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| Open AccessProteolysis of MOB1 by the ubiquitin ligase praja2 attenuates Hippo signalling and supports glioblastoma growth
Tumour suppressors can be inactivated in cancer not only as a result of mutation, but also by proteolytic degradation. Here the authors show that, during glioma development, the accumulation of the ubiquitin ligase praja2 sustains tumour growth by degrading MOB1—a core component of the Hippo pathway.
- Luca Lignitto
- , Antonietta Arcella
- & Antonio Feliciello
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Gene network reconstruction reveals cell cycle and antiviral genes as major drivers of cervical cancer
As cervical tumours become more invasive, levels of episomal human papillomavirus paradoxically tend to decrease. Here the authors identify a network of antiviral and cell cycle genes that is amplified by chromosomal aberrations and promotes cervical tumour progression.
- Karina L. Mine
- , Natalia Shulzhenko
- & Andrey Morgun
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Recruitment of mesenchymal stem cells into prostate tumours promotes metastasis
Cancer-associated fibroblasts promote tumour growth and metastasis by secreting signalling molecules. Jung and colleagues show that prostate cancer cells secrete CXC chemokine ligand 16, which recruits mesenchymal stem cells and converts them into cancer-associated fibroblasts.
- Younghun Jung
- , Jin Koo Kim
- & Russell S. Taichman
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Tyr26 phosphorylation of PGAM1 provides a metabolic advantage to tumours by stabilizing the active conformation
Tumour cells may undergo a dramatic metabolic shift in which glycolysis is favoured despite the presence of oxygen. By solving its crystal structure, Hitosugi et al. reveal how phosphorylation of the enzyme phosphoglycerate mutase 1 regulates glycolytic flux in cancer cells.
- Taro Hitosugi
- , Lu Zhou
- & Jing Chen
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SAPK pathways and p53 cooperatively regulate PLK4 activity and centrosome integrity under stress
Centrosome duplication during cell division is controlled by the polo-like kinase PLK4. Nakamura et al. reveal how stress-activated protein kinase and the tumour suppressor p53 act together to regulate PLK4, and show that their combined loss in cancer cells leads to the appearance of supernumerary centrosomes.
- Takanori Nakamura
- , Haruo Saito
- & Mutsuhiro Takekawa
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| Open AccessAssociation between Gαi2 and ELMO1/Dock180 connects chemokine signalling with Rac activation and metastasis
Chemokines promote breast cancer metastasis by stimulating re-organization of the actin cytoskeleton. Li et al. identify the human engulfment and cell motility protein ELMO1 as an intermediary between chemokine-dependent Gαi2 signalling and small GTPase signalling mediated by Rac.
- Hongyan Li
- , Lei Yang
- & Ning Zhang
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Rewiring of human lung cell lineage and mitotic networks in lung adenocarcinomas
Directly comparing patterns of gene expression in matched normal and cancerous tissues provides a powerful tool to identify drivers of tumour progression. Here the authors discover genes that are recruited into mitotic signalling networks in lung adenocarcinoma.
- Il-Jin Kim
- , David Quigley
- & Allan Balmain
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Microbiota-derived lactate accelerates colon epithelial cell turnover in starvation-refed mice
Epithelial cells in the colon mainly use microbial fermentation products as energy sources. Here Okada et al. find that lactate produced by commensal Lactobacillus murinusregulates colonic epithelial cell proliferation and show that mice are more susceptible to carcinogens when refed after a period of starvation.
- Toshihiko Okada
- , Shinji Fukuda
- & Taeko Dohi
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Monoallelic expression of TMPRSS2/ERG in prostate cancer stem cells
The TMPRSS2/ERG gene fusion is frequently expressed in prostate cancers, however, its clinical significance is unclear. Polsen et al. show that this gene fusion is expressed monoallelically in prostate cancer stem cells, and may influence their self-renewal and maintenance.
- Euan S. Polson
- , John L. Lewis
- & Norman J. Maitland
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Article
| Open AccessIdentification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31
Most confirmed susceptibility variants for epithelial ovarian cancer lie in non-protein-coding sequences. Here Permuth-Wey and colleagues investigate variants in 3′ untranslated regions (UTRs) and uncover a new susceptibility locus.
