Framework Nucleic Acid-Mediated Pull-Down MicroRNA Detection

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Framework Nucleic Acid-Mediated Pull-Down MicroRNA Detection with Hybridization Chain Reaction Amplification Xiangmeng Qu, Mingshu Xiao, Fan Li, Wei Lai, Li Li, Yi Zhou, Chenglie Lin, Qian Li, Zhilei Ge, Yanli Wen, Hao Pei, and Gang Liu ACS Appl. Bio Mater., Just Accepted Manuscript • DOI: 10.1021/acsabm.8b00278 • Publication Date (Web): 08 Aug 2018 Downloaded from http://pubs.acs.org on August 9, 2018

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ACS Applied Bio Materials

Framework Nucleic Acid-Mediated Pull-Down MicroRNA Detection with Hybridization Chain Reaction Amplification Xiangmeng Qu1,2#, Mingshu Xiao2#, Fan Li2#, Wei Lai2, Li Li2*, Yi Zhou3, Chenglie Lin3, Qian Li4, Zhilei Ge4, Yanli Wen1, Hao Pei2 and Gang Liu 1* 1

Laboratory of Biometrology, Shanghai Institute of Measurement and Testing

Technology, 1500 Zhangheng Road, Shanghai 201203, China 2

Shanghai Key Laboratory of Green Chemistry and Chemical Processes, School of

Chemistry and Molecular Engineering, East China Normal University, 500 Dongchuan Road, Shanghai, 200241, China 3

School of Basic Medicine, Chengdu University of Traditional Chinese Medicine,

1166 Liutai avenue, Chengdu 611137, China 4

School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University,

Shanghai 200240, China

Corresponding Author * Li Li, E-mail: [email protected]. Tel.: (+86) 021-54340134. *Gang Liu, E-mail: [email protected]. Tel.: (+86) 021-38839800-35324.

KEYWORDS: microRNA, framework nucleic acid, simultaneous multiplexed detection, gastric cancer, HCR. 1

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ABSTRACT: Gastric cancer remains a disease of high mortality worldwide due to its poor prognosis. Previous studies have shown that microRNAs (miRNAs) are effective biomarkers for early diagnosis of gastric cancer. To realize sensitive detection of related miRNAs for improved early diagnosis, classification, and survival prognosis of gastric cancer, here we develop a framework nucleic acid (FNA)-mediated microarray for quantitative analysis of multiple miRNAs. By rationally designed FNA with different sizes, we could systematically modulate the surface density and lateral interactions of DNA probes, which provides an effective means for programmable tailoring the hybridization efficiency and kinetics of the biosensing interface. We found that the hybridization efficiency was increased along with the size of the FNA and reached optimum for FNA-17. Combining with the hybridization chain reaction (HCR) amplification strategy, this established FNA microarray can serve as an ultrasensitive and selective analytical platform for simultaneous multiplexed detection of miRNAs (e.g., FNA-miR-652, FNA-miR-627, and FNA-miR-629) biomarkers in gastric cancer.

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INTRODUCTION Gastric cancer has been a great threat to public health. It is reported that gastric cancer is the fourth most common cancer but the second major contributor to cancer-related death worldwide1-2. Currently, endoscopic biopsy is still the gold standard for the clinical diagnosis of gastric cancer5. However, as an invasive method, it causes much pain to the patients, and its diagnosis accuracy relies on the skills and experiences of the endoscopists. Blood-based biomarkers (e.g., carcinoembryonic antigen) as noninvasive diagnostic and surrogative biomarkers are capable of reflecting the gastric cancer status6 yet suffered from a high false positive rate in gastric cancer diagnosis7. In spite of a decline in its incidence and mortality with the advent of diagnostic methods and treatments, early-stage diagnosis of gastric cancer remains challenging as a result of lacking effective diagnostic biomarkers3-4. The microRNAs (miRNAs), small noncoding RNA molecules composed of 19–25 nucleotides, are reported to regulate gene expression by inhibiting and/or degrading messenger RNAs10-12. Previous research has revealed that more than half of the human genes are regulated by miRNAs and one type of miRNAs may have several hundreds of target genes13-14. As a result, the dysregulation of miRNA expression is often closely associated with the development and progression of diseases15-18. In addition, accumulating evidence has demonstrated that miRNAs can serve as potential biomarkers in various tumor types, including gastric cancer19-20. For example, Xiao group validated that miRNA-378 can be used as a noninvasive biomarker for gastric

