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REVIEW ARTICLE

Hypoxia-induced tumor malignancy and drug

resistance: Role of microRNAs

Wan-Lin Liao

a

, Shao-Chieh Lin

b

, H. Sunny Sun

c,

**

,

Shaw-Jenq Tsai

a,

*

a

Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

bDepartment of Surgery, College of Medicine, National Cheng Kung University, Tainan, Taiwan c

Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan

Received 15 January 2014; received in revised form 24 January 2014; accepted 24 January 2014

Available online 1 March 2014

KEYWORDS

drug resistance; hypoxia; microRNAs; tumor malignancy

Abstract Hypoxia is an intricate microenvironment associated with aggressiveness and che-moresistance of a variety of solid tumors. Hypoxia-inducible factors (HIFs) regulate down-stream target genes that render cancer cells capacity to adapt to the hostile, low-oxygen stress for survival. HIF has been estimated to regulate more than 5% of total human genes. The HIF-regulated gene network has been shown to be associated with resistance to chemo-therapy, metastasis, tumor recurrence, and reduced overall survival rate. With the increasing findings that microRNAs (miRNAs) are aberrantly expressed under hypoxia, which participate positively or negatively in regulating hypoxia-related genes, the signaling pathway of hypoxia becomes more and more complicated. Based on the roles of miRNAs in tumor development and drug resistance, the potential of targeting miRNAs as a therapeutic regimen has been empha-sized recently. Therefore, understanding the regulation and functions of miRNAs in cancer cells will provide us with useful information for designing more efficacious treatment regi-mens. In this article, we will review the biological kinship of hypoxia and hypoxia-regulated miRNAs in cancer malignancy and drug resistance.

Copyrightª2013, Taiwan Genomic Medicine and Biomarker Society. Published by Elsevier Taiwan LLC. All rights reserved.

Introduction

Cancer is a major public health problem and its treatment creates a huge financial burden for patients. The reasons contributing to tumor development and treatment failure are related to mutations of various oncogenes and tumor suppressor genes or to a continuous change of microenvi-ronment. Despite the increasing understanding of mecha-nisms responsible for tumorigenesis and advancement in * Corresponding author. Shaw-Jenq Tsai, Department of

Physi-ology, College of Medicine, National Cheng Kung University, 1 Uni-versity Road, Tainan 70101, Taiwan.

** Corresponding author. H. Sunny Sun, Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, 1 University Road, Tainan 70101, Taiwan.

E-mail addresses:hssun@mail.ncku.edu.tw(H. Sunny Sun), seantsai@mail.ncku.edu.tw(S.-J. Tsai).

2214-0247/$36 Copyrightª2013, Taiwan Genomic Medicine and Biomarker Society. Published by Elsevier Taiwan LLC. All rights reserved. http://dx.doi.org/10.1016/j.bgm.2014.01.003

Available online atwww.sciencedirect.com

ScienceDirect

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cancer therapy, the complex etiology of carcinogenesis remains a major hurdle to cure patients efficiently. Thus, it is critical to elucidate more information about cancer biology.

MicroRNAs (miRNAs) are short, noncoding RNAs that inhibit the expression of genes by causing either messenger RNA (mRNA) degradation or protein translational repres-sion.1,2Since their discovery in 1993, miRNAs continue to be at the center stage of the “noncoding RNA revolution”. So far, miRNAs have been thought to regulate the expression of most genes and consequently play critical roles in the coor-dination of a wide variety of processes such as cell differ-entiation, proliferation, death, and metabolism.3 Besides, accumulating evidence has shown that miRNAs are associ-ated with various steps of tumorigenesis,4 and altered expression profiles of miRNAs in cancers indicate their po-tential as biomarkers with clinicopathological features.5e8

Given the diverse roles of miRNAs in numerous aspects of cancer biology, it is not surprising that they also play a role in hypoxia, which is an essential feature of the neoplastic microenvironment. Recently, a signature of hypoxia-inducible miRNAs has been identified.9Notably, many hypoxia-induced miRNAs are also overexpressed in human cancers, suggesting that induction of these miRNAs may affect important target genes involved in tumor survival, proliferation, vasculariza-tion, or alteration of the response to chemotherapy. Herein, we will summarize recent findings on hypoxia-associated miRNAs and the impacts of these miRNAs and their target genes on tumor malignancy and/or drug resistance.

