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Circulating microRNAs as Promising Tumor Biomarkers Meng Chen*, George A. Calin†, Qing H. Meng*,1 *Department of Laboratory Medicine, Division of Pathology and Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA † Department of Experimental Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 1 Corresponding author: e-mail address: [email protected]

Contents 1. 2. 3. 4. 5.

Introduction miRNA Biogenesis miRNAs and Cancer Origin and Function of Circulating miRNAs Detection of Circulating miRNAs 5.1 qRT-PCR 5.2 miRNA microarray 5.3 Deep sequencing 6. Circulating miRNAs as Cancer Biomarkers 6.1 Prostate cancer 6.2 Breast cancer 6.3 Lung cancer 6.4 Colorectal cancer 6.5 Hematologic cancers 7. Conclusions References

190 190 190 191 192 193 196 196 196 197 197 199 204 204 207 208

Abstract microRNAs (miRNAs) are small, nonprotein-coding RNAs that function as posttranscriptional regulators of target genes. miRNAs are involved in multiple cell differentiation, proliferation, and apoptosis processes that are closely related to tumorigenesis. Circulating miRNAs are promising cancer biomarkers under development with great translational potential in personalized medicine. Here, we describe the origin and function of circulating miRNAs and compare the current new high-throughput technology applied to miRNA quantitation. The latest publications on circulating miRNAs were summarized, indicating that miRNAs are potential biomarkers of diagnosis, prognosis, and treatment response of major cancer types including prostate, breast, lung, colorectal, and hematological cancers. We addressed the strengths and limitations of applying circulating miRNAs in clinical laboratory and several issues associated with the accurate measurement of circulating miRNAs. Advances in Clinical Chemistry ISSN 0065-2423 http://dx.doi.org/10.1016/bs.acc.2014.09.007

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2014 Elsevier Inc. All rights reserved.

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1. INTRODUCTION microRNAs (miRNAs) are a class of endogenous, single-stranded noncoding small (17–25 nucleotides, typically 22 nucleotides) RNAs that are involved in regulating gene expression at the posttranscriptional level [1]. miRNAs were first discovered in Caenorhabditis elegans in 1993 and have since been found to be highly conserved in nearly all organisms [2]. In humans, miRNAs account for only approximately 1% of the human genome, but they have been estimated to regulate the translation and stability of up to 50–60% of mRNAs [3,4], demonstrating the importance of their functions in gene expression.

2. miRNA BIOGENESIS miRNAs are transcribed in the same way protein-coding genes are transcribed, and their expression is strictly regulated by the processing machinery in their biogenesis pathway [4]. Long primary transcripts of miRNAs (pri-miRNAs) are mainly transcribed by RNA polymerase II and partially by RNA polymerase III. Pri-miRNAs are hundreds of nucleotides long and modified by adding a 50 cap and 30 poly-A tail. These primiRNAs are processed by a RNase III endonuclease-Drosha-into hairpin precursor miRNAs (pre-miRNAs) that are about 70 nucleotides long and are exported from the nucleus to the cytoplasm. The pre-miRNAs are subsequently processed by another RNase III endonuclease—Dicer—to form a mature miRNA duplex with 17–25 nucleotides. One strand (guide strand) of the mature miRNA duplex is incorporated into a miRNA-induced silencing complex that is composed of the argonaute (AGO) protein family and the transactivation-responsive RNA-binding proteins. miRNAs mediate the target mRNA repression or degradation via partial or complete base pairing to the 30 untranslated region of the target mRNA. Limited evidence suggests that miRNAs may also activate gene expression by binding the 50 promoter region of certain genes [5]. The other strand (passenger strand) of pre-miRNAs is either degraded or exported from cells by exosomes, microvesicles, high-density lipoprotein (HDL), and low-density lipoprotein (LDL), or RNA-binding proteins and then released into the circulation [6].

3. miRNAs AND CANCER The link between miRNAs and human diseases, particularly cancer, has been well established. Shortly after miRNA expression was detected in human

