|Year : 2016 | Volume
| Issue : 6 | Page : 175-181
MicroRNA regulating metabolic reprogramming in tumor cells: New tumor markers
Daniel Otero-Albiol, Blanca Felipe-Abrio
Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio, CSIC, Universidad de Sevilla, Seville, Spain
|Date of Submission||10-Oct-2016|
|Date of Acceptance||15-Nov-2016|
|Date of Web Publication||28-Dec-2016|
Dr. Blanca Felipe-Abrio
Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio, CSIC, Universidad de Sevilla, C/Manuel Siurot s/n, 41013 Seville
Source of Support: None, Conflict of Interest: None
Metabolic reprogramming is a feature of cancer cells that provides fast energy production and the abundance of precursors required to fuel uncontrolled proliferation. The Warburg effect, increase in glucose uptake and preference for glycolysis over oxidative phosphorylation (OXPHOS) as major source of energy even in the presence of oxygen, is the main metabolic adaptation of cancer cells but not the only one. Increased glutaminolysis is also observed in cancer cells, being another source of adenosine triphosphate production and supply of intermediates for macromolecule biosynthesis. The ability to shift from OXPHOS to glycolysis and vice versa, known as metabolic plasticity, allows cancer cells to adapt to continuous changes in the tumor microenvironment. Metabolic reprogramming is linked to the deregulation of pathways controlled by hypoxia-inducible factor 1 alpha, MYC, or p53, and microRNAs (miRNAs) have emerged as key regulators of these signaling pathways. miRNAs target metabolic enzymes, oncogenes, and tumor suppressors involved in metabolic reprogramming, becoming crucial elements in the cross talk of molecular pathways that promotes survival, proliferation, migration, and consequently, tumor progression and metastasis. Moreover, several miRNAs have been found downregulated in different human cancers. Due to this fact and their central role in metabolism regulation, miRNAs may be considered as biomarkers for cancer therapy.
Keywords: Aerobic glycolysis, cancer, metabolic reprogramming, microRNAs, miR-210
|How to cite this article:|
Otero-Albiol D, Felipe-Abrio B. MicroRNA regulating metabolic reprogramming in tumor cells: New tumor markers. Cancer Transl Med 2016;2:175-81
|How to cite this URL:|
Otero-Albiol D, Felipe-Abrio B. MicroRNA regulating metabolic reprogramming in tumor cells: New tumor markers. Cancer Transl Med [serial online] 2016 [cited 2019 Dec 10];2:175-81. Available from: http://www.cancertm.com/text.asp?2016/2/6/175/196909
| Introduction|| |
Reprogramming energy metabolism has emerged as a new hallmark of cancer. To sustain uncontrolled proliferation, cells need to adapt their metabolism to fuel cell growth, division, and rapid demand of macromolecules. The shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, known as the “Warburg effect,” provides cancer cells with several advantages as survival in conditions of fluctuating oxygen tension, high production of lactic acid, and abundance of intermediates from glycolytic pathway for anabolic reactions.,, This acidic environment favors tumor invasion and suppresses anticancer immune effectors, allowing cells to survive and metastasize to distal tissues. There are, however, metabolic adaptations beyond aerobic glycolysis, therefore, cancer cells show an increased metabolic plasticity to adapt to different changes in the tumor microenvironment. For instance, when there is a blockade of acid lactic export, cancer cells redirect their metabolism toward OXPHOS to survive. Metabolic plasticity gives tumor cells the ability to switch from OXPHOS to aerobic glycolysis and vice versa depending on environmental conditions. Therefore, not only elevated glucose consumption but also high levels of glutamine oxidation have been described in cancer cells.,,,,[11 The oxidation of glutamine into glutamate and further into alpha-ketoglutarate (α-KG), lactate, or alanine is known as glutaminolysis. The conversion of glutamate into α-KG by glutamate dehydrogenase or transaminases enables adenosine triphosphate production through the tricarboxylic acid (TCA) cycle and provides carbon and nitrogen precursor for macromolecule biosynthesis. Glutaminolysis is also involved in the regulation of redox balance, mammalian target of rapamycin signaling, apoptosis and autophagy, crucial processes in cell proliferation and survival.,,
Metabolic reprogramming is linked to several pathways regulated by oncogenes and tumor suppressors such as hypoxia inducible factor (HIF), MYC, and p53. The activation and inactivation of the oncogenes and tumor suppressors are also regulated by microRNAs (miRNAs),,, small noncoding RNAs with gene regulatory functions that have emerged as key regulators of the tumor microenvironment., miRNAs take part in response to hypoxia, nutrient deprivation, oxidative stress, and angiogenesis through direct regulation of metabolic enzymes or oncogenes and tumor suppressors. In addition, miRNAs are also crucial for the communication of cancer cells and stromal cells as they can be found inside exosomes. This review will focus on the role of miRNAs in glucose metabolism and glutaminolysis, key processes in the metabolic plasticity of cancer cells. A better understanding of metabolic pathways regulation that allows cancer cells to continuously adapt to changes in the tumor microenvironment is necessary to improve anticancer therapies.
