the emerging roles of micrornas in cancer metabolism

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Cancer Letters xxx (2014) xxx–xxx

CAN 12080 No. of Pages 8, Model 5G

23 October 2014

Contents lists available at ScienceDirect

Cancer Letters

journal homepage: www.elsevier .com/locate /canlet

Mini-review

Roles of microRNA in cancer metabolism

http://dx.doi.org/10.1016/j.canlet.2014.10.0110304-3835/Published by Elsevier Ireland Ltd.

⇑ Corresponding author at: Basic Research Laboratory, Stem cell and AnimalAging Section, National Cancer Institute, Frederick, MD 21702, USA. Tel.: +1 301 846733.

E-mail address: [email protected] (S.R. Singh).

Please cite this article in press as: B. Chan et al., Roles of microRNA in cancer metabolism, Cancer Lett. (2014), http://dx.doi.org/1j.canlet.2014.10.011

Brian Chan, Jacob Manley, Jae Lee, Shree Ram Singh ⇑Basic Research Laboratory, National Cancer Institute, Frederick, MD 21702, USA

a r t i c l e i n f o a b s t r a c t

25262728293031323334

Article history:Received 9 October 2014Accepted 9 October 2014Available online xxxx

Keywords:CancerMetabolismMicroRNAsGlycolysisTCA cycleCancer therapy

The major task of cancer therapy to destroy cancer cells without harming normal cells. However, becausecancer cells have incredible heterogeneity and adaptability, it is difficult to target them therapeutically.Metabolic reprogramming has emerged as a common feature of cancer. Ever since microRNAs (miRNAs)have been found to influence metabolism, researchers have been trying to address the connectionbetween cancer cells and specific miRNAs. Many of the well-known miRNAs relate with crucial genes thatcan impact metabolic pathways, both negatively and positively. With a better understanding of howdifferent pathways are affected, the roles of miRNAs will be more transparent, which could lead todiscovering new ideas about the concept of tumorigenesis and other cancer-related topics.

Published by Elsevier Ireland Ltd.

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Introduction

MicroRNAs (miRNAs) are non-coding, 18–24 nucleotide-longRNAs that attach to the 30 untranslated region (UTR) of a targetmRNA, resulting in altered gene expression [1,2]. The first miRNAlin-4, and its target lin-14 were discovered in C. elegans [3,4]. Sincethen a large number of miRNAs have been identified and conservedfrom worms to mammals. miRNA biogenesis initiates withtranscription, followed by several processing steps to produce themature miRNA. miRNAs are originally transcribed by RNA pol IIin the nucleus to produce primary miRNA transcripts (pri-miRNA)[5]. In the next step, a protein known as Pasha binds to Drosha, aRNase III enzyme, to form a microprocessor complex [6–13]. Thiscomplex is able to cleave the stem-loop portion of the pri-miRNAto result in a precursor miRNA (pre-miRNA) sequence. The result-ing sequence is then ready to be exported to the cytoplasm withthe help of exportin 5, which is a RanGTP dependent transporterprotein [14,15]. Once it is in the cytoplasm, the pre-miRNA isconverted to a miRNA: miRNA* duplex due to its interaction withDicer and TRBP [16–18]. The duplex unwinds at this point andthe miRNA* strand is degraded. Meanwhile, an Argonaute proteinis brought in and RISC assembly occurs so that the mature miRNAcan bind with a target mRNA [19]. Once it is bound, translationalrepression or target mRNA cleavage can ensue, depending on thecomplementarity of the strands. mRNAs are conserved across all

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organisms and are involved in many physiological and pathologicalprocesses including development, tissue homeostasis, cell prolifer-ation, tissue growth, cell death, neurogenesis, metabolism, immu-nity, cell fate determination, stem cells, aging, and cancer [20–30].

Altered metabolism is a common feature of cancer. Normally,non-cancerous cells catabolize glucose by oxidative phosphoryla-tion in the mitochondria to produce ATP [31]. However, proliferat-ing cancer cells metabolize significant amounts of glucose intolactate, even in the presence of normal oxygen. These ideas stemfrom an observation known as the ‘‘Warburg effect’’ [32]. The pref-erence to utilize glycolysis offers several advantages to cancer cellsincluding adaptation in hypoxic and acidic environments (lactateproduction), which help cancer cells in invasion, and rapid prolifer-ation [33,34]. Oxidative stress and high levels of ROS (reactionoxygen species) in cells play a crucial role in tumor formation. Can-cer cells use pyruvate and nicotinamide adenine dinucleotidephosphate (NADPH) to counter high oxidative stress [35].