Hypoxia, hypoxia-inducible factor, and cancer

malignancy

Regulation of hypoxia-inducible factor

Cancer malignancy is the most serious problem that causes numerous deaths every year worldwide. Malignancy arises from many factors such as uncontrolled growth of cancer cells, abnormal metabolism, angiogenesis, metastasis, and resistance to chemotherapy. Microenvironment is also an important factor related to malignancy, and hypoxia is the most common neoplastic microenvironment in solid tumors in which oxygen concentration is reduced markedly. In order to overcome hypoxic situation and acquire sufficient oxygen, hypoxic cells activate numerous genes involved in angiogenesis, glucose metabolism, cell proliferation, and survival through transcriptional upregulation by hypoxia-inducible factor (HIF). This adaptive response co-opted by cancer cells usually results in further cancer progression or drug resistance, which ultimately leads to patient mortal-ity.10e14 The well-known HIF is a heterodimeric transcrip-tion factor composed of oneasubunit and onebsubunit. Theasubunit has three isoforms: HIF-1a, HIF-2a, and HIF-3a. HIF-1a is widely expressed in most tissues, but the expression of HIF-2ais more restricted. In contrast to the aforementioned HIFs, the expression and function of HIF-3a are less clear. HIF activities are regulated by the induction or stabilization of theasubunit, which is tightly regulated by oxygen tension. HIF-1ais usually kept at a low level in normoxic condition due to ubiquitination-dependent pro-tein degradation. Oxygen-dependent prolyl hydroxylase

(PHD) hydroxylates the proline residues (Pro402 and Pro564 in human HIF-1a) and promotes the recognition by von HippeleLindau (VHL) protein, an E3 ligase. Ubiquitinated

HIF-ais then degraded by the 26S-proteasomal degradation pathway.15,16 Under hypoxia, hydroxylation of HIF-a is attenuated and HIF-ais stabilized (Fig. 1). In sharp contrast to theasubunit, the bsubunit of HIF, also called aryl hy-drocarbon receptor nuclear translocator, is expressed constitutively.

Metabolic alternation under hypoxia

Increased conversion of glucose to lactate has been regar-ded as a critical cellular metabolic adaptation to hypoxia. This reprogramming in metabolism has a causal impact on tumor progression.17,18 Cancer cells have been found to predominantly produce energy by a high rate of glycolysis followed by lactate fermentation, rather than by oxidation of pyruvate in mitochondria, the major way of producing energy by normal cells (Fig. 2). The elevated glucose up-take by cancer cells is due to an increased expression of genes such as glucose transporters (Glut1 and Glut3) and many glycolytic enzymes (hexokinase1, hexokinase2 (HK1 and HK2), glucosephosphate isomerase (GPI), aldolase A (ALDA) and lactate dehydrogenase A (LDHA)) induced by HIF-1a.19,20 However, the key point of switching mito-chondrial phosphorylation to cytoplasmic glycolysis is the suppression of pyruvate conversion to acetyl coenzyme A (acetyl-CoA). Hypoxia induces the expression of pyruvate dehydrogenase kinase-1 and kinase-3 (PDK1 and PDK3) in an HIF-1- and HIF-2-dependent manner.21e23 PDK1 and PDK3 inactivate pyruvate dehydrogenase (PDH), an enzyme that converts pyruvate to acetyl-CoA, which fuels the tricar-boxylic acid cycle. Inhibition of PDH by PDK prevents mitochondrial phosphorylation and facilitates cytosolic glycolysis. Although the mechanism is not completely un-derstood, the switch from oxidative phosphorylation to aerobic glycolysis increases drug resistance. Indeed, upre-gulation of PDK3 in colon cancer has been found to be associated with drug resistance and early recurrence.24

Alteration in cell proliferation and apoptosis

Dysregulation of cell proliferation under hypoxia is a pivotal cause of tumor malignancy. The PI3K/Akt/mTOR signaling pathway has been demonstrated to participate in a variety of cellular processes such as cell proliferation, migration, and metabolism.25 A plethora of studies have provided supportive evidence indicating that hypoxia induces the PI3K/Akt/mTOR signaling pathway in a HIF-dependent manner in a variety of cancer cells. All this evidence sug-gests that HIF and the PI3K/Akt/mTOR signaling pathway form a feed-forward loop under a hypoxic microenviron-ment, which leads to tumor malignancy.26e28