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cells in 2000, Calin et al. first reported that the deletion and downregulation of miR-15 and miR-16 were associated with high occurrence of chronic lymphocytic leukemia (CLL) [7]. miRNA genes may be located in either proteincoding genes (70%) or intergenic regions (30%) [8], but more than 50% of known miRNAs are located inside or near the cancer-related regions, such as fragile sites, regions of loss of heterozygosity, amplification, rearrangement, and common break points [9]. miRNA profiling of various tumor tissues and corresponding normal tissues has been performed in numerous studies [10]. miRNA expression signatures are tissue-, developmental stage-, and diseasespecific. Thus, miRNAs can not only be applied to discover unknown cancer origins, identify therapeutic targets, and classify cancer subtypes but can also be correlated with tumorigenesis, cancer progression, prognosis, and treatment response [11,12]. miRNAs in cancers can function as either tumor suppressors or oncogenes (oncomirs) depending on the tissue type, mRNA target, and microenvironment [12]. For example, miR-17-5p can act as a tumor suppressor in breast cancer by inhibiting AIB1 translation and inhibiting breast cancer cell proliferation, but in many other cancers, this miRNA is upregulated and acts as an oncogene [13]. miRNA dysregulation—either the decrease of tumor suppressor miRNAs or the overexpression of oncomirs—in cancer can be induced by a number of genetic and epigenetic mechanisms, including deletion, mutation, amplification, hypermethylation, and miRNA processing alterations [12]. miRNA dysregulation is involved in many critical pathways in cancer development such as those that regulate apoptosis, cell proliferation, epithelial-to-mesenchymal transition, and metastasis.

4. ORIGIN AND FUNCTION OF CIRCULATING miRNAs Although most miRNAs are intracellular, a large number of miRNAs have been observed outside cells in various body fluids [14–16]. The first evidence of circulating miRNAs was reported by Lawrie et al.[17] who showed that high levels of miR-155, miR-210, and miR-21 in serum were associated with diffuse large B-cell lymphoma (DLBCL), and high-serum levels of miR-21 were also associated with longer relapse-free survival. At the same time, Mitchell et al. found that miRNAs are present in human plasma in a remarkably stable form that is protected from endogenous RNase activity, and provided direct evidence that tumor-derived miRNAs can enter the circulation [18]. Moreover, Chen et al. conducted a comprehensive analysis of serum miRNA expression pattern and demonstrated that miRNAs are present in the serum and plasma of humans and many animals. The miRNAs in serum are stable, reproducible, and consistent among

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individuals of the same species [19]. The global correlation between different tissue-specific miRNAs and circulating miRNAs in the normal population has been investigated, and liver miRNAs were more closely correlated with circulating miRNAs than were any other tissue-specific miRNAs (miRNAs from the placenta, testis, and brain tissue). On the other hand, Pritchard et al. reported a 50-fold increase of plasma/serum miRNA levels during perturbations and hemolysis of blood cells, indicating that blood cells are a major source of circulating miRNAs [20]. However, miRNAs may be released via a cellular selection mechanism, which would account for different extracellular and cellular miRNA profiles [21]. The origin of miRNAs remains elusive. Two major theories about the source of circulating miRNAs have been proposed: (1) passive leakage of cellular miRNAs into the circulation and (2) active and selective secretion of miRNAs in response to various stimuli as microvesicle-free miRNAs or via binding to cell-derived microvesicles. Passive leakage of miRNAs from broken cells may occur under pathological conditions such as tissue damage, apoptosis, inflammation, or tumor metastasis [16]. The majority of circulating miRNAs are chaperoned by various carriers including exosomes and other larger membrane-bound particles (e.g., apoptotic bodies, shedding vesicles, etc.) [22], HDL and LDL [23], and proteins such as Ago2 [24,25], which explains the stability of circulating miRNAs. These vesicle carriers are believed to protect circulating miRNAs from RNase degradation, mediate cell–cell communication via ligand–receptor interaction, and transport intracellular components, including miRNAs, to recipient cells via fusion or endocytosis [22]. In addition to regulating mRNAs posttranscriptionally, circulating miRNAs interact with the toll-like receptors of immune cells to stimulate the production of prometastatic inflammatory cytokines and to induce the protumor inflammatory [26]. Tumor-derived exosomal miRNAs were first isolated by Taylor et al. and were closely correlated with tissue miRNAs in paired samples, indicating that circulating exosomal miRNAs may be used as surrogate diagnostic markers for biopsy profiling [27,28]. The vast majority of circulating miRNAs are presented in the form of binding with Ago2 [25]. Moreover, posttranscriptional modification of miRNAs, such as methylation, adenylation, and uridylation has been reported [29–31], but whether these modifications exist in circulating miRNAs remains unclear.

5. DETECTION OF CIRCULATING miRNAs miRNAs are stable in cell culture supernatants and in many body fluids such as blood, urine, saliva, milk, and pleural effusions [18,19,32].