Since it was discovered that miRNAs are abnormally expressedin cancer, accumulative studies show that miRNAs play importantroles in tumor growth by regulating oncogenes and tumor suppres-sor genes [20,30,36,37]. In the last few years, a large number ofmiRNAs have been identified to regulate cancer metabolism[31,38–53]; Table 1. Carbohydrate, protein, lipid, and nucleic acidmetabolism are all affected by miRNAs that influence the growthand production of cells. Many researchers seem to focus oncarbohydrate/glucose metabolism far more than other types ofmetabolism (e.g. lipid) when it comes to cancer metabolism, butit is beneficial to look at metabolism in a broader view sincemiRNAs are involved in all these metabolic processes. Because of

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the importance of metabolism in cancer, studying the role of miR-NAs is crucial in understanding their effect on metabolic pathways,and their ultimate effect on cancer cells. Here we present a briefoverview on the involvement of miRNAs in cancer metabolismand their targets in cancer therapy.

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miRNAs in cancer metabolism

miRNAs in glucose metabolism

As seen with the Warburg effect, alterations in glucose metab-olism can result in the proliferation of cancer cells. One reasonfor this effect can be attributed to specific modifications from miR-NAs in the glycolysis pathway. There are a large number of miRNAsreported to regulate gene transcription and expression of glucosetransporters (GLUTs). Of the 14 members of the GLUT familyreported, only 11 of them facilitate glucose transport. However,only three of the GLUTs (GLUT1, GLUT2, and GLUT3) are highlyexpressed in most cancer tissues [54]. Deregulation of GLUTsresults in high glucose uptake, accelerated metabolism, andincreased glucose requirements by tumorous tissues. miRNAs canpossibly control the glucose uptake by regulating the expressionof some GLUTs in cancer tissues. It has been reported that mir-195-5p directly regulates the expression of GLUT3 in bladder can-cer [55]. In addition, Yang et al. [56] also reported that miR-21 reg-ulates the expression of GLUT1 and GLUT3 in bladder cancer.Further, a study involving renal cell carcinoma showed that miR-1291 regulates the GLUT1 expression [57].

Accumulative studies suggest that miRNAs control severalessential enzymes of glycolysis including hexokinases (HKs), glyc-eraldehyde-3-phosphate dehydrogenase (GAPDH), and 6-phosp-hofructo-1-kinase (PFK1). HKs catalyze the first reversible step ofglucose metabolism and exist in four isoforms HK1 through HK4.Among them is HK2, which is frequently overexpressed in cancerand plays an important role in tumor growth, survival, and metas-tasis by repressing mitochondrial function [58]. It has been demon-strated that miR-143 down-regulates HK2 and inhibits glucosemetabolism in head and neck squamous cell carcinoma (HNSCC)[59], breast cancer [60], lung cancer [61], and colon cancer [62].In addition, Zhao et al. [63] reported that miR-143 is downregu-lated in human and rat glioblastoma and the overexpression ofmiR-143 inhibits glycolysis by downregulating HK2. Jiang et al.[64] have shown that miR-155 promotes HK2 transcription bythe activation of signal transducer and activator of transcription3 (STAT3), and represses miR-143 by targeting c/EBPb. Further,miR-125a/b reported to regulate HK2 in lung cancer [61], miR-125b in hepatocellular carcinoma cells [64], and in chronic lym-phocytic leukemia [65]. Furthermore, p53-inducible miR-34arepressed HK1 and HK2 in lung and colon cancer [66]. In addition,miR-34a and miR-21 regulate the expression of HK1 and HK2 incolon cancer [66], and bladder cancer [56].