Defective apoptosis and cell cycle have been found in hypoxia. For most normal cells, the cell-cycle arrest and apoptosis are induced under hypoxia in an HIF-dependent manner. By contrast, tumor cells exert different responses to hypoxia by activating antiapoptotic genes (e.g., Bcl2,

Bcl-xL, Mcl-1, NF-kB, and survivin) in an HIF-dependent manner instead of activating proapoptotic genes.29,30

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Figure 1 Regulation of HIF-1aprotein under normoxia and hypoxia. HIFZhypoxia-inducible factor; PHDZprolyl hydroxylase; VHLZvon HippeleLindau.

Figure 2 Schematic drawing showing hypoxia-mediated metabolic switch. Acetyl-CoA Zacetyl coenzyme A; HIFZ hypoxia-inducible factor; PDHZpyruvate dehydrogenase; PDKZpyruvate dehydrogenase kinase; TCAZtricarboxylic acid.

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Angiogenesis in tumor

Angiogenesis is defined as the formation of new blood vessels from the pre-existing vasculature and has been demonstrated to play essential roles in tumor growth, in-vasion, and metastasis. It is well known that angiogenesis is regulated by mediating angiogenic factors such as vascular endothelial growth factor (VEGF). Tumor hypoxia is the most well-studied stimulus for the induction of angiogen-esis, and the involvement of HIF-1a in the regulation of VEGF expression is well documented.31

Hypoxia, HIF, and drug resistance

To overcome the adversity of drug resistance occurring in patients with advanced and inoperable cancer is always deemed to be a difficult task. Three basic categories that describe the cause of chemotherapy failure are as follows: inadequate pharmacokinetic properties of a drug, intrinsic factors such as adenosine triphosphate (ATP)-binding cassette transport protein that affects drug efflux, and extrinsic conditions that exist in the tumor microenviron-ment, such as hypoxia. Intrinsic and extrinsic factors often interact with each other to enhance drug resistance, making the situation even more complicated. Hypoxia is a hallmark of the neoplastic microenvironment and a well-documented source of therapeutic failure in clinical oncology. Contribution of HIFs to drug resistance has been observed in a wide spectrum of solid tumor cellsin vitro.

The multidrug resistance 1 (MDR1) gene, which encodes a membrane-resident P-glycoprotein, is a member of the ATP-binding cassette family and is reported to be upregu-lated under hypoxia.32As a drug efflux pump, upregulation of MDR1 will lead to chemoresistance by pumping chemo-therapeutic drugs. A significant correlation between the expression of HIF-1a and upregulation of MDR1 has been reported in colon cancer.33,34 MRP-1 (a multidrug-resistance-associated protein), another ATP-binding cassette transporter, has also been found to be relevant to HIF-1a-mediated drug resistance.35e37

MiRNAs and cancer

Since the discovery of the first miRNA in 1993, the role of miRNAs in gene regulation has been exploited, especially in recent years.1,38MiRNAs are small, 19e25 nucleotide

non-coding RNAs and act as negative regulators of gene expression. Like a conventional protein-coding mRNA, pri-mary miRNA transcripts are generated by RNA polymerase II. Then in the nucleus, primary miRNA transcripts are processed by an RNase III endonuclease, Drosha, to form hairpin-containing precursor miRNAs. These hairpin-containing precursor miRNAs are subsequently exported to the cytoplasm by exportin 5. In the cytoplasm, precursor miRNAs are then processed by Dicer to form mature miR-NAs. Usually, mature miRNAs are incorporated into the RNA-induced silencing complex and target specific se-quences located in the 30untranslated region of mRNA. This perfect or imperfect base pairing will lead to an mRNA cleavage or translational repression of the targeted mRNA.39It has been reported that miRNAs regulate most of

the physiological and pathological cellular processes1 and also influence numerous cancer-relevant processes such as proliferation, cell-cycle control, apoptosis, differentiation, migration, and metabolism.40Some miRNAs are aberrantly expressed due to genomic abnormalities or epigenetic modification.41,42The microarray expression profile from a wide spectrum of cancer diseases has shown that aberrant miRNAs are expressed in cancers.43e46Importantly, mouse models featuring miRNA overexpression or ablation have demonstrated causal links between miRNAs and cancer development, implying that miRNAs have the potential to serve as biomarkers and putative therapeutic targets in clinic.47,48