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Previous studies showed that higher concentrations of miRNAs can be extracted from whole blood samples than from serum and plasma, but whole blood sample may increase the background signal or interfere with immunoassays or downstream molecular assays [24]. Therefore, serum and plasma miRNAs are more commonly measured in current biomarker studies [33]. A pilot study reported that circulating miRNA expression levels in plasma were highly correlated with those in serum [34]. However, another paper demonstrated a considerable discrepancy between the circulating miRNA expression pattern in plasma and serum [35]. A recent study reported higher miRNA concentrations in sera than in corresponding plasma samples, suggesting that the coagulation process may affect the spectrum of circulating miRNAs in blood [36]. The correlation between plasma and serum miRNAs remains controversial. Therefore, specimen types should not be mixed, and the type of specimen should be consistent in the same study. Many techniques have been applied in measuring miRNA levels, including Northern blotting, in situ hybridization, quantitative reverse transcription polymerase chain reaction (qRT-PCR), microarray, and deep sequencing; the latter three techniques have been widely adopted in recent studies. These three techniques are summarized in Table 1 [37,38] and described in further detail in subsequent sections. The detection of circulating miRNAs in serum or plasma deals with extremely low initial amount of samples, which demands high performance in sample preparation and RNA extractions. Many preanalytical factors may affect circulating miRNA levels. For example, the centrifugal protocols, abnormal increases of blood cell and white blood cell counts in disease status, and hemolysis have remarkable influence on circulating miRNA measurements [20,25]. Current commercially available products for RNA extraction include TRIzol (Life Technologies), miRNeasy (QIAGEN), and mirVana (Life Technologies). Enrichment of small RNAs is required for sequencing, during which the samples are subjected to fractionation and recovered by electrophoresis and purification.

5.1. qRT-PCR qRT-PCR is the gold standard for quantifying circulating miRNAs with high sensitivity and specificity and with a wide analytical measurement range [34,39]. Two methods, stem loop primer RT-PCR and poly-A tailed RT-PCR, were developed to amplify circulating miRNAs. Normalization is critical for miRNA quantification, and there is no standard internal control for circulating miRNAs. Some controls, such as U6 snRNA or housekeeping miRNAs, do not exist in cell-free conditions. Invariant miRNAs such as

Table 1 Comparison of main technologies in circulating miRNA detection Methods

Advantages

Disadvantages

Throughput Assay or platform

Vendor

Quantitative reverse transcriptionPCR

High sensitivity and specificity. Can be used for absolute quantification

Only medium throughput with respect to the number of samples processed per day

Semi-high

TaqMan individual assays

ABI

miRCURY LNA qPCR

Exiqon

TaqMan OpenArray

ABI

RNA required Cost

μg

Low/miR High/sample

2–5 days

Discovery and confirmation

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HiSeq 2000 (or Genome Analyzer IIX)

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miR-16 are commonly selected as endogenous controls because they are consistently and highly expressed in plasma and serum [17,40,41]. However, miR-16 levels may increase during metastasis [42]. Recently, spike-in nonhuman mature miRNA controls have been applied as normalization controls [18,34].

5.2. miRNA microarray High-throughput microarray-based analysis is less expensive than qRTPCR and miRNA sequencing but has lower specificity [43]. This method can be used to predict the function of each miRNA in combination with the gene expression data. The miRNAs are enzymatically or chemically labeled with fluorescent dyes and hybridized to capture probes on the microarray plate. The signals from hybridized probes are detected by a scanner. The hybridization is sequence specific, and the efficiency depends on the guanine–cytosine content and DNA-melting temperature. Cross-hybridization may occur between different miRNAs. This method can measure the relative abundance of miRNAs but not the absolute value.

5.3. Deep sequencing Massive parallel sequencing technology enables the profiling of all expressed miRNAs and the discovery of novel miRNAs and isomiRNAs that are generated from alternative processing [44–46]. Many sequencing platforms from various manufacturers are currently commercially available (Table 1) [47]. This complicated method requires multistep sample purification, a series of reactions including miRNA reverse transcription, enzymatic ligation of adaptors, and amplification before sequencing, as well as sophisticated computational analysis after sequencing [48,49]. qRT-PCR, microarray, and deep sequencing are compared in Table 1. The correlations between miRNA measurements from different platforms or even from the same platform using different products are not optimal [36,50,51]. More accurate and reproducible methods need to be developed, reagents need to be improved, and sample preparation and normalization should be standardized in the future.

6. CIRCULATING miRNAs AS CANCER BIOMARKERS The associations between circulating miRNAs and cancer development, progression, and treatment have been heavily investigated; more than 250 related articles have been published since 2008. In this section, we

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summarize the recent findings on miRNAs in serum or plasma as potential biomarkers for the diagnosis, prognosis, and treatment response of major cancer types. The diagnostic biomarkers include biomarkers for monitoring high-risk populations, detecting early stage cancer, and discriminating between benign and malignant diseases. The prognostic biomarkers are used for predicting disease outcome and estimating progression-/recurrence-free survival and overall survival. The treatment response predictive biomarkers can monitor sensitivity to therapy and treatment response and aid in making treatment decisions.