- Jennifer Permuth-Wey
- , Kate Lawrenson
- & Simon A. Gayther
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| Open AccessEpigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer
HNF1B is overexpressed in the clear cell subtype and epigenetically silenced in the serous subtype of ovarian cancer. Pearce and colleagues now show that genetic variants in HNF1B are differentially associated with risks of developing these two cancer subtypes, possibly through an epigenetic mechanism.
- Hui Shen
- , Brooke L. Fridley
- & Celeste Leigh Pearce
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PKA-induced dimerization of the RhoGAP DLC1 promotes its inhibition of tumorigenesis and metastasis
Deleted in Liver Cancer 1 (DLC1) is a tumour suppressor that inhibits metastasis by inactivating the small GTPase, RhoA. Here the authors reveal that DLC1 function is stimulated by protein kinase A, which induces phosphorylation-dependent DLC1 dimerization.
- Frankie Chi Fat Ko
- , Lo-Kong Chan
- & Judy Wai Ping Yam
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Aldara activates TLR7-independent immune defence
The skin cancer treatment Aldara generates psoriasis-like symptoms in mice, which are thought to be due to stimulation of TLR7 by the active ingredient imiquimod. The authors show that some of these inflammatory effects are independent of both imiquimod and TLR7, implicating an unexpected role for the vehicle.
- Anne Walter
- , Matthias Schäfer
- & Maries van den Broek
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Siva1 inhibits p53 function by acting as an ARF E3 ubiquitin ligase
The proapoptotic protein Siva1 has been shown to inhibit the tumour suppressor p53, however, it remains unclear how this activity is mediated. Here the authors show that Siva1 is an E3 ubiquitin ligase which inhibits p53 by promoting the degradation of ARF.
- Xingwu Wang
- , Meng Zha
- & Mian Wu
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Loss of TRPM2 function protects against irradiation-induced salivary gland dysfunction
A debilitating side effect of radiotherapy in patients with head and neck cancers is xerostomia as a result of salivary gland dysfunction. Here Liu et al. show that activation of the calcium channel TRPM2 in salivary gland cells contributes to irradiation-induced loss of salivary fluid secretion.
- Xibao Liu
- , Ana Cotrim
- & Indu Ambudkar
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LGALS3BP regulates centriole biogenesis and centrosome hypertrophy in cancer cells
Dysregulation of centrosome size and number is frequently associated with cancer. Fogeron et al. construct a protein-interaction network to identify proteins that are relevant for centrosome abnormalities in cancer, and show that deregulation of LGALS3BP affects centrosomal biogenesis.
- Marie-Laure Fogeron
- , Hannah Müller
- & Bodo M.H. Lange
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| Open AccessPI(4,5)P2 5-phosphatase A regulates PI3K/Akt signalling and has a tumour suppressive role in human melanoma
Inositol polyphosphate 5-phosphatases, such as PIB5PA, terminate signalling downstream of phosophoinositide-3 kinase; however, their biological roles remain unclear. Here the authors report that PIB5PA has a tumour suppressive role in melanoma.
- Yan Ye
- , Lei Jin
- & Xu Dong Zhang
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DNA replication timing and higher-order nuclear organization determine single-nucleotide substitution patterns in cancer genomes
Human cancer genomes often contain large amounts of single-nucleotide substitutions (SNS). Liu et al. catalogued SNS signatures across various cancer and normal genomes, demonstrating coordinative effects between replication timing and nuclear architecture on SNS patterns in cancer genomes.
- Lin Liu
- , Subhajyoti De
- & Franziska Michor
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Single-cell and subcellular pharmacokinetic imaging allows insight into drug action in vivo
Current pharmacokinetic models describe the distribution of drugs within tissues but usually lack single-cell resolution. Here Weissleder and colleagues visualize the subcellular distribution of an anticancer drug in real time in living animals and develop a model to extrapolate these findings to humans.
- Greg M. Thurber
- , Katy S. Yang
- & Ralph Weissleder
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| Open AccessReal-time single-molecule co-immunoprecipitation analyses reveal cancer-specific Ras signalling dynamics
Co-immunoprecipitation provides static and qualitative information about protein–protein interactions. Lee et al.create real-time movies of single protein–protein interactions during co-immunoprecipitation, and use them to assess the dynamics of mutant Ras proteins derived from tumours.