Although limited miRNA promoters were characterized experimentally, several studies, which determined global miRNA promoter architecture, showed their similarity to promoters of protein-coding mRNA.49,50 Not surprisingly, miRNA promoters are also replete with consensus binding sites of transcription factors, and thus the expression of specific subsets of miRNAs can be regulated by a hypoxia-induced transcription factor in the context of cellular hypoxia. These miRNAs regulated by hypoxic stress are termed hypoxamirs.51,52Recent evidence indicates that the transcription of some hypoxamirs can be induced by HIF through its binding to a hypoxia response element (HRE) located in the promoter.53,54

Hypoxia and miRNAs

Hypoxia-regulated miRNAs

Despite myriads of reports demonstrating that altered miRNA expression is a common phenomenon in human cancer and correlated with malignancy or resistance to conventional therapy, relatively few reports elucidate mechanisms involving in this profile alteration. The pro-posed mechanism described that dysregulated signal transduction pathways, which in turn activate/repress the transcription ofmiRNAgenes, could be involved in cancer progression.55 Although the microenvironment of tumors also affects tumor pathogenesis and response to chemo-therapy,56,57relatively little is known about the abnormal expression of miRNA in cancer cells, which is also regulated by microenvironmental factors.

As mentioned above, hypoxia is an essential feature of the neoplastic microenvironment. Thus, hypoxia-regulated miRNAs (HRMs) are deemed to play some role in cancer invasion or drug resistance. As such, cancer-associated miRNA profiles should exhibit a hypoxic signature. Based on this idea, Kulshreshtha and colleagues9first used human cancer cell lines to characterize miRNAs responding to ox-ygen deprivation by microarray-based screening. Candi-dates selected using the microarray data were confirmed by Northern analysis or quantitative real-time polymerase chain reaction to confirm the bona fide character of HRMs. They showed experimental evidence that caspase activa-tion is inhibited by several HRMs during hypoxia. Interest-ingly, they further used programs such as TargetScan, PicTar, and miRBase to predict that several HRMs can target core components of apoptotic genes such as BAK1 (targeted by miR-26), BIM (miR-24 and miR-181), BID (miR-23), and

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caspase-7 (miR-23). This is the first hint that hypoxia may represent a key “trigger” contributing to miRNA alteration in tumors. This alteration may affect downstream target genes that are involved in cell survival and apoptosis, which cause malignancy and drug resistance.

Shortly after this pioneering study, several studies demonstrating specific HRMs and their target genes have been conducted, and the number of such reports is increasing. From these published studies, we can find that HRMs are classified into two groups: miRNAs that are induced under hypoxia in an HIF-dependent pathway or through an unclear mechanism, and miRNAs that are reduced under hypoxia. Up- or downregulated miRNAs may impact tumor malignancy or drug resistance according to the target genes they affect. Here, we summarized some published studies demonstrating that the target genes of HRMs exert significant effects on tumor malignancy or drug resistance (Table 1,Fig. 3).

MiR-103/107

Death-associated protein kinase (DAPK) is a metastasis suppressor. The expression of DAPK has been reported to inhibit metastasis of Lewis lung carcinoma by increasing apoptosis of tumor cells.76 Kru¨ppel-like factor 4 (KLF4), a zinc finger transcriptional factor, is maximally expressed in

epithelial cells of the gastrointestinal tract, skin, and vascular endothelial cells. Downregulation of KLF4 protein expression in the colon may contribute to cellular hyper-proliferation and malignant transformation.77 Chen et al58 found that, in colorectal cancer, DAPK and KLF4 were tar-gets of miR-103 and miR-107. High levels of miR-103/107 result in low expressions of DAPK and KLF4, which corre-late with metastasis state and poor prognosis. In addition, they also found that miR-103/107 levels were induced by hypoxia, and meanwhile, DAPK and KLF4 were down-regulated. This observation indicates that hypoxia-induced miR-103/107 contributes to cancer migration and invasion.