6.1. Prostate cancer The first evidence of circulating miRNAs as cancer biomarkers was observed in prostate cancer in 2008. Mitchell et al. found that miR-141 levels were higher in men with advanced prostate cancer than in healthy men [18]. A subsequent study showed that plasma miR-141 levels were correlated with the levels of prostate specific antigen (PSA), circulating tumor cells, and lactate dehydrogenase [52]. The findings on miRNAs in prostate cancer are summarized in Table 2[18,53–64]. There is a significant differential expression pattern of miRNAs in prostate cancer. For example, miR-141 [18,55,57,62,64] and miR-375 [55,57,62,64] are upregulated in metastatic prostate cancer whereas elevated miR-21 and miR-221 levels are significantly associated with localized prostate cancer [54,58,61,63]. We have recently demonstrated that miR-221 and miR-222 are highly expressed in PC-3 cells. Inhibition of miR-221 or miR-222 leads to reduced cell proliferation and migration and increased apoptosis in prostate cancer cells [65]. Currently, prostate cancer prognosis is still based on PSA levels, Gleason score, and tumor stage [66]. In 2011, Brase et al. first reported that miR-141, miR-200b, and miR-375 levels were elevated in men with increasing stage and Gleason score [62]. miRNAs have shown promise in refining clinical variables for predicting prognosis in prostate cancer patients. Yet evidence of the utility of miRNAs in the early diagnosis of prostate cancer and monitoring therapeutic response is limited. Further studies are needed to identify those miRNAs and determine their quantitative cutoff values for predicting the prognosis of prostate cancer.

6.2. Breast cancer Two serum-based tumor biomarkers (CA15-3 and carcinoembryonic antigen, CEA) [67] and circulating tumor cells [68] are used for the prognostic assessment of advanced breast cancer, but no circulating biomarker has yet

Table 2 Potential circulating miRNAs as biomarkers of prostate cancer Type of biomarker

Upregulated miRNAs

Downregulated miRNAs

Sample Method

Study design

References

Serum qRT-PCR

25 metastatic PCa vs. 25 controls

[18]

miR-16, -92a, -103, -107, -197, -34b, -328, -485-3p, -486-5p, -92b, -574-3p, -636, -640, -766, -885-5p

Serum MiR microarray/ RT-PCR

5 PCa vs. 8 controls (other cancers tested)

[53]

miR-221

Plasma qRT-PCR

28 PCa vs. 20 controls

[54]

miR-141, -298, -346, -375

Serum qRT-PCR

25 metastatic PCa vs. 25 controls

[55]

Diagnostic miR-100, -125b, -141, -143, -296

let-7e, let-7c

Plasma Microarray/ qRT-PCR

25 PCa vs. 17 BPH, then validation in [56] 80 PCa, 44 BPH, and 54 HI

miR-375, -141

miR-181a-2

Plasma qRT-PCR

78 PCa vs. 28 controls, then 16 metastatic vs. 55 nonmetastatic

[57]

Plasma qRT-PCR

51 PCa (18 localized, 8 locally advanced, 25 metastatic) vs. 20 HI

[58]

miR-21, -221 miR-93, -106a, -874, -1207

miR-24, -26b, Serum Multiplexed -30c, -223 qRT-PCR

36 PCa (12 low risk, 12 medium risk, [59] 12 high risk) vs. 12 controls

miR-26a, -195, let-7i, -16

Serum qRT-PCR

45 (37 localized, 8 metastatic) PCa vs. [60] 38 controls (18 BPH, 20 HI)

miR-20a, -21

Plasma qRT-PCR

82 PCa assessing association with CAPRA score

Serum qRT-PCR

7 metastatic PCa vs. 14 localized PCa [62]

Serum qRT-PCR

50 PCa (20 localized, 20 ADPC, 10 HRPC) vs. 6 BPH

[63] [57]

Prognostic miR-9*, -141, -200b, -375, -516a miR-21

[61]

miR-375, -141

miR-181a-2

Plasma qRT-PCR

78 PCa vs. 28 controls, then 16 metastatic vs. 55 nonmetastatic

miR-375, -141, -378*

miR-409-3p

Serum microarray, qRT-PCR

26 metastatic PCa vs. 28 localized Pca [64]

*Where one hairpin miR precursor gives rise to two mature miRs, one from each arm, an asterisk is used to denote the least predominant form. ADPC: androgen-dependent prostate cancer; HRPC: hormone refractory prostate cancer; BPH: benign prostatic hypertrophy; HI: healthy individuals; PCa: prostate cancer; CAPRA: Cancer of the Prostate Risk Assessment.