| Regulation of Glycolytic and Pentose Phosphate Pathways by Micrornas|| |
Aerobic glycolysis is the most studied event of metabolic reprogramming in cancer cells. This mechanism of adaptation includes an increased intake of glucose. To obtain higher glucose concentrations, cancer cells induce the expression of glucose transporters (GLUTs). Downregulation of miR-195-5p and miR-106a in bladder cancer and glioma, respectively, results in increased levels of GLUT3 and poor prognosis [Table 1]., In addition to GLUTs, glycolytic enzymes are upregulated in aerobic glycolysis as well. The hexokinase 2 (HK2) is the first rate-limiting enzyme of glycolysis and is highly expressed in cancer cells, leading to an increase of the glycolytic rate., This enzyme is repressed by miR-143, which inversely correlates with HK2 expression in head and neck squamous cell carcinoma and in lung tumors.,HK2 is also a target of miR-181b, which is downregulated in human gastric cancers. In addition, it has been reported that miR-155 represses miR-143, acting as an activator of HK2 expression in breast cancer cells. miR-155 also promotes HK2 transcription through the activation of signal transducer and activator of transcription 3, a transcriptional activator for HK2. Another enzyme that plays a role in glycolysis is aldolase A, which transforms fructose 1, 6-bisphophate into glyceraldehyde 3-phophate and dihydroxyacetone. This enzyme is the target of the miR-15-a/16-1 cluster and miR-122 liver-specific miRNA, being downregulated in both cases., Lactate production is the final step of fermentative glycolysis. Increased expression levels of lactate dehydrogenase A (LDHA) and monocarboxylic acid transporters 1 and 4 (MCT1 and 4) are involved in pyruvate uncoupling of OXPHOS in favor of lactate production, leading to tumor acidosis.LDHA is negatively regulated by miR-34a, miR-34c, miR-369-3p, miR-374a, and miR-4524a/b and a negative correlation between these miRNAs and LDHA has been found in colorectal cancer tissues, where LDHA expression is elevated. MCTs are targets of miRNAs as well. It has been described that miR-124, frequently downregulated in medulloblastomas, is a negative regulator of MCT1.
Finally, the muscle-specific pyruvate kinase M (PKM) has a pivotal role in metabolic reprogramming in tumor cells. PKM shows two isoforms, PKM1 and PKM2, as a result of alternative splicing of exons 9 and 10. These two isoforms are different in conformation and tissue expression. PKM1 forms tetramers, is expressed in normal differentiated tissue, and promotes OXPHOS, while PKM2 has a dimmer conformation, an elevated expression during embryonic development and foment glycolysis. Depending on the PKM1/PKM2 ratio, cancer cells rely on OXPHOS or glycolysis. This ratio is modulated by miR-124, miR-137, and miR-340. High expression levels of these three miRNAs produce a high PKM1/PKM2 ratio and reduce glycolytic rate, directing glucose to OXPHOS. On the contrary, reduced levels of these miRNAs lead to a low PKM1/PKM2 ratio, a high glycolytic rate, and promote cell growth.PKM2 overexpression is frequent in many cancers as the result of the reduction in several miRNAs, as miR-133a and miR-133b in squamous cell carcinoma of tongue, miR-326 in glioblastoma, and miR-122 in hepatocellular carcinoma.,, PKM2 overexpression promotes the accumulation of phosphoenolpyruvate, leading to the redirection of glycolytic intermediates toward the pentose phosphate pathway (PPP), which provides the ribose-5-phosphate and NADPH required for nucleotides and fatty acid biosynthesis.
PPP increased activity is another feature of metabolic reprogramming; hence, upregulation of enzymes that take part in this pathway has also been found in cancer cells. For instance, glucose-6-phosphate dehydrogenase (G6PD), an enzyme that catalyzes the rate-limiting step of PPP, is negatively regulated by miR-206. Reduced levels of miR-206 and increased levels of G6PD have been observed in rhabdomyosarcoma primary tumors compared to normal cells.
| Regulation of the Tricarboxylic Acid Cycle by Micrornas|| |
The TCA cycle is a central process in cellular metabolism. In normal cells, TCA performs the full oxidation of acetyl-coenzyme A (CoA) CO2, resulting in the main source of energy production. Before TCA begins, the pyruvate produced in glycolysis needs to be converted into Acetyl-CoA; a key step that is catalyzed by pyruvate dehydrogenase (PDH). As cancer cells mainly obtain energy through glycolysis, the transformation of pyruvate into acetyl-CoA is downregulated to uncouple glucose oxidation from mitochondrial respiration. To reduce PDH activity, cancer cells overexpress PDH kinases (PDK), enzymes that phosphorylate and inhibit PDH complex. There are four PDK isoenzymes, PDK 1–4, PDK1 and PDK4 being the most involved in cancer metabolism. PDK1 has been associated to the Warburg effect because it is a target gene of HIF-1α, and PDK4 expression is highly influenced by physiological conditions. The expression of both isoenzymes is regulated by miRNAs. PDK1 is a target of miR-125b, which is downregulated in chronic lymphocytic leukemia, and PDK4 is negatively regulated by miR-211, which is reduced in melanoma cells. In addition, PDH complex activity is also inhibited as the result of the downregulation of one of its components, the PDH protein X (PDHX). miR-26a inhibits PDHX expression by targeting the 3'untranslated region of PDHX messenger RNA (mRNA). While miR-26a expression levels are increased in colon cancer cell lines, PDHX levels are reduced, turning into PDH inhibition and pyruvate accumulation.