MiR-424

Cullin 2 (CUL2) is a scaffold protein of the VHL protein critical to the assembly of the ubiquitin ligase system. In normoxia, HIF-1ais hydroxylated at two proline residues by PHDs,78then the hydroxylated HIF-1ais recognized by the VHL protein, an E3 ligase that ubiquitinates HIF-1a, and subjected to degradation by 26S-proteasome.15,16Thus, the level of HIF-1a is very low under normoxic condition. In Ghosh et al’s59study, they found that CUL2 is a target of miR-424 and, under hypoxic conditions, the expression of miR-424 is elevated, resulting in a decreased expression of CUL2 in endothelial cells. The inhibition of CUL2

Table 1 Targets of hypoxia-regulated miRNAs and their functional roles. miRNA Effect of

hypoxia

miRNA target(s)

Biological process Resistance to drug

Cell types Refs miR-103/107 Upregulate DAPK, KLF4 Oncogenesis Unknown Colorectal cancer 58 miR-424 Upregulate CUL2 Angiogenesis Unknown Endothelial cell 59 miR-20a Upregulate DUSP2 Proliferation/

angiogenesis

Unknown Endometriotic stromal cell

60 miR-210 Upregulate ISCU1/2,

RAD52, ephrinA3 Mitochondrial metabolism DNA repair, angiogenesis

Unknown Most cell lines 61e66

miR-200b Upregulate PHD2 Angiogenesis Unknown Neuroblast cell 67 miR-200b Unknown PTPN12 Oncogenesis Gemcitabine Cholangiocarcinoma

cell

68 miR-200b Downregulate Ets-1 Angiogenesis Unknown Endothelial cell 69 miR-15b Downregulate VEGF Angiogenesis Unknown Nasopharyngeal

carcinoma cell

70 miR-16 Downregulate VEGF Angiogenesis Unknown Nasopharyngeal

carcinoma cell, anaplastic large cell lymphoma

70,71

miR-15b Unknown Bcl-2 Drug resistance Vincristine, doxorubicin

Gastric cancer cell 72 miR-16 Unknown Bcl-2 Drug resistance Etoposide,

cisplatin

Gastric cancer cell 72 miR-100 Downregulate FGFR3 Proliferation Unknown Bladder cancer cell 73 miR-199a Downregulate HIF-1a,

Sirtuin1

Induction of proapoptotic genes, proliferation

Unknown Cardiac myocytes/ non-small-cell lung cancer

74,75

CULZcullin; DAPKZdeath-associated protein kinase; DUSPZdual-specificity phosphatase; Ets-1Zv-ets erythroblastosis virus E26 oncogene homolog 1; FGFR Z fibroblast growth factor receptor; HIF Z hypoxia-inducible factor; KLF Z Kru¨ppel-like factor; PHDZprolyl hydroxylase; VEGFZvascular endothelial growth factor.

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contributes to the stabilization of HIF-1aand an increase in angiogenesis. Furthermore, they also proved an elusive mechanism that miR-424 expression was regulated by C/ EBP-a/RUNX-1-mediated transactivation. This finding in-dicates that not only HIF-1aregulates the transcription of miRNAs, but the stability of HIF-1aprotein is also affected by the expression of some miRNAs. This finding is very interesting because it shows that miR-424 is a critical mediator affecting the proteasome degradation pathway and thus increasing HIF-1a expression under hypoxia. Be-sides, this finding also shows that miR-424 is physiologically upregulated in tissues undergoing vascular remodeling and angiogenesis, which are important factors for cancer malignancy.