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been recommended for determining diagnosis, assessing prognosis, or monitoring therapeutic response. Mammography [69] remains the primary choice for breast cancer screening, but the costs are high and the sensitivity is low. Mammography is limited to high-risk populations only and is not recommend for young women without a family history of cancer. There is an urgent need for rapid and reliable blood-based assays for assessing diagnosis, prognosis, and treatment response in breast cancer. Circulating miRNAs have been extensively studied in breast cancer (Table 3) [70–87]. In particular, miR-155 [76,77,84] and miR-21 [71,73] were found to be elevated in the serum of primary breast cancer patients. Moreover, miR-155 is related to progesterone receptor status [76] and can predict chemotherapy response [77]. Recent in vitro evidence indicates that suppression of miR-221 and miR-222 increases the sensitivity of estrogen receptorpositive MCF-7 breast cancer cells to tamoxifen [88]. In addition, circulating miR-125b and miR-210 were reported associated with the chemoresistance in breast cancer patients. Another emerging area in breast cancer is the identification of miRNAs in circulating tumor cells; a dozen miRNAs were found to be more abundant in circulating tumor cells, which may be associated with metastasis [83,89].

6.3. Lung cancer Lung cancer is the leading cause of cancer mortality, and most studies of lung cancer focus on nonsmall cell lung cancer (NSCLC), which accounts for more than 80% of cases. Two studies have been conducted to comprehensively screen and identify circulating miRNAs as early detection markers in asymptomatic patients [90,91]. Bianchi et al. developed a test based on 34 miRNAs from serum to detect NSCLC [90]. Boeri et al. identified a group of plasma miRNAs that could both predict the development of lung cancer in asymptomatic patients (1–2 years prior to diagnosis) and detect new cases [91]. The study by Boeri et al. also showed that miR-197, miR-221, miR-486-5p, miR-140-5p, miR-106a, and miR-16 were associated with the aggressiveness of the disease. There was no significant correlation between plasma miRNAs and serum miRNAs, and this discrepancy was also reported in a study by Heegaard et al.[35]. Numerous case–control studies have been conducted in lung cancer, and the levels of several miRNAs were shown to be either higher or lower in cases than in controls, although these results were not entirely consistent and need to be validated in independent populations (Table 4). miR-21 appears to be the most

Table 3 Potential circulating miRNAs as biomarkers of breast cancer Type of biomarker

Upregulated miRNAs

Diagnostic

Downregulated miRNAs

Method

Study design

References

miR-376c, -409-3p, -801, -148b

Plasma

Microarray/ qRT-PCR

127 BC cases and 80 controls

[70]

Diagnostic

miR-10b, -21, -125b, -145, -155, -191, -382

Serum

qRT-PCR

61 breast cancer and 10 controls

[71]

Diagnostic

miR-451

miR-145

Plasma

qRT-PCR

240 breast cancer and 150 controls; correlated [72] to PBC

Diagnostic

miR-21

miR-92a

Diagnostic

miR-215, -299-5p, -411

Diagnostic

miR-30a

Serum

qRT-PCR

100 PBC vs. 20 controls

[73]

Serum

Microarray/ qRT-PCR

75 BC (including 16-untreated MBC vs. 20 controls); increased in MBC

[74]

Plasma

qRT-PCR

100 PBC vs. 64 controls; decreased in PBC; correlated to receptor status

[75]

Diagnostic

miR-155

Serum

qRT-PCR

8 BC; correlated to progesterone receptor status

[76]

Diagnostic

miR-155

Serum

qRT-PCR

103 PBC vs. 55 controls; increased in PBC

[77]

Diagnostic

miR-195, let-7a

Whole blood

qRT-PCR

83 patients vs. 44 controls; increased in patients

[78]

let-7a

Correlated with lymph node positivity

miR-10b, -21 Diagnostic

miR-425*, -302b

Diagnostic

miR-202

Higher in ER negative compared to ER positive let-7c

Plasma

Microarray/ qRT-PCR

45 BC vs. 45 controls

[79]

Whole blood

Microarray/ qRT-PCR

92 early stage BC vs. 81 controls

[80]

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Sample

miR-122

Serum

Sequencing/ qRT-PCR

68 stages II–III and inflammatory BC patients [81] who received neoadjuvant chemotherapy; predicts BC metastasis in early stage patients

Diagnostic and prognostic

miR-21

Serum

qRT-PCR

102 BC patients with different disease stages vs. 20 controls; increased in BC patients; increased in metastasis

[82]