The TCA, however, is not useless for cancer cells; it works as a source of amino acids, nucleotides, and lipid precursors in a process known as “cataplerosis”. Mutations and downregulation of TCA enzymes contribute to this purpose. For instance, isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) are regulated by miR-181 and miR-183, respectively., miR-181 inhibits IDH1 expression leading to a reduction in expression of genes involved in lipid synthesis, an increased expression of genes implicated in β-oxidation, and finally to an inhibition of lipid accumulation. miR-183 is upregulated in gliomas and reduces IDH2 mRNA levels. As IDH2 converts isocitrate to α-KG, its inhibition turns into the reduction of α-KG cellular levels and HIF-1α stabilization, because α-KG is a substrate of prolyl hydroxylases (PHDs). In addition, miR-210 is a relevant miRNA that plays a role in the control of the TCA. miR-210 is upregulated at late stages of nonsmall cell lung cancer and directly targets NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4, a subunit of electron transport chain (ETC) complex I, and succinate dehydrogenase complex subunit D, a subunit of the ETC complex II, inducing mitochondrial dysfunctions. Iron-sulfur cluster scaffold homolog (ISCU) and cytochrome C oxidase assembly protein (COX10) have also been identified as potential miR-210 targets. Reduction in ISCU expression levels by miR-210 disrupts iron homeostasis, altering mitochondrial functions, while downregulation of COX10 affects the proper action of ETC complex I and IV. Nevertheless, not only enzymes involved in the TCA but also major regulators of mitochondrial biogenesis are regulated by miRNAs. For instance, miR-23 is a negative regulator of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), while miR-378 inhibits the expression of PGC-1β, leading to the shift from mitochondrial respiration to aerobic glycolysis.
As intermediates of the TCA are used as precursors in biosynthetic pathways, there are reactions in charge of the replenishment of these intermediates to maintain a balance in the supply of biosynthetic precursors. The main anaplerotic reactions that ensure this balance are glutaminolysis and pyruvate carboxylation., The first reaction of glutaminolysis is the conversion of glutamine to glutamate, catalyzed by the enzyme glutaminase (GLS). It has been reported that miR-23 targets GLS reducing its expression; therefore, the downregulation of miR-23 in cancer cell would be expected.
| Micrornas Controlling Signaling Pathways Involved in Metabolic Reprogramming|| |
Many of the miRNAs mentioned before are responsible for additional oncogenic effects beyond the metabolism reprogramming. Among these functions, it is particularly important to point out their influence over signaling pathways. Both roles of miRNAs contribute to enhance cancer development, especially because of the existent cross talk among metabolic pathways, cell cycle, survival, and migration pathways. The main pathways influencing metabolic reprogramming which can promote other oncogenic properties are regulated by HIF, MYC, and p53.
HIF is a transcription factor that regulates gene expression under oxygen deprivation. In the presence of oxygen, PHDs modify HIF-1α so that von Hippel–Lindau protein (VHL) can ubiquitinate it. Just when these modifications are made, HIF-1α is degraded in the proteasome. However, under hypoxic conditions, HIF-1α can form a heterodimer complex with HIF-1β and regulate the transcription of genes containing hypoxia response elements (HREs). HIF-1α is in charge of the regulation of genes included in metabolic pathways such as GLUT1, GLUT3, HK1, HK2, ALDHA, PGK, and LDHA., It means that HIF-1α can increase the glycolytic flux and reduce the amount of pyruvate entering into the TCA.HIF-1 α can be stabilized by miR-92-1, which directly targets VHL [Table 2]; however, many other miRNAs that are frequently overexpressed in renal cancer are potential regulators of VHL, such as miR-20a/b, miR-21, miR-22, miR-101, miR-106a/b, miR-150, and miR-200b. Nevertheless, the hypoxic environment is characterized by the presence of miR-210, which is induced by HIF-1α and, at the same time, avoids its degradation. miR-210 is involved in very different processes including regulation of mitochondria function, cell cycle control, angiogenesis, and metastasis.,
In addition, it has been shown that miR-210 is also a target of HIF-2 α, another HIF isoform which joins HIF-1β to regulate HRE-containing gene transcription. HIF-2α is specifically expressed in several tissues, and its target genes differ from HIF-1α regulated genes in a context-dependent manner. Even though there is much evidence that HIF-2α does not regulate glycolysis directly,, its role in metabolism reprogramming has been suggested as a consequence of the promotion of GLUT1 and other genes such as OCT-4, necessary for the stem cell phenotype acquisition. HIF-2α is also able to promote cell cycle by enhancing c-MYC activity. Further, it has been proved that miR-182 suppresses the expression of HIF-2 α, inhibiting its reprogramming ability and decreasing glioblastoma progression.,
MYC, another oncogenic transcription factor, can promote survival, cellular growth, and proliferation as well. MYC regulatory effects over metabolism reprogramming are coordinated with the regulatory action of HIF-1α. Thus, c-MYC can activate the transcription of glycolytic enzymes such as HK2, some GLUTs such as GLUT1, and also other important enzymes such as LDHA and PDK1.,, Among the pool of miRNAs that regulate the expression of MYC, the most important one is let-7a, which can reduce c-MYC mRNA levels if it is overexpressed. It has also been shown that let-7a can reduce tumor growth in mouse models of lung cancer. Moreover, there are several miRNAs that are transcriptionally regulated by c-MYC. First of these, miRNAs discovered are included within the miR-17-92 cluster, and the most relevant ones are miR-19a and miR-19b1. These two miRNAs can downregulate PTEN expression, and as a consequence of this, phosphoinositide 3-kinase activity is enhanced in cancer cells, increasing glucose metabolism because of the expression of GLUT genes and the activity of glycolytic enzymes. In addition, some miRNAs can indirectly regulate MYC so that the metabolic shift finally occurs. One example is the recently described regulatory network formed by miR-448 and KDM2B, a histone demethylase. miR-448, which is overexpressed in gastric cancer, downregulates KDM2B that reduces MYC, resulting in enhanced glycolysis and proliferation.