MiR-20a

It is reported that constitutive activation of extracellular signal-regulated kinase (ERK) signaling pathway is associ-ated with tumor progression in many cancers such as colon, ovary, pancreas, and lung cancers.79e81 In addition, it is demonstrated that activation of ERK signaling in cancer cells also results in drug resistance.82e84 Dual-specificity phosphatases (DUSPs) comprise a group of phosphatases that regulate MAPKs negatively by dephosphorylating phosphothreonine and phosphotyrosine residues.85 DUSPs are classified into three groups according to their subcel-lular localization. Dual-specificity phosphatase 2 (DUSP2) belongs to class I DUSPs, which dephosphorylates nuclear substrates and inactivates ERK activity predominantly.86,87 It has been demonstrated that the expression of DUSP2 is

suppressed under hypoxia, resulting in prolonged ERK activation, which in turn elevates malignancy and drug resistance in human cancers.34Another study reported that DUSP2 was a target of miR-20a, and miR-20a was tran-scriptionally upregulated by HIF-1aunder hypoxia.60It was also found that some genes downstream of ERK, such as

EGR-1, MDR-1, CYP61, and osteopontin, were induced under hypoxia in an miR-20a-dependent manner.60Notably, EGR-1, MDR-1, CYR-61, and osteopontin have been reported to be involved in tumor aggression and drug resistance.88,89 The oncogenic function of miR-20a in a variety of cancer types was reported in many studies.90e93 MiR-20a was upregulated significantly in colorectal cancers,94 and an increased miR-20a level in colorectal cancers has been found to contribute to chemotherapy resistance.95 The finding that hypoxia-induced miR-20a suppresses DUSP2 expression, thereby activating ERK activation and inducing some angiogenesis-related genes, indicates the important role of miR-20a under hypoxia and its potential influence on malignancy and drug resistance in cancer cells.

MiR-210

MiR-210 is the most well-known HRM and a versatile miRNA that regulates many aspects of hypoxia pathways, in both physiological and malignant conditions.61 MiR-210 is induced under hypoxia in a wide range of primary and transformed cells.61,62 HIF-1a has been demonstrated to recognize HRE on the miR-210 promoter.63When comparing miR-210 core promoters across species, this HRE site is highly conserved, indicating that the regulation of miR-210

Figure 3 Biological functions of HIF-1a-regulated miRNA. CULZcullin; DAPKZdeath-associated protein kinase; DUSPZ dual-specificity phosphatase; EFNAZephrin-A3; Ets-1Zv-ets erythroblastosis virus E26 oncogene homolog 1; FGFRZfibroblast growth factor receptor; HIFZhypoxia-inducible factor; KLFZKru¨ppel-like factor; PHDZprolyl hydroxylase; VEGFZvascular endo-thelial growth factor.

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expression by hypoxia is a universal phenomenon in these species. In addition, the presence of HRE in the miR-210 promoter region also suggests that the expression level of miR-210 may be a reflection of HIF activity. The upregula-tion of miR-210 in solid tumors is associated negatively with the prognosis, indicating that the target genes affected by miR-210 have functional impact on tumor malignancy and drug resistance. Recently, a number of miR-210 targets have been reported, whose functional roles include mito-chondrial metabolism, angiogenesis, DNA repair, and cell survival.

It was reported that miR-210 decreases mitochondrial function and upregulates glycolysis.64 From the identified functions influenced by miR-210, we know that intervention of miR-210 has a potential in therapeutic application. Recent studies revealed that suppression of miR-210 can sensitize tumor cells to radiation in a variety of cancers by inhibiting proliferation and promoting apoptosis.65,66Based on the identified target genes of miR-210 and the finding that expression of miR-210 is elevated in a variety of solid tumors, we speculate that targeting miR-210 may create a new avenue for more effective cancer treatment.

MiR-200b

MiR-200b was reported to be upregulated during ischemic preconditioning and PHD2, the enzyme activity of which was inhibited under hypoxia, was found to be targeted by miR-200b.67 This finding shows an additional example that miRNAs affect HIF-1aactivity by targeting PHD2 and further influence angiogenesis. Notably, in another study by Meng et al,68 they found that overexpression of miR-200b con-tributes to chemoresistance in cholangiocarcinoma by inhibiting PTPN12. Based on the finding of miR-200b in regulating HIF-1aand its mentioned role in chemoresponse, hypoxia-regulated miR-200b in drug resistance in cancer cells is worth further investigation.