Diagnostic and prognostic

miR-141, -200a, -200b, miR-768-3p -200c, -203, -210, -375, -801

Plasma

Microarray/ qRT-PCR

61 CTC-positive, 72 CTC-negative; 60 CTC-low MBC cases, and 76 controls; increased in MBC; correlated to CTC status

[83]

Diagnostic and prognostic

miR-10b, -34a

Serum

Microarray/ qRT-PCR

59 PBC vs. 30 MBC vs. 29 controls; increased [84] in MBC compared to PBC and controls

Diagnostic and prognostic

miR-155

Prognostic

miR-10b, 373

Plasma

qRT-PCR

35 MBC, 25 PBC, 10 control; increased in MBC

[85]

Predictive

miR-155

Serum

qRT-PCR

29 BC patients with surgery and chemotherapy vs. 103 PBC decrease after surgery and chemotherapy

[77]

Predictive

miR-125b

Serum

qRT-PCR

56 invasive ductal carcinoma BC; correlated with chemoresistance

[86]

Predictive

miR-210

Plasma

qRT-PCR

39 preoperative; 30 postoperative; 43 PBC without treatment; correlated with trastuzumab resistance, tumor presence, and lymph node metastasis

[87]

Increased in PBC and MBC compared to controls; increased in PBC compared to MBC

*Where one hairpin miR precursor give rise to two mature miRs, one from each arm, an asterisk is used to denote the least predominant form. CTC: circulating tumor cells; BC: breast cancer; PBC: primary breast cancer; MBC: metastatic breast cancer; ER: estrogen receptor.

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Prognostic

Table 4 Potential circulating miRNAs as biomarkers of lung cancer Type of biomarker

Upregulated miRNAs

Downregulated miRNAs

Method

Sample

Microarray/ Plasma qRT-PCR

Study design

References

Diagnostic

miR-21, -19b, -30c, -92a, -17, -28-3p, -106a, -140-5p, -451, -660,

91 LC and 81 controls; increased in LC [91]

Prognostic

miR-197, -221, -486-5p, -140-5p, miR-16 -106a

Diagnostic

34 different miRNAs

Microarray/ Serum qRT-PCR

59 patients vs. 69 controls, identify [90] NSCLCs from asymptomatic population

Diagnostic

miR-25, -223

Sequencing/ Serum qRT-PCR

152 LC vs. 75 controls; increased in LC [19]

Diagnostic

miR-574-5p, -1254

qRT-PCR

Serum

33 NSCLC vs. 42 controls; increased in [92] NSCLC

Diagnostic

miR-29c

let-7a, miR-17-5p, -27a, -106a, -146b, -155, -221

qRT-PCR

Plasma and serum

220 early stage NSCLC vs. 220 controls; [35] correlated with NSCLC; differences between distinct ethnic groups

Prognostic

miR-30d, -486

miR-1, -499

Sequencing/ Serum qRT-PCR

303 patients and 113 death; correlated to [93] poorer overall survival

Diagnostic

miR-16, -452*, -518a-5p, -574-5p, -593*, -663, -718, -1228*, -1972, -2114*

qRT-PCR

Serum

8 cancer patients vs. 6 controls; decreased [94] in pre- and postdiagnostic samples

Diagnostic

miR-21, -24, -30d, -205

qRT-PCR

Serum

82 pre- vs. postoperative LC, 50 healthy [95] controls; increased in LC and early stage LC

Increased in aggressive disease

[91]

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Prognostic

miR-21, -30d

Prognostic

Correlated to poorer overall survival miR-21, -24 miR-141, -200c

Decrease in postoperative samples

Diagnostic

miR-21

qRT-PCR

Serum

70 NSCLC vs. 44 controls; correlated with NSCLC

Prognostic

miR-21

Diagnostic

miR-21, -182, -210

miR-126, -486-5p

Microarray/ Plasma qRT-PCR

28 stage I NSCLC, 58 NSCLC, vs. 29 controls

[97]

Diagnostic

miR-21, -155

miR-145

qRT-PCR

Plasma

62 patients vs. 60 controls; and 34 malignant patients vs. 30 benign vs. 32 controls

[98]

Diagnostic and predictive

miR-21

qRT-PCR

Plasma

63 NSCLC vs. 30 controls; increased in [99] NSCLC; predictive for platinum-based chemotherapy

Diagnostic, prognostic, and predictive

miR-155, -182, -197

qRT-PCR

Plasma

74 LC patients and 68 controls; increased [100] in cases; increased in patients with metastasis; decreased in patients responding to therapy

[96]

Lymph node metastasis and advanced clinical stage of NSCLC

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*Where one hairpin miR precursor give rise to two mature miRs, one from each arm, an asterisk is used to denote the least predominant form. NSCLC: nonsmall cell lung cancer; LC: lung cancer.

