Interference Regulate Expression of the Small Temporal RNAs that Control C. elegans Developmental Timing , 2001, Cell.

[44]  Nóra Varga,et al.  Sensitive and specific detection of microRNAs by northern blot analysis using LNA-modified oligonucleotide probes. , 2004, Nucleic acids research.

[45]  P. Knoepfler Why myc? An unexpected ingredient in the stem cell cocktail. , 2008, Cell stem cell.

[46]  J. M. Thomson,et al.  Lin-28 interaction with the Let-7 precursor loop mediates regulated microRNA processing. , 2008, RNA.

[47]  Yong Zhao,et al.  Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis , 2005, Nature.

[48]  D. Katsaros,et al.  Hypermethylation of let-7a-3 in epithelial ovarian cancer is associated with low insulin-like growth factor-II expression and favorable prognosis. , 2007, Cancer research.

[49]  Manfred Kunz,et al.  MicroRNA let-7b targets important cell cycle molecules in malignant melanoma cells and interferes with anchorage-independent growth , 2008, Cell Research.

[50]  Michael T. McManus,et al.  Dysregulation of Cardiogenesis, Cardiac Conduction, and Cell Cycle in Mice Lacking miRNA-1-2 , 2007, Cell.

[51]  Ying Liu,et al.  Evolutionarily Conserved Transcriptional Co-Expression Guiding Embryonic Stem Cell Differentiation , 2008, PloS one.

[52]  M. Clarke,et al.  Cancer stem cells: models and concepts. , 2007, Annual review of medicine.

[53]  A. Antsaklis,et al.  CRD-BP/IMP1 Expression Characterizes Cord Blood CD34+ Stem Cells and Affects c-myc and IGF-II Expression in MCF-7 Cancer Cells* , 2005, Journal of Biological Chemistry.

[54]  Kenichi Sugihara,et al.  Clinical Significance of High Mobility Group A2 in Human Gastric Cancer and Its Relationship to let-7 MicroRNA Family , 2008, Clinical Cancer Research.

[55]  R. Yeh,et al.  MicroRNA regulation of cell lineages in mouse and human embryonic stem cells. , 2008, Cell stem cell.

[56]  Hong Duan,et al.  The regulatory activity of microRNA* species has substantial influence on microRNA and 3′ UTR evolution , 2008, Nature Structural &Molecular Biology.

[57]  G. Chiappetta,et al.  The expression of the high mobility group HMGI (Y) proteins correlates with the malignant phenotype of human thyroid neoplasias. , 1995, Oncogene.

[58]  Patricia Soteropoulos,et al.  MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. , 2007, Cancer research.

[59]  R. Bernards,et al.  A System for Stable Expression of Short Interfering RNAs in Mammalian Cells , 2002, Science.

[60]  Mark Gerstein,et al.  The temporal patterning microRNA let-7 regulates several transcription factors at the larval to adult transition in C. elegans. , 2005, Developmental cell.

[61]  S. Elledge,et al.  A lentiviral microRNA-based system for single-copy polymerase II-regulated RNA interference in mammalian cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[62]  F. Slack,et al.  RAS Is Regulated by the let-7 MicroRNA Family , 2005, Cell.

[63]  S. Kauppinen,et al.  LNA-modified oligonucleotides mediate specific inhibition of microRNA function. , 2006, Gene.

[64]  Mark Graham,et al.  miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. , 2006, Cell metabolism.

[65]  Lena Smirnova,et al.  The FASEB Journal • Research Communication Post-transcriptional regulation of the let-7 microRNA during neural cell specification , 2022 .

[66]  P. Dröge,et al.  Do cells let-7 determine stemness? , 2008, Cell stem cell.

[67]  A. Abderrahmani,et al.  MicroRNA-9 Controls the Expression of Granuphilin/Slp4 and the Secretory Response of Insulin-producing Cells* , 2006, Journal of Biological Chemistry.

[68]  M. Richards,et al.  The Transcriptome Profile of Human Embryonic Stem Cells as Defined by SAGE , 2004, Stem cells.

[69]  E. Kistner,et al.  Let-7 expression defines two differentiation stages of cancer , 2007, Proceedings of the National Academy of Sciences.

[70]  B. Louis,et al.  Enjoy the Silence: The Story of let-7 MicroRNA and Cancer. , 2007, Current genomics.

[71]  A. Delacourte,et al.  Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/β-secretase expression , 2008, Proceedings of the National Academy of Sciences.

[72]  Piotr Sliz,et al.  Determinants of MicroRNA Processing Inhibition by the Developmentally Regulated RNA-binding Protein Lin28* , 2008, Journal of Biological Chemistry.

[73]  W. Fang,et al.  Detection of let-7a MicroRNA by Real-time PCR in Colorectal Cancer: a Single-centre Experience from China , 2007, The Journal of international medical research.

[74]  Debmalya Barh,et al.  Let-7, miR-125, miR-205, and miR-296 are prospective therapeutic agents in breast cancer molecular medicine , 2008 .

[75]  Theresa A. Storm,et al.  Fatality in mice due to oversaturation of cellular microRNA/short hairpin RNA pathways , 2006, Nature.

[76]  Xianjun Wang,et al.  Detection of let-7a microRNA by real-time PCR in gastric carcinoma. , 2007, World journal of gastroenterology.