In addition to HKs, other components in glycolysis are regulatedby miRNAs as well. Aldolase A (Aldo A), a glycolytic enzyme, whichcatalyzes the reversible conversion of fructose-1,6-bisphosphate toglyceraldehyde 3-phosphate and dihydroxyacetone phosphate, isshown to be a target of miR-122 in liver cancer [67] and miR-15a/16-1 inhibit the expression of Aldo A, aldehyde dehydrogenase6 family, member A1 (Aldo6A1) and triosephosphate isomerase 1(TPI1) in leukemia [68]. Further, TPI1 is also reported to beregulated by miR-195 in bladder cancer [69]. Further, it has beenreported that Glucose-6-phosphate isomerase (PGI), an enzy-me that catalyzes the conversion of glucose-6-phosphate into fruc-tose 6-phosphate in the second step of glycolysis, regulates theexpression of miR-200 in breast cancer cells [53]. In addition, astudy demonstrated that miR-29a regulates the expression of

Please cite this article in press as: B. Chan et al., Roles of microRNAj.canlet.2014.10.011

Phosphoglucomutase-1 (PGM1), Enolase 1 (ENO1) and Phospho-glycerate kinase 1 (PGK1) in lung cancer cell lines [70]. In the lastfew years, pyruvate kinase muscle isozyme (PKM2) has emerged asa major player in cancer development because it gives metabolicadvantage to cancer cells to utilize phosphor-metabolitesupstream of pyruvate as precursors for the synthesis of lipids,amino acids and nucleic acids [41,71,72]. There are several miRNAsregulating the expression of PKM1 and PKM2 such as miR-99, miR-133a and 133b, miR-326, miR-124, miR-137, miR-340, miR-122and miR-21 [56,72–76]; see Table 1. During aerobic glycolysis,most of the pyruvate is converted to lactate in the cytoplasm byenzyme lactate dehydrogenase (LDH). Lactate is then secreted out-side of the cells by monocarboxylate transporter 1 (MCT1), whichin humans is encoded by the SLC16A1 gene. Li et al. [77] demon-strated that miR-124 is a direct regulator of SLC16A1 in medullo-blastoma cells. Further, miR-375 is involved in regulation oflactate dehydrogenase B (LDHB), an enzyme that catalyzes thereversible conversion of lactate and pyruvate, and NAD and NADH,in the glycolytic pathway, in maxillary sinus squamous cell carci-noma [78].

miRNAs in TCA cycle, ROS and glutamine metabolism

Like glycolysis, the tricarboxylic acid (TCA) cycle has also seen avariety of miRNAs that target the steps in this pathway. Cancercells mostly utilize aerobic glycolysis (lactate production) thanthe TCA cycle. These changes in metabolism allow cancer cells toproduce crucial biosynthesis materials by maintaining high ATPlevels. It was predicted that miR-103 and miR-107 controlsacetyl-coA and lipid levels by upregulating the pantothenatekinase (PanK), the first enzyme in the Coenzyme A biosyntheticpathway that phosphorylates pantothenate to form 40-phospho-pantothenate [79]. There are several other miRNAs that are knownto downregulate or upregulate the expression of metabolic associ-ated genes. miR-183 regulates isocitrate dehydrogenase 1 (IDH2)in glioma cells [80]. miR-210 regulates the TCA cycle by targetingiron-sulfur cluster assembly proteins (ISCU1/2), cytochrome c oxi-dase10 (COX10), succinate dehydrogenase, subunit D (SDHD), ADHdehydrogenase (ubiquinone) 1 alpha subcomplex, 4 (NDUFA4) inseveral cancers [81–84], miR-1 and miR-206 regulates glycerol-3-phosphate dehydrogenase 2 (GPD2) [48], and miR-378* also reg-ulates the TCA cycle in breast cancer [85].

Production of ROS is a crucial component of cellular metabolismthat is generated by mitochondria and NADPH oxidases (NOX)[86]. A recent study demonstrates that miR-17* can suppresstumorigenicity in prostate cancer by inhibiting the importantmitochondrial antioxidant enzymes such as manganese superoxidedismutase (MnSOD), glutathione peroxidase-2 (GPX2), and thiore-doxin reductase-2 (TrxR2) [87]. Studies suggest that ROS levels arealso regulated by several other miRNAs such as miR-17-92, miR-126, miR-128a, miR-141, miR-200, miR-21, miR-34a, miR-210,miR-122, miR-335, and miR-320 [82,88–92,43,93].