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prominent biomarker in lung cancer and has been shown in several papers including one of our unpublished papers to be correlated with the risk of NSCLC, advanced disease stage and metastasis, poor overall survival, and chemotherapy response [95–99].

6.4. Colorectal cancer Colorectal cancer (CRC) is the third most common and deadly cancer in the United States [101,102]. The current tumor marker for CRC is serum CEA levels, but this blood test is neither sensitive nor specific. Recent studies of circulating miRNAs have focused on early diagnosis and prognosis (Table 5). In these studies, miR-29a was differentially expressed in CRC patients compared to controls and was also associated with liver metastasis [41,103,108]. miR-141 was also significantly associated with metastasis and poor prognosis [105]. Altered levels of miR-92 can differentiate CRC from gastric cancer [104]. These miRNAs are promising diagnostic and prognostic biomarkers in CRC.

6.5. Hematologic cancers The first report of circulating miRNAs was from Lawrie et al.[17] who showed that serum levels of miR-21, miR-155, and miR-210 were significantly higher in DLBCL patients than in healthy controls (Table 6). Furthermore, higher serum levels of miR-21 were also correlated with longer relapse-free survival in these patients [17]. Of note, the finding of elevated miR-155 in DLBCL was recently validated by another group [110]. The prognostic value of miR-155 was reported by Ferrajoli et al., who found that higher serum levels of miR-155 were associated with increased disease progression in CLL [111]. miR-92a was significantly decreased in the plasma of patients with non-Hodgkin lymphoma [112] and acute myelogenous leukemia [113]. Three publications have indicated that circulating miRNAs may become predictive markers for response to chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone. Plasma levels of miR-155 were shown to be higher in CLL patients who did not achieve a complete response than in patients who did achieve a complete response [111]. Elevated plasma miR-221 levels were associated with shorter after chemotherapy in patients with natural killer/T-cell lymphoma, suggesting poor treatment response [114]. Low plasma levels of miR-92a were correlated with shorter relapse-free survival in non-Hodgkin lymphoma patients [113] (Table 6).

Table 5 Potential circulating miRNAs as biomarkers of colorectal cancer Type of biomarker

Upregulated miRNAs

Diagnostic

miR-15b, -18a, -19a, -29a, -335

Downregulated miRNAs

Method

Microarray/ Plasma 123 patients vs. 73 controls; increased in CRC qRT-PCR

miR-18a Diagnostic

miR-17-3p

Sample Study design

References

[103]

Increased advanced adenomas compared to controls qRT-PCR

[104]

Increase in CRC; decrease in postoperative samples; can differentiate CRC from gastric cancer IBD and controls

Prognostic

miR-141

qRT-PCR

Plasma 258 stage IV colon cancer; correlated to poor survival

Diagnostic

miR-92a, -29a

qRT-PCR

Plasma 130 CRC vs. 37 adenoma vs. 59 controls; increased in CRC [41] and advanced adenomas compared to controls

Diagnostic

miR-21

Microarray/ Plasma 50 CRC patients vs. 50 controls; increased in CRC qRT-PCR

Diagnostic and prognostic

miR-221

qRT-PCR

Plasma 103 CRC patients and 37 healthy normal controls; increased in [107] CRC patients; correlated to OS and p53 score

Diagnostic and prognostic

miR-29a

qRT-PCR

Serum 58 CRC with liver metastasis vs. 56 CRC without metastasis; [108] increased in CRC with liver metastasis vs. nonmetastatic CRC

Diagnostic

miR-601, -760 qRT-PCR

CRC: colorectal cancer; OS: overall survival; IBD: inflammatory bowel disease.

Plasma 100 CRC, 43 advanced adenoma, 68 controls; decreased in CRC and advanced adenomas compared to controls

[105]

[106]

[109]

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Plasma 95 CRC, 20 gastric cancer, 20 IBD, 55 controls; increase in CRC; decrease in postoperative samples

Table 6 Potential circulating miRNAs as biomarkers of hematologic cancers Type of biomarker

Upregulated miRNAs

Downregulated miRNAs

Cancer

Sample Method

Study design

References

75 DLBCL vs. 75 controls; increased in DLBCL

[110]

Diagnostic

miR-15a, -16-1, -29c, -155

miR-34a

DLBCL

Serum qRT-PCR

Diagnostic

let-7b, miR- 523

let-7d, miR-150, -339, -342

AML

Plasma Microarray/ 20 AML without CR, 20 controls, 20 AML with qRT-PCR CR; correlated to AML