- Hong-Won Lee
- , Taeyoon Kyung
- & Tae-Young Yoon
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Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer
Diabetes and obesity pose an increased risk for breast cancer; however, the reasons for this link remain unclear. Di et al.provide evidence that CtBP, a metabolically regulated transcriptional repressor, regulates a gene network that is selectively downregulated in more aggressive forms of breast cancer.
- Li-Jun Di
- , Jung S. Byun
- & Kevin Gardner
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Src activation by β-adrenoreceptors is a key switch for tumour metastasis
The neurotransmitter noradrenaline can regulate cellular processes that contribute to cancer progression, but the underlying mechanisms remain largely unknown. Here the authors identify Src as a key mediator of noradrenaline signalling networks in tumour metastasis.
- Guillermo N. Armaiz-Pena
- , Julie K. Allen
- & Anil K. Sood
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| Open AccessComputational identification of a transiently open L1/S3 pocket for reactivation of mutant p53
About 40% of human cancers carry missense mutations in the tumour suppressor protein p53. Here the authors identify a transiently open pocket in the protein, and by targeting a small molecule to it, partially restore mutant p53 tumour suppressor activity.
- Christopher D. Wassman
- , Roberta Baronio
- & Rommie E. Amaro
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MicroRNA-30c inhibits human breast tumour chemotherapy resistance by regulating TWF1 and IL-11
The role of microRNAs in chemotherapy resistance remains to be elucidated. Bockhorn et al.report that microRNA-30c, a human breast tumour prognostic marker, has a key role by targeting the epithelial-to-mesenchymal transition promoter twinfilin 1 and downstream interleukin-11 expression.
- Jessica Bockhorn
- , Rachel Dalton
- & Huiping Liu
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Interaction between p68 RNA helicase and Ca2+-calmodulin promotes cell migration and metastasis
Cell migration requires motor protein-driven delivery of proteins to the leading edge. This study shows that p68 RNA helicase behaves as a microtubule-based motor upon binding calmodulin, and that blocking this interaction inhibits cancer cell metastasis.
- Haizhen Wang
- , Xueliang Gao
- & Zhi-Ren Liu
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Germinal centre protein HGAL promotes lymphoid hyperplasia and amyloidosis via BCR-mediated Syk activation
The human germinal centre-associated lymphoma gene is expressed in germinal centre B-lymphocytes; however, its function is unknown. Here the authors show that human germinal centre-associated lymphoma activates Syk kinase, leading to lymphoid hyperplasia and systemic reactive amyloid A amyloidosis in transgenic mice.
- Isabel Romero-Camarero
- , Xiaoyu Jiang
- & Izidore S Lossos
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Elevated oncofoetal miR-17-5p expression regulates colorectal cancer progression by repressing its target gene P130
Tumorigenesis has been likened to a form of cellular reversion to the embryonic state. Ma et al.identify a foetal miRNA as an oncogenic activator of the Wnt/β-catenin pathway in colorectal cancer, whose expression is negatively correlated with survival but is positively correlated with response to adjuvant chemotherapy.
- Yanlei Ma
- , Peng Zhang
- & Huanlong Qin
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Delivery of chemotherapeutic drugs in tumour cell-derived microparticles
Microparticles are small vesicular structures that are shed from cellular plasma membranes. Tang and colleagues show that cells treated with chemotherapeutic drugs produce drug-containing microparticles, which can be used as anticancer agents in mice.
- Ke Tang
- , Yi Zhang
- & Bo Huang
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Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism
ErbB2 is a receptor tyrosine kinase that localizes to the plasma membrane. Dinget al. now show that ErbB2 also localizes to mitochondria, where it regulates mitochondrial respiratory function and resistance to cancer chemotherapy.
- Yan Ding
- , Zixing Liu
- & Ming Tan
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A fast and accurate SNP detection algorithm for next-generation sequencing data
The amount of data supplied by next-generation sequencing technologies presents a challenge for traditional algorithms to detect single-nucleotide polymorphisms. Xu et al.develop an efficient detection program and demonstrate its utility by identifying polymorphisms in cancer genomes and human populations.