Glutaminase is crucial in mitochondrial metabolism as it con-verts glutamine to glutamate, which further converts to producea-ketoglutarate. Glutaminolysis is also controlled by several miR-NAs [94–96]. Further, studies suggest that p53, which is a directtarget of miR-125b, miR-30, miR-504, plays an essential role insustaining glutamine levels by activating GLS2 [97]. In addition,it has been demonstrated that Myc downregulates mir-23a and23b in lymphoma and prostate cancer cells and increases gutamin-ase expression [96]. Since autophagy plays a crucial role in cancercell survival when there is decreased oxygen, insufficient nutrients,and metabolic stress, it has been demonstrated that miR-23b cansuppress autophagy by regulating ATG12 in pancreatic cancer cells[98].

in cancer metabolism, Cancer Lett. (2014), http://dx.doi.org/10.1016/



Table 1MicroRNAs, targets, and regulation of cancer metabolism.

microRNAs Target genes Metabolic activity/Pathway Phenotypes/cancer types References

miR-210 ISCU Hypoxia, Krebs cycle,glycolysis

Breast, colon, head and neckcancer

Favaro et al. [81]

ISCU, COX10 Hypoxia, ROS, glycolysis Colon, breast, andesophageal cancer

Chen et al. [82]

SDHD, NDUFA4, ISCU1/2 HIF-1a, ETC Non-small cell lung cancer Puissegur et al. [83]ISCU1/2 Hypoxia, ROS, TCA cycle,

ETCHuman colorectaladenocarcinoma, breastcancer, promyelocyticLeukemia cell lines

Chan et al. [84]

miR-122 SMARCD1, MAP3K3, CAT-1 Mitochondrial metabolism,Krebscycle

Hepatocellular carcinoma Burchard et al. [89]

PKM2 Glycolysis Hepatocellular carcinoma Liu et al. [73]AldoA, TPI1 Glycolysis Leukemia Calin et al. [68]Agpat1, Cidec, Stard4 Lipid metabolism Liver cancer Hsu et al. [103]

Tsai et al. [104]

miR-155/miR-143 HK2 Aerobic glycolysis Breast cancer Jiang et al. [60]

miR-143 HK2 Glycolysis, Glucosemetabolism

Human lung cancer Fang et al. [61]Human and ratglioblastoma,

Zhao et al. [63]

colon cancer cell line, Gregersen et al [62]head and neck squamouscell carcinoma

Peschiaroli et al. [59]

miR-23a/miR-23b GLS2 c-Myc, glutaminemetabolism,gluconeogenesis, STAT3

Lymphoma and prostatecancer cells, hepatocellularcarcinoma

Gao et al. [94]PGC-1a, G6PC Wang et al. [95]

miR-23b ATG12 Autophagy Pancreatic cancer cells Wang et al. [98]mir-23b* POX/PRODH c-Myc, proline and

glutamine metabolismLymphoma and prostatecancer

Liu et al. [96]

miR-26a PDHX Glucose metabolism Colorectal cancer cells Chen et al. [29]

miR-34a HK1, HK2, GP1, PDK1 P53, glucose metabolism Human Non-small cell lungand colon cancer cell lines

Kim et al. [66]

NOX2 ROS Human glioma cell line Li et al. [93]

miR-21 SOD3 and TNFa ROS Human bronchial epithelialcell lines

Zhang et al. [91]

GLUT1, GLUT3, LDHA,LDHB, HK1, HK2, PKM,HIF-1a

PTEN/PI3K/AKT/mTOR pathways,aerobic glycolysis

Bladder cancer Yang et al. [56]

miR-326 PKM2 AMPK Glioblastoma Kefas et al. [75]miR-126 IRS1 Mitochondrial energy

metabolism, AKT signalingMesothelioma Tomasetti et al. [43]

miR-451 CAB39 LKB1/AMPK Glioblastoma Godlewski et al. [110]miR-185, miR-342 SREBP-1, SREBP-2, FASN,

HMGCRSREBP-lipogenesis-cholesterogenesis

Prostate cancer cells Li et al. [76]

miR-320 PFKm Glycolysis Human lungadenocarcinoma

Tang et al. [47]

miR-1, miR-206 G6PD, TKT, 6PGD, GPD2 Carbon flux toward the PPPand the TCA cycle,reprogramming glucosemetabolism