p53 action as a tumor suppressor goes beyond DNA damage response, cell cycle regulation, and apoptosis. It can modify the expression of genes involved in the metabolism shift. p53 can reduce the glycolytic flux in favor of OXPHOS by downregulating GLUTs GLUT1, GLUT2, and GLUT3, PGM1, MCT1, and the activation of PDH1 α.,, p53 regulates the transcription of some of the miRNAs mentioned before, like let-7 or miR-17-92 clusters, but also some others such as miR-107 which directly targets mRNA of metabolism enzymes, such as LDHA or SIRT1 and the transcription factors MYC and HIF-1 α., However, miR-34a could be considered the most important miRNA regulated by the tumor suppressor p53. This miRNA expression is enhanced by the action of p53 and its role in metabolism consists on downregulating glycolytic enzymes HK1, HK2, GPI, and also PDK. However, suppressing the transcription of LDHA could be considered the most important function of this miRNA because this enzyme promotes glycolysis and cellular proliferation in cancer cells., In addition to this, p53 can also suppress the expression of some oncogenic miRNAs such as miR-16-1, miR-143, and miR-145., Otherwise, some miRNAs can reduce the transcription of p53 gene; among this kind of miRNAs, we can find miR-30d, miR-504, miR-125b, miR-372, and miR-373.,
| Conclusion|| |
There is much evidence that those points to metabolic changes in cancer cells beyond aerobic glycolysis; indeed metabolic plasticity allows tumor cells to adapt to continuous modifications in the surrounding microenvironment. In this context, miRNAs have emerged as key regulators of metabolic reprogramming as they target such metabolic enzymes as oncogenes and tumor suppressors involved in signaling pathways. miRNAs especially play a pivotal role in the regulation of the cross talk among metabolic reprogramming, survival and proliferation pathways, appearing as crucial elements for tumor progression and metastasis. The current status of miRNAs involved in metabolic reprogramming has been analyzed in this review. Some of these miRNAs, as miR-106a targeting GLUT3, have been associated with poor survival in patients, making them interesting for using as biomarkers and molecules for cancer therapy. In this sense, miR-210 and miR-34 would be suitable for translational studies, because miR-210 is the most characteristic miRNA in the hypoxic microenvironment and miR-34 is directly regulated by p53, which is frequently mutated in cancer. However, despite the great interest that miRNAs are acquiring in translational research, the variety of functions developed by every miRNA complicate the translation of the results obtained in basic research to the clinic. More studies are necessary to move forward the understanding of miRNAs as regulators of signaling pathways involved in tumorigenesis and make them a reality as biomarkers for cancer therapy.
Financial support and sponsorship
This work was supported by grants from the Spanish Ministry of Economy and Competitiveness, Plan Estatal de I + D + I 2013–2016, ISCIII (Fis: PI15/00045), and co-funded by FEDER from the Regional Development European Funds (European Union), Consejeria de Ciencia e Innovacion (CTS-1848) and Consejeria de Salud of the Junta de Andalucia (PI-0306-2012 and PI-0096-2014), and Fundacion BBVA. Additionally, this work has been supported by Plan Estatal I+ D + i 2013-2016 (Grant PIE13/0004), and co-funded by the ISCIII and FEDER funds. BFA was funded by the Spanish Ministry of Education (FPU12/01380).
Conflicts of interest
There are no conflicts of interest.
| References|| |
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell
2011; 144 (5): 646–74.
Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer
2011; 11 (2): 85–95.
Kroemer G, Pouyssegur J. Tumor cell metabolism: cancer's Achilles' heel. Cancer Cell
2008; 13 (6): 472–82.
Warburg O. On the origin of cancer cells. Science
1956; 123 (3191): 309–14.
Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell
2012; 21 (3): 297–308.
Marchiq I, Le Floch R, Roux D, Simon MP, Pouyssegur J. Genetic disruption of lactate/H+symporters (MCTs) and their subunit CD147/BASIGIN sensitizes glycolytic tumor cells to phenformin. Cancer Res
2015; 75 (1): 171–80.
Yuneva M. Finding an “Achilles' heel” of cancer: the role of glucose and glutamine metabolism in the survival of transformed cells. Cell Cycle
2008; 7 (14): 2083–9.
Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J, Hiller K, Jewell CM, Johnson ZR, Irvine DJ, Guarente L, Kelleher JK, Vander Heiden MG, Iliopoulos O, Stephanopoulos G. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature
2011; 481 (7381): 380–4.
Wise DR, Ward PS, Shay JE, Cross JR, Gruber JJ, Sachdeva UM, Platt JM, DeMatteo RG, Simon MC, Thompson CB. Hypoxia promotes isocitrate dehydrogenase-dependent carboxylation of alpha-ketoglutarate to citrate to support cell growth and viability. Proc Natl Acad Sci U S A
2011; 108 (49): 19611–6.