- Feng Xu
- , Weixin Wang
- & Junwen Wang
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Detection and differential diagnosis of colon cancer by a cumulative analysis of promoter methylation
Changes in the methylation pattern of gene promoters are hallmarks of certain cancers, such as colon cancer. Here Yang et al.identify and validate a set of genes and measure the cumulative methylation of promoters, which allows them to distinguish between two stages of colon cancer.
- Qiong Yang
- , Ying Dong
- & Shu Wang
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Self-luminescing BRET-FRET near-infrared dots for in vivo lymph-node mapping and tumour imaging
Fluorescence imaging in vivo is hampered by autofluorescence and the scattering and absorption of short-wavelength light. To address these problems, Xiong et al. produce self-luminescing nanoparticles that enable in vivonear-infrared imaging without external light excitation.
- Liqin Xiong
- , Adam J. Shuhendler
- & Jianghong Rao
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The metastasis-promoting S100A4 protein confers neuroprotection in brain injury
Multifunctional S100 proteins are upregulated in brain injury, but their role in neurodegeneration is not clear. Dmytriyeva and colleagues study in vivomodels of brain trauma and find that the S100A4 protein and its peptide mimetics protect neurons via the interleukin-10 receptor and the Janus kinase (JAK)/STAT pathway.
- Oksana Dmytriyeva
- , Stanislava Pankratova
- & Darya Kiryushko
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Sos-mediated cross-activation of wild-type Ras by oncogenic Ras is essential for tumorigenesis
The ras family of oncogenes consists of H-ras, K-ras and N-ras, and usually only one of these genes is mutated in a given tumour type. In this study, K-ras is found to promote the activation of wild-type H-ras and N-ras in a manner dependent on the Ras guanine nucleotide exchange factor Son of sevenless.
- Hao-Hsuan Jeng
- , Laura J Taylor
- & Dafna Bar-Sagi
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A combinatorial extracellular matrix platform identifies cell-extracellular matrix interactions that correlate with metastasis
Interactions of cells with extracellular matrix are important in normal physiology and cancer metastasis. Here, an extracellular matrix molecule array is developed and used to show that conserved changes in adhesive properties are associated with metastasis, including binding to fibronectin in combination with galectin-3, galectin-8 or laminin.
- Nathan E. Reticker-Flynn
- , David F. Braga Malta
- & Sangeeta N. Bhatia
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Insights into the biomedical effects of carboxylated single-wall carbon nanotubes on telomerase and telomeres
Single-walled carbon nanotubes can selectively stabilize telomeric i-motif DNA and have been suggested as a treatment for cancer. Here, carbon nanotubes are found to inhibit telomerase activity by stabilizing i-motif DNA, leading to telomere uncapping and altered telomere function in cancer cells.
- Yong Chen
- , Konggang Qu
- & Xiaogang Qu
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Article
| Open AccessEnhanced HSP70 lysine methylation promotes proliferation of cancer cells through activation of Aurora kinase B
HSP70 is a molecular chaperone that aids protein folding. In this study, HSP70 is shown to be methylated and this post-translationally modified protein is elevated in expression in human cancers and promotes the activity of Aurora kinase B.
- Hyun-Soo Cho
- , Tadahiro Shimazu
- & Ryuji Hamamoto
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TGFβ induces the formation of tumour-initiating cells in claudinlow breast cancer
TGF-β signalling suppresses tumorigenesis in breast cancer cells but its effects on breast cancer initiating cells have not been reported. Using cells in culture, Brunaet al. show that TGF-β increases breast cancer initiating cell numbers in cells that have low levels of the tight junction protein claudin.
- Alejandra Bruna
- , Wendy Greenwood
- & Carlos Caldas
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Article
| Open AccessHigh-fat or ethinyl-oestradiol intake during pregnancy increases mammary cancer risk in several generations of offspring
Environmental factors can influence one's susceptibility to cancer, but it is not clear whether such an influence extends beyond the directly exposed generations. Here, feeding pregnant rats with a high-fat diet or a hormone derivative, the authors observe increased breast cancer risk in up to three subsequent generations.