However, a recent study showed that miR-200b over-expression in human microvascular endothelial cells sup-pressed the angiogenic response. In the study published by Chan et al,69 they found that v-ets erythroblastosis virus E26 oncogene homolog 1 (Ets-1), a transcription factor that controls the expression of genes related to angiogenesis, is a novel target of miR-200b. In human microvascular endo-thelial cells, the expression of miR-200b was significantly inhibited under hypoxia, allowing Ets-1 upregulation to promote angiogenesis. This evidence explains that one miRNA may have opposite response to hypoxia according to the cellular context, duration, and severity of oxygen deprivation thus exert different biological functions by affecting diverse target genes.

MiR-15b and miR-16

Angiogenesis is an important trait, by which the hypoxic region of cancer cells can acquire oxygen and nutrients again. This neovascular network allows tumor growth and metastasis.96VEGF, the most well-studied angiogenic fac-tor, is upregulated under hypoxia.31 As reported in the study published by Hua et al,70 miR-15b and miR-16 in human nasopharyngeal carcinoma cells were

downregulated by hypoxia treatment, and both miR-15b and miR-16 were found to have repressive effects on VEGF under normoxia. Dejean et al71found that miR-16 was downregulated in an HIF-1a-dependent manner, and the expressions of miR-16 and VEGF presented an inverse cor-relation in anaplastic large cell lymphomas. Interestingly, downregulation of miR-15b and miR-16 was found to result in drug resistance in gastric cancer cells, and this resistance was ascribed to elevated BCL-2, a target of miR-15b and miR-16.72 Thus, downregulation of miR-15b and miR-16 under hypoxia implies the potential mechanism that regu-lates the drug resistance induced by hypoxia.

MiR-100

Fibroblast growth factor receptor 3 (FGFR3), one of four members of the FGFR family of receptor tyrosine kinases, is of paramount importance in the pathogenesis of bladder cancer.97Signals elicited by FGFRs lead to the activation of multiple intracellular signaling pathways such as MAPK and PI3K signaling cascades.98Blick and colleagues73found that FGFR3 is a target of miR-100, and the upregulation of FGFR3 is mediated through HIF-1a-dependent transcriptional upregulation and suppression of miR-100, leading to elevation of FGFR3. This finding provides additional evi-dence that deregulated miRNA under hypoxia affects pro-liferation signals of cancer cells.

MiR-199a

Differentially expressed miRNA in the heart revealed that miR-199a was reduced to an undetectable level during cardiac ischemia. Functional analysis indicates that this reduction is required for upregulation of hypoxia-induced apoptotic genes. Computational prediction and experi-mental evidence show that HIF-1ais a direct target of miR-199a. Knockdown of miR-199a under normoxia results in the upregulation of HIF-1a, suggesting that it might be associ-ated with the inhibition or downregulation of PHD2. Sur-prisingly, PHD2 was found to be reduced in miR-199a knockdown cells and this reduction was reversed by over-expression of miR-199a. Further analysis showed that Sir-tuin 1, a class III histone deacetylase that is responsible for downregulating PHD2, is also a target of miR-199a. This finding demonstrated that miR-199a regulates two key molecules that are functionally linked under hypoxia.74 In addition to this finding, it was demonstrated that the reduction in miR-199a levels is highly associated with the progression of non-small-cell lung cancer, and this effect is also related to the corresponding upregulation of HIF-1a.75

Interaction among miRNAs in cancer

development

As miRNAs influence many biological processes such as human diseases, maintaining accurate levels of miRNAs is important. Regulation of miRNA biogenesis and turnover occur both transcriptionally and post-transcriptionally.99 Numerous Pol II-associated transcription factors are involved in the transcriptional control ofmiRNAgenes. For

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example, tumor suppressor p53 activates the miR-34 fam-ily,100whereas the proto-oncogene c-Myc transactivates or represses a number of miRNAs that are involved in the cell cycle and apoptosis.77,101,102

Post-transcriptional regulation of miRNAs occurs at various steps, including processing, maturation, stabiliza-tion, and degradation of miRNAs.103Although many regu-latory factors involved in this processing are still unclear, it is plausible that some RNA-binding proteins influence miRNA processing through specific interactions. The let-7 miRNA is an example indicating that its expression pattern is controlled post-transcriptionally. Experimental evidence shows that the primary transcript of let-7 is expressed in both undifferentiated and differentiated em-bryonic stem cells, whereas mature let-7 is detected only in differentiated cells; similar post-transcriptional inhibition of let-7 also takes place in tumor cells.104,105Recent studies have shown that LIN28, an RNA-binding protein, is respon-sible for the suppression of let-7 biogenesis, through interference with Dicer processing106 and terminal uridy-lation of pre-let-7.107