Le A, Lane AN, Hamaker M, Bose S, Gouw A, Barbi J, Tsukamoto T, Rojas CJ, Slusher BS, Zhang H, Zimmerman LJ, Liebler DC, Slebos RJ, Lorkiewicz PK, Higashi RM, Fan TW, Dang CV. Glucose-independent glutamine metabolism via TCA cycling for proliferation and survival in B cells. Cell Metab
2012; 15 (1): 110–21.
Mullen AR, Wheaton WW, Jin ES, Chen PH, Sullivan LB, Cheng T, Yang Y, Linehan WM, Chandel NS, DeBerardinis RJ. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature
2011; 481 (7381): 385–8.
Jin L, Alesi GN, Kang S. Glutaminolysis as a target for cancer therapy. Oncogene
2016; 35 (28): 3619–25.
Duran RV, Oppliger W, Robitaille AM, Heiserich L, Skendaj R, Gottlieb E, Hall MN. Glutaminolysis activates Rag-mTORC1 signaling. Mol Cell
2012; 47 (3): 349–58.
Jin L, Li D, Alesi GN, Fan J, Kang HB, Lu Z, Boggon TJ, Jin P, Yi H, Wright ER, Duong D, Seyfried NT, Egnatchik R, DeBerardinis RJ, Magliocca KR, He C, Arellano ML, Khoury HJ, Shin DM, Khuri FR, Kang S. Glutamate dehydrogenase 1 signals through antioxidant glutathione peroxidase 1 to regulate redox homeostasis and tumor growth. Cancer Cell
2015; 27 (2): 257–70.
Eng CH, Yu K, Lucas J, White E, Abraham RT. Ammonia derived from glutaminolysis is a diffusible regulator of autophagy. Sci Signal
2010; 3 (119): ra31.
Gao P, Sun L, He X, Cao Y, Zhang H. MicroRNAs and the warburg effect: new players in an old arena. Curr Gene Ther
2012; 12 (4): 285–91.
Pinweha P, Rattanapornsompong K, Charoensawan V, Jitrapakdee S. MicroRNAs and oncogenic transcriptional regulatory networks controlling metabolic reprogramming in cancers. Comput Struct Biotechnol J
2016; 14: 223–33.
Tomasetti M, Amati M, Santarelli L, Neuzil J. MicroRNA in metabolic re-programming and their role in tumorigenesis. Int J Mol Sci
2016; 17 (5). pii: E754.
Frediani JN, Fabbri M. Essential role of miRNAs in orchestrating the biology of the tumor microenvironment. Mol Cancer
2016; 15 (1): 42.
Rottiers V, Naar AM. MicroRNAs in metabolism and metabolic disorders. Nat Rev Mol Cell Biol
2012; 13 (4): 239–50.
Zhao M, Zhang Z. Glucose transporter regulation in cancer: a profile and the loops. Crit Rev Eukaryot Gene Expr
2016; 26 (3): 223–38.
Fei X, Qi M, Wu B, Song Y, Wang Y, Li T. MicroRNA-195-5p suppresses glucose uptake and proliferation of human bladder cancer T24 cells by regulating GLUT3 expression. FEBS Lett
2012; 586 (4): 392–7.
Dai DW, Lu Q, Wang LX, Zhao WY, Cao YQ, Li YN, Han GS, Liu JM, Yue ZJ. Decreased miR-106a inhibits glioma cell glucose uptake and proliferation by targeting SLC2A3 in GBM. BMC Cancer
2013; 13: 478.
Peschiaroli A, Giacobbe A, Formosa A, Markert EK, Bongiorno-Borbone L, Levine AJ, Candi E, D'Alessandro A, Zolla L, Finazzi Agro A, Melino G. miR-143 regulates hexokinase 2 expression in cancer cells. Oncogene
2013; 32 (6): 797–802.
Fang R, Xiao T, Fang Z, Sun Y, Li F, Gao Y, Feng Y, Li L, Wang Y, Liu X, Chen H, Liu XY, Ji H. MicroRNA-143 (miR-143) regulates cancer glycolysis via targeting hexokinase 2 gene. J Biol Chem
2012; 287 (27): 23227–35.
Li LQ, Yang Y, Chen H, Zhang L, Pan D, Xie WJ. MicroRNA-181b inhibits glycolysis in gastric cancer cells via targeting hexokinase 2 gene. Cancer Biomark
2016; 17 (1): 75–81.
Jiang S, Zhang LF, Zhang HW, Hu S, Lu MH, Liang S, Li B, Li Y, Li D, Wang ED, Liu MF. A novel miR-155/miR-143 cascade controls glycolysis by regulating hexokinase 2 in breast cancer cells. EMBO J
2012; 31 (8): 1985–98.
Calin GA, Cimmino A, Fabbri M, Ferracin M, Wojcik SE, Shimizu M, Taccioli C, Zanesi N, Garzon R, Aqeilan RI, Alder H, Volinia S, Rassenti L, Liu X, Liu CG, Kipps TJ, Negrini M, Croce CM. MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci U S A
2008; 105 (13): 5166–71.
Fabani MM, Gait MJ. miR-122 targeting with LNA/2'-O-methyl oligonucleotide mixmers, peptide nucleic acids (PNA), and PNA-peptide conjugates. RNA
2008; 14 (2): 336–46.