Prognostic

miR-150, -342

Prognostic and predictive

miR-155

CLL

Diagnostic, prognostic, and predictive

miR-221

NK/TPlasma qRT-PCR cell lymphoma

79 patients and 37 normal subjects; increased in lymphoma; correlated to shorter OS

[114]

Diagnostic

miR-21, -155, -210

Serum qRT-PCR

60 patients vs. 43 controls; increased in DLBCL

[17]

Prognostic

miR-21

De novo DLBCL AML

Plasma Microarray/ 77 AML patients vs. 16 controls; decreased in AML [112] qRT-PCR

AML

Serum Sequencing qRT-PCR

miR-92a

Diagnostic

miR-10a-5p, -93-5p, -129-5p, -155-5p, -181b-5p, -320d

Prognostic

miR-181b-5p

Diagnostic and predictive

Increased in cases with CR compared to those without CR Plasma qRT-PCR

228 CLL patients; increased in CLL progression and [111] poor treatment response

High levels correlated with improved RFS

140 AML patients and 135 controls; increased in AML patients

[116]

Correlates to shorter OS miR-92a

NHL

[113] Plasma Microarray/ 126 patients vs. 37 controls; decreased in NHL; qRT-PCR further decreased in patients with shorter RFS after chemotherapy

DLBCL: diffuse large B-cell lymphoma; RFS: relapse-free survival; OS: overall survival; CLL: chronic lymphocytic leukemia; NHL: non-Hodgkin lymphomas; AML: acute myelogenous leukemia; CR: complete remission.

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7. CONCLUSIONS Current cancer biomarkers available in clinics are mostly proteins, and the U.S. Food and Drug Administration has not approved any new biomarkers in more than a decade. These biomarkers have complex compositions and are rendered vulnerable by many posttranslational modifications. With the low abundance and numerous sequence variations of protein biomarkers, the development of assays for protein biomarkers is challenging, often resulting in low sensitivity and specificity for the assays. Circulating miRNAs are being developed as promising cancer biomarkers with great translational potential, although technical issues still exist. Circulating miRNAs are extremely stable in RNase-rich body fluids. With the rapid advances in measurement methods, circulating miRNAs are readily detected even in extremely small amounts. Numerous studies in a wide spectrum of cancers have provided solid evidence that circulating miRNAs are reliable and sensitive in predicting disease occurrence and detecting changes in pathology, disease recurrence and progression, and treatment response. Disease-associated miRNA changes may be detected years prior to disease onset in asymptomatic patients, suggesting the value of these miRNAs in screening and early detection. However, several issues still hamper the clinical application of circulating miRNAs in cancers. First, most differentially detected miRNAs are not limited to a single cancer type, but are detected consistently across different cancer types and various pathologic statuses. For example, serum miR-21 is elevated in breast, lung, colorectal, and hematologic cancer and is also correlated with prognosis and treatment response. These nontissue-, organ-, or cancer type-specific miRNAs raise concerns about the specificity of the test and limits to its application. Cancer typespecific circulating miRNAs are desired. In contrast, several aberrant miRNAs can be seen in one cancer type and even at different stages of same cancer. Most likely, the combination of a panel of miRNAs, rather than a single miRNA, will be needed to reach high specificity. Second, considering the heterogeneous origin of circulating miRNAs, distinguishing tumorderived miRNAs, and avoiding the interference of miRNAs from other resources such as blood cells and the liver is critical in establishing the concordance between miRNA expression in tumor tissue and in the circulation. Third, the reported association of circulating miRNAs with cancer diagnosis and prognosis is confounded by many factors, such as age, sex, ethnicity, and types of sample (i.e., plasma, serum, or whole blood). The vast majority of

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recent studies were conducted retrospectively with limited sample sizes, and the results are not consistent and need to be validated prospectively in large independent populations. Although the levels of circulating miRNAs have been shown to be either elevated or reduced in cancer patients, only those with elevated expression are likely to be used as early detection and diagnosis markers, considering the practical issues in clinical laboratories. Finally, various approaches have been applied to identify and quantify circulating miRNAs. There are still technical challenges to preparing samples, choosing normalization controls, and normalizing data. There is a lack of quality control program in monitoring the performance and proficiency of these assays. The assays will need to be standardized for different platforms to allow comparisons of the identified circulating miRNAs across different laboratories. The cutoff values of aberrant miRNAs in each type of cancer need to be established for the ease of clinical interpretation.

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Circulating microRNAs as Promising Tumor Biomarkers.

microRNAs (miRNAs) are small, nonprotein-coding RNAs that function as posttranscriptional regulators of target genes. miRNAs are involved in multiple ...
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