Although the possibility of miRNAs regulating other miRNAs has been postulated, little evidence exists in the literature. Chen et al108found that miR-107 can interact directly with let-7 and promote let-7 degradation. Let-7 has been reported to suppress proliferation by targeting the oncogene Ras109In their study, they also found that miR-107 was highly expressed in patients with advanced breast cancer, with an inverse correlation with the levels of let-7. Functional assays demonstrated that downregulation of the tumor suppressor miRNA let-7 is important for miR-107-mediated tumorigenesis. The interaction among miR-107 and let-7 provides an explanation for the acceleration of tumor progression by miR-107. Besides, the authors also indicated that the two miRNAs have reciprocal suppression to each other, suggesting that the interaction among miR-NAs should be in a balanced situation under normal condi-tion, but the balance is disturbed by cancer development. This study shows that miRNA expression can be controlled post-transcriptionally by interaction with other miRNAs.

Conclusion and future perspectives

A comprehensive understanding of the roles of miRNAs in tumor malignancy and chemoresistance in hypoxia requires a complete knowledge of the target genes that influence hypoxia-induced cellular activities. Although identification of new targets of HRMs is a bottleneck in the miRNA field, more and more targets can be identified in the future with the application of screening techniques and experimental evidence.

Due to the pervasive failure of traditional chemothera-peutic drugs in treating hypoxic cancers, new strategies have been developed. MiRNAs should be new considerations in future clinical assays to help guide therapeutic decisions or even to be valuable therapeutic tools for specific can-cers. The concept of therapeutic modulation of miRNAs is to design molecules that can inhibit or mimic mature miR-NAs effectively, in order to achieve losses or gains of miRNA function, respectively. Based on this idea, targeting miRNAs overexpressed in cancer or re-expressing those

downregulated in cancer represents an optional approach. Currently, antisense oligonucleotides (ASOs) complemen-tary to mature miRNAs are designed to block miRNA func-tion in the miRNP silencing complex; this has become an effective technology for controlling miRNA expression experimentally and/or therapeutically.110 In order to in-crease their stability, chemical modification is applied to ASOs to prevent nuclease degradation. Evidence has shown that ASO-mediated miR-21 inhibition in prostate cancer increases cell sensitivity to apoptosis and inhibits cell motility and invasion,111 whereas transfection of breast cancer cells with anti-miR-21 oligonucleotides show sup-pressed cell proliferation.112 In addition to ASOs, which contain only one binding site for the target miRNA, a different class of miRNA inhibitors containing multiple binding sites per molecule, named miRNA sponges, was developed.113In breast cancer, an miR-9 sponge trapping overexpresses miR-9 related to cancer metastasis, thereby effectively reducing invasiveness of tumor cells,114and an miR-17-92 cluster sponge significantly inhibits the prolifer-ation of cultured B-cell lymphoma cells.115

MiRNA mimics and plasmid or virally encoded miRNA constructs have widely been used as replacement therapies for the downregulated tumor suppressor miRNA. It was re-ported that delivery of let-7 miRNA intratumorally in a mouse model with non-small-cell lung cancer led to a reduction of tumor burden.116Another deregulated miRNA associated with several cancers is miR-34. Recent studies show that re-expression of miR-34 in human colon cancer cells inhibits cell proliferation significantly.117

The above evidence shows that miRNAs are promising potential therapeutic targets, but their challenges regarding stability, safety, and effective delivery to specific sites are of concern. Future clinical trials should focus on improving the safety and efficacy of miRNA-based anti-cancer therapies.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgments

We apologize to authors whose work could not be cited due to space constraints. This work was supported by grants from the National Research Program for Biopharmaceuticals (NSC 101-2325-B-006-017) and the National Health Research Institute (NHRI-EX-102-10244BI).

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Figure

Figure 1 Regulation of HIF-1 a protein under normoxia and hypoxia. HIF Z hypoxia-inducible factor; PHD Z prolyl hydroxylase;
Table 1 Targets of hypoxia-regulated miRNAs and their functional roles.

References

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