- Sonia de Assis
- , Anni Warri
- & Leena Hilakivi-Clarke
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Lysine methylation of VCP by a member of a novel human protein methyltransferase family
Methyltransferases modify cellular proteins in addition to DNA and histones. These authors identify a new family of lysine-specific methyltransferases and show that a member of this family, which is associated with tumour metastasis, methylates the ATP-dependent protein chaperone VCP/p97.
- Stefan Kernstock
- , Erna Davydova
- & Pål Ø. Falnes
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DNA replication timing and selection shape the landscape of nucleotide variation in cancer genomes
Cancer cells form by somatic mutations and natural selection, but how these factors affect tumorigenesis is not clear. Here, somatic mutations are characterized in human cancer genomes, revealing that DNA replication timing influences the frequency of single-nucleotide variants in different genomic regions.
- Yong H Woo
- & Wen-Hsiung Li
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FOXO3 signalling links ATM to the p53 apoptotic pathway following DNA damage
The protein ataxia-telangiectasia mutated (ATM) detects DNA damage and can trigger cellular apoptosis, but how this process is regulated at the molecular level is unclear. Here, Chunget al. show that the transcription factor FOXO3 controls the formation of ATM-containing signalling complexes at sites of DNA damage that trigger apoptosis.
- Young Min Chung
- , See-Hyoung Park
- & Mickey C.-T. Hu
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Ubiquitination and degradation of the FADD adaptor protein regulate death receptor-mediated apoptosis and necroptosis
Fas-associated protein with death domain (FADD) is part of a signalling complex that controls some forms of programmed cell death. Lee and colleagues demonstrate that FADD ubiquitination by the E3 ubiquitin ligase MKRN1 regulates FADD protein stability and thereby cell death.
- Eun-Woo Lee
- , Jung-Hoon Kim
- & Jaewhan Song
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Tumour lineage-homing cell-penetrating peptides as anticancer molecular delivery systems
Cell-penetrating peptides can be used to deliver nucleic acids and proteins to cells, however they lack selectivity. In this study, cell-penetrating peptides are generated that can selectively target tumour cells of different cellular origins and these may be useful in the treatment of cancer.
- Eisaku Kondo
- , Ken Saito
- & Masayuki Matsushita
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Article
| Open AccessProtein L-isoaspartyl methyltransferase regulates p53 activity
Protein L-isoaspartyl methyltransferase (PIMT) is a carboxyl methyltransferase, but its role in regulating the tumour suppressor p53 is unclear. Here, PIMT is shown to methylate p53, obstructing the tumour suppressor function of p53 through reduced protein levels and stability.
- Jae-Cheol Lee
- , Sung-Ung Kang
- & Jeung-Whan Han
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SUMO1 modification of PTEN regulates tumorigenesis by controlling its association with the plasma membrane
PTEN is a tumour suppressor that inhibits activation of the phosphatidylinositol 3-kinase pathway. These authors show that PTEN is SUMOylated on two lysine residues and that this modification is required for binding to acidic phospholipids and blocking tumour formation in mice.
- Jian Huang
- , Jie Yan
- & Jianxiu Yu
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Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell
CD44 is a cell surface protein that is a marker for stem cell-like cancer cells and has a role in invasion and metastasis. Here, epithelial splicing regulatory protein 1 is shown to generate a CD44 variant protein that enhances metastasis in a mouse model and protects cells from oxidative stress.
- Toshifumi Yae
- , Kenji Tsuchihashi
- & Osamu Nagano
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Article
| Open AccessMelanoma induction by ultraviolet A but not ultraviolet B radiation requires melanin pigment
Exposure to ultraviolet light is responsible for a large proportion of melanomas but the molecular mechanisms are unknown. In this study, melanoma is found to be induced in mice by UVA and UVB light in a pigment-dependent and -independent manner, respectively, resulting in different types of DNA damage.
- Frances P. Noonan
- , M. Raza Zaidi
- & Edward C. De Fabo
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Metformin elicits anticancer effects through the sequential modulation of DICER and c-MYC
Metformin is used to treat diabetes and its use has been associated with reduced cancer incidence, but the mechanism is unclear. In this study, metformin is shown to alter microRNA expression including an increase in mir-33a, which decreases the expression of the oncogenec-Myc.
- Giovanni Blandino
- , Mariacristina Valerio
- & Sabrina Strano
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