Wang J, Wang H, Liu A, Fang C, Hao J, Wang Z. Lactate dehydrogenase A negatively regulated by miRNAs promotes aerobic glycolysis and is increased in colorectal cancer. Oncotarget
2015; 6 (23): 19456–68.
Li KK, Pang JC, Ching AK, Wong CK, Kong X, Wang Y, Zhou L, Chen Z, Ng HK. miR-124 is frequently down-regulated in medulloblastoma and is a negative regulator of SLC16A1. Hum Pathol
2009; 40 (9): 1234–43.
Sun Y, Zhao X, Zhou Y, Hu Y. miR-124, miR-137 and miR-340 regulate colorectal cancer growth via inhibition of the Warburg effect. Oncol Rep
2012; 28 (4): 1346–52.
Wong TS, Liu XB, Chung-Wai Ho A, Po-Wing Yuen A, Wai-Man Ng R, Ignace Wei W. Identification of pyruvate kinase type M2 as potential oncoprotein in squamous cell carcinoma of tongue through microRNA profiling. Int J Cancer
2008; 123 (2): 251–7.
Kefas B, Comeau L, Erdle N, Montgomery E, Amos S, Purow B. Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells. Neuro Oncol
2010; 12 (11): 1102–12.
Liu AM, Xu Z, Shek FH, Wong KF, Lee NP, Poon RT, Chen J, Luk JM. miR-122 targets pyruvate kinase M2 and affects metabolism of hepatocellular carcinoma. PLoS One
2014; 9 (1): e86872.
Coda DM, Lingua MF, Morena D, Foglizzo V, Bersani F, Ala U, Ponzetto C, Taulli R. SMYD1 and G6PD modulation are critical events for miR-206-mediated differentiation of rhabdomyosarcoma. Cell Cycle
2015; 14 (9): 1389–402.
Tili E, Michaille JJ, Luo Z, Volinia S, Rassenti LZ, Kipps TJ, Croce CM. The down-regulation of miR-125b in chronic lymphocytic leukemias leads to metabolic adaptation of cells to a transformed state. Blood
2012; 120 (13): 2631–8.
Mazar J, Qi F, Lee B, Marchica J, Govindarajan S, Shelley J, Li JL, Ray A, Perera RJ. MicroRNA 211 functions as a metabolic switch in human melanoma cells. Mol Cell Biol
2016; 36 (7): 1090–108.
Chen B, Liu Y, Jin X, Lu W, Liu J, Xia Z, Yuan Q, Zhao X, Xu N, Liang S. MicroRNA-26a regulates glucose metabolism by direct targeting PDHX in colorectal cancer cells. BMC Cancer
2014; 14: 443.
Chu B, Wu T, Miao L, Mei Y, Wu M. MiR-181a regulates lipid metabolism via IDH1. Sci Rep
2015; 5: 8801.
Tanaka H, Sasayama T, Tanaka K, Nakamizo S, Nishihara M, Mizukawa K, Kohta M, Koyama J, Miyake S, Taniguchi M, Hosoda K, Kohmura E. MicroRNA-183 upregulates HIF-1alpha by targeting isocitrate dehydrogenase 2 (IDH2) in glioma cells. J Neurooncol
2013; 111 (3): 273–83.
Puissegur MP, Mazure NM, Bertero T, Pradelli L, Grosso S, Robbe-Sermesant K, Maurin T, Lebrigand K, Cardinaud B, Hofman V, Fourre S, Magnone V, Ricci JE, Pouyssegur J, Gounon P, Hofman P, Barbry P, Mari B. miR-210 is overexpressed in late stages of lung cancer and mediates mitochondrial alterations associated with modulation of HIF-1 activity. Cell Death Differ
2011; 18 (3): 465–78.
Chen Z, Li Y, Zhang H, Huang P, Luthra R. Hypoxia-regulated microRNA-210 modulates mitochondrial function and decreases ISCU and COX10 expression. Oncogene
2010; 29 (30): 4362–8.
Safdar A, Abadi A, Akhtar M, Hettinga BP, Tarnopolsky MA. miRNA in the regulation of skeletal muscle adaptation to acute endurance exercise in C57Bl/6J male mice. PLoS One
2009; 4 (5): e5610.
Eichner LJ, Perry MC, Dufour CR, Bertos N, Park M, St-Pierre J, Giguere V. miR-378(*) mediates metabolic shift in breast cancer cells via the PGC-1beta/ERRgamma transcriptional pathway. Cell Metab
2010; 12 (4): 352–61.
Rathore MG, Saumet A, Rossi JF, de Bettignies C, Tempe D, Lecellier CH, Villalba M. The NF-kappaB member p65 controls glutamine metabolism through miR-23a. Int J Biochem Cell Biol
2012; 44 (9): 1448–56.
Katagiri M, Karasawa H, Takagi K, Nakayama S, Yabuuchi S, Fujishima F, Naitoh T, Watanabe M, Suzuki T, Unno M, Sasano H. Hexokinase 2 in colorectal cancer: a potent prognostic factor associated with glycolysis, proliferation and migration. Histol Histopathol
2016. doi: 10.14670/HH-11-799.
Chen J, Zhang S, Li Y, Tang Z, Kong W. Hexokinase 2 overexpression promotes the proliferation and survival of laryngeal squamous cell carcinoma. Tumour Biol
2014; 35 (4): 3743–53.