Human lung carcinoma andprostate cancer cell lines

Singh et al. [48]

miR-378* ESRRG, GABPA, ERRc Shift from aerobic, oxidativemetabolism (OXPHOS) toglycolytic metabolism

Human breast cancer Eichner et al. [85]

miR-124, miR-137, miR-340 PKM alternative splicing Inhibit the glycolysis rate,elevate the glucose flux intooxidative phosphorylation(glucose metabolism)

Colorectal cancer Sun et al. [72]Proteins (PTB1, hnRNAPA1,hnRNAPA2)

miR-124 SLC16A1 Eflux lactic acid duringaerobic glycolysis

Medulloblastoma Li et al. [77]

PKM1, HNF4a Glucose metabolism Colorectal cancer cells Sun et al. [125]miR-125 HK2 Glucose metabolism Human hepatocellular

carcinoma cellsJiang et al. [64]

miR-125b PCTP, LIPA, GSS, ACSS1, HK2,SCD1, AKT2, PDK1

Glucose, glutathione, lipid,and glycerolipidmetabolism

chronic lymphocyticleukemias

Tili et al. [65]

miR-181a PTEN Glycolysis, PTEN/AKTpathway

Colon cancer cells Wei et al. [49]

miR-183 IDH2 TCA cycle Glioma cells Tanaka et al. [80]miR-520 PFKP Glycolysis Hepatocellular carcinoma Park et al. [133]miR-205 ACSL1 Lipid metabolism Hepatocellular carcinoma Cui et al. [102]miR-1291 NMN, NNMT Nicotinamide metabolism Pancreatic cancer Bi et al. [45]

SLC2A1/GLUT1 Gucose metabolism Renal cell carcinoma Yamasaki et al. [57]

(continued on next page)

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Table 1 (continued)

microRNAs Target genes Metabolic activity/Pathway Phenotypes/cancer types References

miR-195-5p GLUT3 Glucose uptake (glucosemetabolism)

Human bladder cancer Fei et al. [55]

miR-106a SLC2A3 Glucose uptake (glucosemetabolism)

Gioblastoma Dai et al. [51]

miR-17* MnSOD, GPX2, TrxR2 Mitochondrial antioxidant Prostate cancer Xu et al. [87]miR-17-3p LDH-A Enhance glycolysis pathway

and inhibit mitochondrialmetabolism

Prostate cancer Velez and Xu [52]

miR-17-92 E2F1 ROS Lung cancer Ebi et al. [88]miR-200 PGI Glycolysis Breast cancer Ahmad et al. [53]miR-133a, miR-133b PKM2 Glycolysis Tongue squamous cell

carcinomaWong et al. [74]

miR-375 LDHB Anaerobic glycolysis Maxillary sinus squamouscell carcinoma

Kinoshita et al. [78]



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miRNAs in lipid and amino acid metabolism

Lipids are crucial biosynthesis materials for organelles and cells.Altered lipid metabolism is a unique feature of cancer metabolism.Several miRNAs are involved in regulating lipid metabolism incancer [98–102]. miR-122 was found to regulate fat and choles-terol metabolism by controlling the expression of 1-acylglycerol-3-phosphate O-acyltransferase 1 (Agpat1), cell death-inducingDFFA-like effector c (Cidec) and StAR-related lipid transfer protein4 (Stard4) in live cancer [103,104]. It has been demonstrated thatmiR-185 and miR-342 control lipogenesis and cholesterogenesisin prostate cancer cells by reducing the expression of SREBP-1and 2 and down-regulating their targeted genes, including fattyacid synthase (FASN) and 3-hydroxy-3-methylglutaryl CoA reduc-tase (HMGCR) [101]. Further, Tili et al. [100] reported that meta-bolic enzymes such as phosphatidylcholine transfer protein(PCTP), lipase A (LIPA), glutathione synthetase (GSS), argininosuc-cinate synthase 1 (ACSS1), HK2, stearoyl-CoA desaturase-1(SCD1), AKT2, and pyruvate dehydrogenase lipoamide kinase iso-zyme 1 (PDK1), are potential targets of miR-125b and miR-125b.Recently, it has been demonstrated that miR-205 deregulates lipidmetabolism in hepatocellular carcinoma by targeting ACSL1, a lipidmetabolism enzyme in liver [102]. miRNAs have also reported toregulate amino acid catabolism. Liu et al. [96] reported thatmiR-32b* regulates the proline oxidase in kidney cancer. Thesestudies indicate that miRNAs alter the lipid and amino acid metab-olism in cancer.