[77]  S. Morrison,et al.  Spatial differences in hematopoiesis but not in stem cells indicate a lack of regional patterning in definitive hematopoietic stem cells. , 2005, Developmental biology.

[78]  V. Tarasov,et al.  Differential Regulation of microRNAs by p53 Revealed by Massively Parallel Sequencing: miR-34a is a p53 Target That Induces Apoptosis and G1-arrest , 2007, Cell cycle.

[79]  M. Peter Let-7 and miR-200 microRNAs: Guardians against pluripotency and cancer progression , 2009, Cell cycle.

[80]  F. Slack,et al.  The let-7 microRNA reduces tumor growth in mouse models of lung cancer , 2008, Cell cycle.

[81]  F. Nielsen,et al.  A Family of Insulin-Like Growth Factor II mRNA-Binding Proteins Represses Translation in Late Development , 1999, Molecular and Cellular Biology.

[82]  Gaofeng Wang,et al.  Variation in the miRNA-433 binding site of FGF20 confers risk for Parkinson disease by overexpression of alpha-synuclein. , 2008, American journal of human genetics.

[83]  J. Weiler,et al.  Anti-miRNA oligonucleotides (AMOs): ammunition to target miRNAs implicated in human disease? , 2006, Gene Therapy.

[84]  Y. Atomi,et al.  An increased high-mobility group A2 expression level is associated with malignant phenotype in pancreatic exocrine tissue , 2003, British Journal of Cancer.

[85]  Todd R. Golub,et al.  MicroRNA Expression Signatures Accurately Discriminate Acute Lymphoblastic Leukemia from Acute Myeloid Leukemia. , 2007 .

[86]  F. Slack,et al.  The let-7 microRNA represses cell proliferation pathways in human cells. , 2007, Cancer research.

[87]  Xianjin Zhou,et al.  Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C , 1995, Nature.

[88]  Y. Akao,et al.  let-7 microRNA functions as a potential growth suppressor in human colon cancer cells. , 2006, Biological & pharmaceutical bulletin.

[89]  O. Maes,et al.  Murine microRNAs implicated in liver functions and aging process , 2008, Mechanisms of Ageing and Development.

[90]  Sun-Mi Park,et al.  Let-7 Prevents Early Cancer Progression by Suppressing Expression of the Embryonic Gene HMGA2 , 2007, Cell cycle.

[91]  M. Frasch A matter of timing: microRNA-controlled temporal identities in worms and flies. , 2008, Genes & development.

[92]  W. L. Ruzzo,et al.  MicroRNA Discovery and Profiling in Human Embryonic Stem Cells by Deep Sequencing of Small RNA Libraries , 2008, Stem cells.

[93]  Bing Yu,et al.  Construction and identification of a human liver specific microRNA eukaryotic expression vector. , 2007, Cellular & molecular immunology.

[94]  Asli Silahtaroglu,et al.  Altered MicroRNA expression confined to specific epithelial cell subpopulations in breast cancer. , 2007, Cancer research.

[95]  T. Hansen,et al.  Dwarfism and Impaired Gut Development in Insulin-Like Growth Factor II mRNA-Binding Protein 1-Deficient Mice , 2004, Molecular and Cellular Biology.

[96]  Danish Sayed,et al.  MicroRNAs Play an Essential Role in the Development of Cardiac Hypertrophy , 2007 .

[97]  Anindya Dutta,et al.  The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. , 2007, Genes & development.

[98]  J. Melamed,et al.  Antiproliferative Effects by Let-7 Repression of High-Mobility Group A2 in Uterine Leiomyoma , 2008, Molecular Cancer Research.

[99]  Y. Ishikawa,et al.  let-7 microRNA expression is reduced in bronchioloalveolar carcinoma, a non-invasive carcinoma, and is not correlated with prognosis. , 2007, Lung cancer.

[100]  A. Rougvie,et al.  Regulatory mutations of mir-48, a C. elegans let-7 family MicroRNA, cause developmental timing defects. , 2005, Developmental cell.

[101]  V. Ambros,et al.  Drosophila let-7 microRNA is required for remodeling of the neuromusculature during metamorphosis. , 2008, Genes & development.

[102]  W. Lukiw,et al.  Induction of specific micro RNA (miRNA) species by ROS-generating metal sulfates in primary human brain cells. , 2007, Journal of inorganic biochemistry.

[103]  C. Lengner,et al.  Oct4 expression is not required for mouse somatic stem cell self-renewal. , 2007, Cell stem cell.

[104]  Danish Sayed,et al.  MicroRNAs Play an Essential Role in the Development of Cardiac Hypertrophy , 2007, Circulation research.

[105]  B. Reinhart,et al.  The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans , 2000, Nature.

[106]  H. Soifer,et al.  MicroRNAs in disease and potential therapeutic applications. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[107]  D. Bartel,et al.  MicroRNAs Modulate Hematopoietic Lineage Differentiation , 2004, Science.

[108]  Jian-Fu Chen,et al.  The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation , 2006, Nature Genetics.

[109]  Zuoshang Xu,et al.  An RNA polymerase II construct synthesizes short-hairpin RNA with a quantitative indicator and mediates highly efficient RNAi , 2005, Nucleic acids research.

[110]  Stefanie Dimmeler,et al.  Role of Dicer and Drosha for Endothelial MicroRNA Expression and Angiogenesis , 2007, Circulation research.