Parks SK, Mazure NM, Counillon L, Pouyssegur J. Hypoxia promotes tumor cell survival in acidic conditions by preserving ATP levels. J Cell Physiol
2013; 228 (9): 1854–62.
Christofk HR, Vander Heiden MG, Harris MH, Ramanathan A, Gerszten RE, Wei R, Fleming MD, Schreiber SL, Cantley LC. The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth. Nature
2008; 452 (7184): 230–3.
Tamada M, Suematsu M, Saya H. Pyruvate kinase M2: multiple faces for conferring benefits on cancer cells. Clin Cancer Res
2012; 18 (20): 5554–61.
Chen X, Qian Y, Wu S. The Warburg effect: evolving interpretations of an established concept. Free Radic Biol Med
2015; 79: 253–63.
Jeoung NH. Pyruvate dehydrogenase kinases: therapeutic targets for diabetes and cancers. Diabetes Metab J
2015; 39 (3): 188–97.
Owen OE, Kalhan SC, Hanson RW. The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem
2002; 277 (34): 30409–12.
Jitrapakdee S, St Maurice M, Rayment I, Cleland WW, Wallace JC, Attwood PV. Structure, mechanism and regulation of pyruvate carboxylase. Biochem J
2008; 413 (3): 369–87.
Kolch W, Halasz M, Granovskaya M, Kholodenko BN. The dynamic control of signal transduction networks in cancer cells. Nat Rev Cancer
2015; 15 (9): 515–27.
Bruick RK. Oxygen sensing in the hypoxic response pathway: regulation of the hypoxia-inducible transcription factor. Genes Dev
2003; 17 (21): 2614–23.
Li Z, Zhang H. Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression. Cell Mol Life Sci
2016; 73 (2): 377–92.
Semenza GL. HIF-1: upstream and downstream of cancer metabolism. Curr Opin Genet Dev
2010; 20 (1): 51–6.
Cairns RA. Drivers of the warburg phenotype. Cancer J
2015; 21 (2): 56–61.
Ghosh AK, Shanafelt TD, Cimmino A, Taccioli C, Volinia S, Liu CG, Calin GA, Croce CM, Chan DA, Giaccia AJ, Secreto C, Wellik LE, Lee YK, Mukhopadhyay D, Kay NE. Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells. Blood
2009; 113 (22): 5568–74.
Chow TF, Youssef YM, Lianidou E, Romaschin AD, Honey RJ, Stewart R, Pace KT, Yousef GM. Differential expression profiling of microRNAs and their potential involvement in renal cell carcinoma pathogenesis. Clin Biochem
2010; 43 (1–2): 150–8.
Dang K, Myers KA. The role of hypoxia-induced miR-210 in cancer progression. Int J Mol Sci
2015; 16 (3): 6353–72.
Huang X, Zuo J. Emerging roles of miR-210 and other non-coding RNAs in the hypoxic response. Acta Biochim Biophys Sin (Shanghai)
2014; 46 (3): 220–32.
Kouri FM, Ritner C, Stegh AH. miRNA-182 and the regulation of the glioblastoma phenotype – Toward miRNA-based precision therapeutics. Cell Cycle
2015; 14 (24): 3794–800.
Kouri FM, Hurley LA, Daniel WL, Day ES, Hua Y, Hao L, Peng CY, Merkel TJ, Queisser MA, Ritner C, Zhang H, James CD, Sznajder JI, Chin L, Giljohann DA, Kessler JA, Peter ME, Mirkin CA, Stegh AH. miR-182 integrates apoptosis, growth, and differentiation programs in glioblastoma. Genes Dev
2015; 29 (7): 732–45.
He XY, Chen JX, Zhang Z, Li CL, Peng QL, Peng HM. The let-7a microRNA protects from growth of lung carcinoma by suppression of k-Ras and c-Myc in nude mice. J Cancer Res Clin Oncol
2010; 136 (7): 1023–8.
Mu P, Han YC, Betel D, Yao E, Squatrito M, Ogrodowski P, de Stanchina E, D'Andrea A, Sander C, Ventura A. Genetic dissection of the miR-17 ~ 92 cluster of microRNAs in Myc-induced B-cell lymphomas. Genes Dev
2009; 23 (24): 2806–11.
DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB. The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab
2008; 7 (1): 11–20.
Hong X, Xu Y, Qiu X, Zhu Y, Feng X, Ding Z, Zhang S, Zhong L, Zhuang Y, Su C, Hong X, Cai J. MiR-448 promotes glycolytic metabolism of gastric cancer by downregulating KDM2B. Oncotarget
2016; 7 (16): 22092–102.
Hermeking H. MicroRNAs in the p53 network: micromanagement of tumour suppression. Nat Rev Cancer
2012; 12 (9): 613–26.
Zhang DG, Zheng JN, Pei DS. P53/microRNA-34-induced metabolic regulation: new opportunities in anticancer therapy. Mol Cancer
2014; 13: 115.
Xiao X, Huang X, Ye F, Chen B, Song C, Wen J, Zhang Z, Zheng G, Tang H, Xie X. The miR-34a-LDHA axis regulates glucose metabolism and tumor growth in breast cancer. Sci Rep
2016; 6: 21735.
Kumar M, Lu Z, Takwi AA, Chen W, Callander NS, Ramos KS, Young KH, Li Y. Negative regulation of the tumor suppressor p53 gene by microRNAs. Oncogene
2011; 30 (7): 843–53.