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Cancer metabolism: microRNAs and signaling pathways

Dysregulation of signaling pathways and altered expression ofmiRNAs results in defective cell metabolism and carcinogenesis[39] Fig. 1. These pathways include p53, c-Myc, Ras, AMPK, AKTand HIFs. p53 is one of the well-known tumor suppressor genesthat regulate cellular metabolism by modulating glycolysis andoxidative phosphorylation. It has been demonstrated that p53 con-trols the glycolysis by inhibiting the expression of GLUT1, GLUT4,phosphoglycerate mutase (PGM) and TP53-inducible glycolysisand apoptosis regulator (TIGAR), and enhances the expression ofcytochrome c oxidase, SCO2, and p53R2 [31,39,105]. p53 regulatesseveral miRNAs to control metabolism in cancer. Some otherstudies reported that p53 controls the expression of miR-34, let-7, miR-107, which further inhibits their target genes’ expressionsuch as lactate dehydrogenase A (LDHA), MYC, sirtuin-1 (SIRT1),hypoxia inducible factor 1 (HIF1) [66,21,106].p53 also controlsthe expression of c-Myc, a proto-oncogene that is known beinvolved in cancer metabolism. p53 regulate c-Myc expression bymiR-145 [107]. c-Myc targets LDHA as well as GLUT1, HK2, PFKM,and ENO1 expression [108]. These genes are essential for the


proper function of glycolysis and oxidative phosphorylation aswell. c-Myc regulates the expression of several miRNAs includingmiR-17-92, miR-23a/b and miR-23* [94,96,109].

In addition to p53 and c-Myc, other pathways such as AMP-activated protein kinase (AMPK), AKT, RAS, and hypoxia-induciblefactors (HIFs) are interact with several miRNAs and regulate metab-olism in cancer. AMPK is activated during metabolic stress toincrease energy conservation and glucose uptake. This allows cellsto survive when the energy supply is low. It has been shown thatmiR-451 controls the AMPK signaling in glioma cells [110].Recently, it has been demonstrated that miR-195 and miR-451 tar-get calcium binding protein 9 (CAB39) and regulate LKB1/AMPKsignaling [39]. Kefas et al. [75] reported that PKM2 is a target ofmiR-326 and that knocking down PKM2 decreased ATP and gluta-thione levels and resulted in activation of AMPK. The AKT pathwayis generally activated in human cancers, which is a major regulatorof apoptosis. AKT is downstream of PI3 K and elevates glycolysis byenhancing the expression of glucose transporters and phosphory-lating hexokinase. It has been shown that with the continuouselevation of the PI3/AKT/mTOR pathway in cancer, the pathwaycan control metabolism possibly by HIF-1a induction undernormoxia [38,41]. There are several miRNAs that are known to reg-ulate the PI3/AKT/mTOR pathway in cancer [41,56,111–114]. TheHIFs are crucial for the maintenance of cellular oxygen homeosta-sis and hypoxia adaptation when oxygen supplies are too low forthe cell. Hypoxia and HIFs are known to regulate different pro-cesses of metabolism in cancer cells [115]. There are severalreports that show the association between miRNAs and hypoxiain regulating cancer metabolism including miR-210 [81–84].Further, Kras also known to regulate cancer metabolism becauseit abrupt the mitochondrial function by inactivating oxidativephosphorylation. Kras also enhance tumor growth by suppressingpyruvate flux through TCA cycle and stimulates glutamine metab-olism [31,116,117]. In recent years, there have been several miR-NAs reported to be associated with Kras in regulating cancermetabolism [118,119].

