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 Table of Contents  
REVIEW
Year : 2016  |  Volume : 2  |  Issue : 6  |  Page : 175-181

MicroRNA regulating metabolic reprogramming in tumor cells: New tumor markers


Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocio, CSIC, Universidad de Sevilla, Seville, Spain

Date of Submission10-Oct-2016
Date of Acceptance15-Nov-2016
Date of Web Publication28-Dec-2016

Correspondence Address:
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
Spain
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2395-3977.196909

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  Abstract 

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 Top


Reprogramming energy metabolism has emerged as a new hallmark of cancer.[1] 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.[2],[3],[4] This acidic environment favors tumor invasion and suppresses anticancer immune effectors, allowing cells to survive and metastasize to distal tissues.[5] 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.[6] 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.[7],[8],[9],[10],[11 The oxidation of glutamine into glutamate and further into alpha-ketoglutarate (α-KG), lactate, or alanine is known as glutaminolysis.[12] 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.[13],[14],[15]

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),[16],[17],[18] small noncoding RNAs with gene regulatory functions that have emerged as key regulators of the tumor microenvironment.[19],[20] 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.[19] 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 Top


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).[21] 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].[22],[23] 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.[47],[48] This enzyme is repressed by miR-143, which inversely correlates with HK2 expression in head and neck squamous cell carcinoma and in lung tumors.[24],[25]HK2 is also a target of miR-181b, which is downregulated in human gastric cancers.[26] 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.[27] 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.[28],[29] 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.[49]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.[30] MCTs are targets of miRNAs as well. It has been described that miR-124, frequently downregulated in medulloblastomas, is a negative regulator of MCT1.[31]
Table 1: MicroRNAs regulating metabolic enzymes

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Finally, the muscle-specific pyruvate kinase M (PKM) has a pivotal role in metabolic reprogramming in tumor cells.[50] PKM shows two isoforms, PKM1 and PKM2, as a result of alternative splicing of exons 9 and 10.[51] 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.[32]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.[33],[34],[35] 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.[51]

PPP increased activity is another feature of metabolic reprogramming;[52] 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.[36]


  Regulation of the Tricarboxylic Acid Cycle by Micrornas Top


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.[53] The expression of both isoenzymes is regulated by miRNAs. PDK1 is a target of miR-125b, which is downregulated in chronic lymphocytic leukemia,[37] and PDK4 is negatively regulated by miR-211, which is reduced in melanoma cells.[38] 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.[39]

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”.[54] 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.[40],[41] 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.[42] Iron-sulfur cluster scaffold homolog (ISCU) and cytochrome C oxidase assembly protein (COX10) have also been identified as potential miR-210 targets.[43] 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),[44] while miR-378 inhibits the expression of PGC-1β, leading to the shift from mitochondrial respiration to aerobic glycolysis.[45]

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.[12],[55] 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;[46] therefore, the downregulation of miR-23 in cancer cell would be expected.


  Micrornas Controlling Signaling Pathways Involved in Metabolic Reprogramming Top


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.[56] 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).[57] HIF-1α is in charge of the regulation of genes included in metabolic pathways such as GLUT1, GLUT3, HK1, HK2, ALDHA, PGK, and LDHA.[58],[59] It means that HIF-1α can increase the glycolytic flux and reduce the amount of pyruvate entering into the TCA.[60]HIF-1 α can be stabilized by miR-92-1, which directly targets VHL [Table 2];[61] 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.[62] 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.[63],[64]

In addition, it has been shown that miR-210 is also a target of HIF-2 α,[76] 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,[57],[77] 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.[78] HIF-2α is also able to promote cell cycle by enhancing c-MYC activity.[79] Further, it has been proved that miR-182 suppresses the expression of HIF-2 α, inhibiting its reprogramming ability and decreasing glioblastoma progression.[65],[66]

MYC, another oncogenic transcription factor, can promote survival, cellular growth, and proliferation as well.[80] 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.[60],[81],[82] 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.[67] 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,[68] increasing glucose metabolism because of the expression of GLUT genes and the activity of glycolytic enzymes.[69] 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.[70]

p53 action as a tumor suppressor goes beyond DNA damage response, cell cycle regulation, and apoptosis.[83] It can modify the expression of genes involved in the metabolism shift.[84] 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.[85],[86],[87] 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.[71],[88] 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.[72],[73] In addition to this, p53 can also suppress the expression of some oncogenic miRNAs such as miR-16-1, miR-143, and miR-145.[89],[90] 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.[74],[75]


  Conclusion Top


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.
Table 2: MicroRNAs involved in regulation of signaling pathways

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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.

 
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