Voorhoeve PM, le Sage C, Schrier M, Gillis AJ, Stoop H, Nagel R, Liu YP, van Duijse J, Drost J, Griekspoor A, Zlotorynski E, Yabuta N, De Vita G, Nojima H, Looijenga LH, Agami R. A genetic screen implicates miRNA-372 and miRNA-373 as oncogenes in testicular germ cell tumors. Cell
2006; 124 (6): 1169–81.
Zhang Z, Sun H, Dai H, Walsh RM, Imakura M, Schelter J, Burchard J, Dai X, Chang AN, Diaz RL, Marszalek JR, Bartz SR, Carleton M, Cleary MA, Linsley PS, Grandori C. MicroRNA miR-210 modulates cellular response to hypoxia through the MYC antagonist MNT. Cell Cycle
2009; 8 (17): 2756–68.
Dengler VL, Galbraith MD, Espinosa JM. Transcriptional regulation by hypoxia inducible factors. Crit Rev Biochem Mol Biol
2014; 49 (1): 1–15.
Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE, Hjelmeland AB, Rich JN. Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell
2009; 15 (6): 501–13.
Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC. HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell
2007; 11 (4): 335–47.
Stine ZE, Walton ZE, Altman BJ, Hsieh AL, Dang CV. MYC, metabolism, and cancer. Cancer Discov
2015; 5 (10): 1024–39.
Dang CV. MYC, metabolism, cell growth, and tumorigenesis. Cold Spring Harb Perspect Med
2013; 3 (8). pii: a014217.
Zeller KI, Jegga AG, Aronow BJ, O'Donnell KA, Dang CV. An integrated database of genes responsive to the Myc oncogenic transcription factor: identification of direct genomic targets. Genome Biol
2003; 4 (10): R69.
Harris SL, Levine AJ. The p53 pathway: positive and negative feedback loops. Oncogene
2005; 24 (17): 2899–908.
Puzio-Kuter AM. The role of p53 in metabolic regulation. Genes Cancer
2011; 2 (4): 385–91.
Kruiswijk F, Labuschagne CF, Vousden KH. p53 in survival, death and metabolic health: a lifeguard with a licence to kill. Nat Rev Mol Cell Biol
2015; 16 (7): 393–405.
Schwartzenberg-Bar-Yoseph F, Armoni M, Karnieli E. The tumor suppressor p53 down-regulates glucose transporters GLUT1 and GLUT4 gene expression. Cancer Res
2004; 64 (7): 2627–33.
Berkers CR, Maddocks OD, Cheung EC, Mor I, Vousden KH. Metabolic regulation by p53 family members. Cell Metab
2013; 18 (5): 617–33.
Braun CJ, Zhang X, Savelyeva I, Wolff S, Moll UM, Schepeler T, Orntoft TF, Andersen CL, Dobbelstein M. p53-Responsive micrornas 192 and 215 are capable of inducing cell cycle arrest. Cancer Res
2008; 68 (24): 10094–104.
Yan HL, Xue G, Mei Q, Wang YZ, Ding FX, Liu MF, Lu MH, Tang Y, Yu HY, Sun SH. Repression of the miR-17-92 cluster by p53 has an important function in hypoxia-induced apoptosis. EMBO J
2009; 28 (18): 2719–32.
Suzuki HI, Miyazono K. p53 actions on microRNA expression and maturation pathway. Methods Mol Biol
2013; 962: 165–81.
[Table 1], [Table 2]
|This article has been cited by|
||Hypoxia-induced tumor exosomes promote M2-like macrophage polarization of infiltrating myeloid cells and microRNA-mediated metabolic shift
| ||Jung Eun Park,Bamaprasad Dutta,Shun Wilford Tse,Nikhil Gupta,Chee Fan Tan,Jee Keem Low,Kheng Wei Yeoh,Oi Lian Kon,James P. Tam,Siu Kwan Sze |
| ||Oncogene. 2019; |
|[Pubmed] | [DOI]|
||MicroRNA-30d inhibits the migration and invasion of human esophageal squamous cell carcinoma cells via the post-transcriptional regulation of enhancer of zeste homolog 2
| ||Rui Xie,Shang-Nong Wu,Cheng-Cheng Gao,Xiao-Zhong Yang,Hong-Gang Wang,Jia-Ling Zhang,Wei Yan,Tian-Heng Ma |
| ||Oncology Reports. 2017; 37(3): 1682 |
|[Pubmed] | [DOI]|
||RSF1 functions as an oncogene in osteosarcoma and is regulated by XIST/miR-193a-3p axis
| ||Dapeng Wu,Xingguo Nie,Chao Ma,Xianghua Liu,Xue Liang,Yongbo An,Bin Zhao,Xuejian Wu |
| ||Biomedicine & Pharmacotherapy. 2017; 95: 207 |
|[Pubmed] | [DOI]|
||Hexokinase 2 (HK2), the tumor promoter in glioma, is downregulated by miR-218/Bmi1 pathway
| ||Hui Liu,Nan Liu,Yingduan Cheng,Weilin Jin,Pengxing Zhang,Xin Wang,Hongwei Yang,Xiaoshan Xu,Zhen Wang,Yanyang Tu,Aamir Ahmad |
| ||PLOS ONE. 2017; 12(12): e0189353 |
|[Pubmed] | [DOI]|