miRNAs, metabolism and metastatic microenvironment

The proper condition of tumor microenvironment is vital totumor growth and development. The tumor microenvironment iscollection of cancer-associated fibroblasts (CAF), inflammatorycells, endothelial cells (ECs), extracellular matrix, and cytokines[120–123]. In addition to the genes and pathways that influencethe tumor cell metabolism, unusual tumor microenvironmentsplay crucial parts in deciding the fate of tumor cells. Tumors residein a very heterogeneous environments and mutual communicationbetween the cancer cells and tumor stromal cells (tumor microen-vironment) is crucial in determining whether a tumor cell is in a




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367Q3368369370371372373374375376377378379380381382383384385386387388389390391392393394395396397398399

Metabolic reprogramming in

cancer cellsOncogenes

cMyc, HIF1α, Ras, PI3K/AKT

Tumor supressorsp53, LKB1/AMPK

Tumorigenesis

Oncogenic miRNAs

Tumor suppressor

miRNAs

Fig. 1. Metabolic regulation by the tumor suppressors and oncogenes, and involvement of microRNAs in enhancing or suppressing tumorigenesis.



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quiescent state or whether it should become invasive and result inmetastatic cancer. miRNAs play critical roles in the activation oftumor stromal cells, from their quiescent state to cancer angiogen-esis [124]. Several microRNAs regulate cancer angiogenesis, CAFs,ECs, and tumor microenvironment [121,127]. miR-29 emerged asa master orchestrator of the tumor microenvironment (Chouet al., 2013). It has been reported that the metabolic interactionbetween mitochondria in cancer cells and catabolism in CAFsenhance tumor growth and metastasis [126]. Further, it has beensuggested that miRNAs establish a novel communication betweencancer and stromal cells through microvasicles to facilitate angio-genesis and tumor growth [127].

microRNAs as a target in cancer therapy

Metabolic reprogramming plays an essential step in tumordevelopment and metastasis. Targeting cancer metabolism holdsgreat promise in developing anti-cancer therapy. There are manytypes of compounds that have been developed to specificallyinhibit the metabolic enzymes, which are crucial in tumor develop-ment [128]. However, some of the cells have similar metabolicprogramming as cancer cells such as T lymphocytes, which use glu-tamine metabolism [128]. Studies show that miRNA deregulationdoes not affect the growth of normal cells, but it does reduce thegrowth of cancer cells, which suggest that miRNAs can be thera-peutic targets in cancer [41,129]. In addition, tumor suppressorp53 induced several miRNAs, such as miR-34, let-7, miR-107, andmiR-200, which function as regulators of LDHA, Myc and SIRT1[130]. These suggest that p53/miR-34 is the major metabolic regu-lator in tumor suppression and that targeting LDHA, Myc and SIRT1or other metabolic pathways or enzymes would be an innovativestrategy in cancer treatment [130]. Further, it has been reportedthat metformin is effective in reprogramming the metabolism incancer cells by directly modulating the metabolic genes, and miR-NAs [131]. miRNAs can be used both as targets and tools in anti-cancer therapy, however, development of engineered animal mod-els to examine cancer-associated miRNAs and the advancement ofthe effectiveness of microRNAs/anti-miRs in vivo delivery is still amajor hurdle in clinics [132]. Some recent studies, however, dem-onstrated that systematic administration of microRNAs reducesdifferent types of cancer growth in vivo without cell toxicity[41,104,133–135].

Conclusion

miRNAs are crucial regulators of cancer metabolism. miRNAscontrol the cancer metabolic reprogramming by regulating theexpression of genes/pathways/enzymes involved in glycolysis


and energy metabolism. Although there are many roles of miRNAsthat are unknown at this moment, it is important to study them tounderstand how tumor cells form. Further, the specific miRNAsthat regulate glycolysis or mitochondrial metabolism in cancerwould be promising therapeutic targets in cancers. However,improving in vivo delivery of these microRNAs is crucial in exploit-ing the full potential of miRNAs. It is hopeful that scientists can usethe knowledge gained from miRNAs to develop cancer treatmentsthat will target areas or pathways of metabolic alteration.

Conflicts of Interest

The authors declare no conflict of interest.

Acknowledgement

This research was supported by the Intramural Research Pro-gram of the National Cancer Institute, National Institutes of Health.

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the emerging roles of micrornas in cancer metabolism

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