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cancer in routine clinical trials21. Accordingly, miRNAs have sparked a growing interest in the early noninvasive diagnosis of cancers22-26. Nevertheless, sensitive and specific miRNA detection is usually hampered by their short length, sequence similarity, and low abundance27-29. Moreover, simultaneous quantitative analysis of multiplexed miRNAs is needed to improve the diagnostics accuracy for many pathologies that are related with miRNA abnormal expression30-33. In a word, simultaneous, and multiplexed detection of miRNAs with high sensitivity and specificity has been given great importance as an effective approach for early clinical diagnosis of gastric cancer. The microfluidic technology integrated with the pull-down assay could provide a simple, direct and multiplex way for miRNA analysis. Classical pull-down assay is constructed by firstly isolating a bait (the molecule or protein of interest) from biological extracts through the specific recognition with a ligand immobilized on surface, then simultaneously capturing the prey (physiological binding partners of the bait)34, and the captured complexes are subsequently analyzed using mass spectrometry or western blotting. Compared to mass spectrometry or western blotting, which need complicated sample preparation steps, a pull-down assay integrated in microfluidics offers advantages of direct optical readout from a droplet of picoliter or nanoliter simply using a fluorescence scanner. Since the performance of biosensor is governed by the recognition and reaction between the surface-assembled probes and the specific targets, the properties of the

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sensing interface in the microfluidic channel (e.g., the density, orientation, and configuration of capture probes) is reported to play a crucial role for the thermodynamics and kinetics of target-probe interactions. Recently, the rapid emerging DNA nanotechnology offers a convenient and powerful approach to programmable engineer the biosensing interface. For instance, our recent work has demonstrated a rapid pull-down assay inside nanoliter-sized droplet using an aptamer on top of a DNA nanostructure, for the analysis of cellular molecules from HNE1 cells under convective flux in microfluidic channels35. Beyond bioactive molecules, this analytical platform can be easily extended to multiple analysis of heavy-metal ions36. In this work, we developed a framework nucleic acid (FNA) microarray based on pull-down triggered hybridization chain reaction (HCR) in nanoliter droplets for miRNA detection. Microarray-based technique is particularly attractive for miRNA profiling because they allow the analysis of large numbers of miRNAs simultaneously32. In this design (Fig 1), we employed target-specific FNAs by sequentially immobilizing them onto the designed locations along the glass capillaries with a droplet array generator35-36. It is worth to note that, such spatially resolved FNA microarray possesses several intrinsic advantages for engineering the sensing-interface for the subsequent HCR, such as tunable density, ordered probe orientation, and circular arrangement37-38. The target miRNAs were then introduced into the glass capillary and hybridized with the corresponding FNAs on the surface, which served as the initiator that triggers cascade of DNA polymerization via HCR39. 5



With HCR for effective signal enhancement, the detection sensitivity of the FNA microarray can be greatly improved to 100 fM for miRNA detection. Moreover, the HCR-H1 with the hairpin structure capable of discriminating single-based mismatch targets endows this method with high specificity.

Figure 1. Illustration of the HCR amplification based on an FNA microarray for simultaneous multiplexed detection of miRNAs. The inset showed the nanoliter droplets containing 3 different FNAs for the detection of 3 different microRNAs (FNA-mir-627, FNA-miR-629, FNA-miR-652 from left to right). EXPERIMENTAL SECTION Chemical and reagents. All oligonucleotides were synthesized by Sangon Biotech Shanghai Co. Ltd. (Shanghai, China). HPLC-purified miRNAs together with RNase inhibitor and diethyl pyrocarbonate (DEPC)-treated water were from Takara 6


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Biotechnology Co., Ltd. (Dalian, China). The sequence of oligonucleotides and miRNAs are listed in Table S1 and Table S2. 3,3′,5,5′-tetramethylbenzidine (TMB) substrate and tris (2-carboxyethyl)-phosphine hydrochloride (TCEP) were obtained from Sigma-Aldrich (St. Louis, MO). All chemicals were of analytical grade and used without further purification. All aqueous solutions were prepared with a Milli-Q water purification system (Millipore Corp., Bedford, MA). All solution in this work were prepared with 0.1% DEPC and treated with autoclave for an RNase-free environment, except the micropipette tips and tubes were purchased as RNase-free products and do not need further pretreatment. The buffers used in this work were as follows: 1) the tetrahedron preparation buffer was 20 mM Tris, 50 mM MgCl2, pH 8.0 (TM buffer). 2) The immobilization buffer was 1 M NaCl, 0.15 M NaHCO3. 3) The hybridization reactions were carried out in 1× SPSC buffer (1 M NaCl, 50 mM Na2HPO4, and 20 mM MgCl2, pH 7.4). Synthesis of FNAs. Typically, the procedure for synthesizing FNAs was as follows: four strands (FNA-A, FNA-B, FNA-C, and FNA-D) were separately dissolved in TM buffer, yielding a final concentration of 50 µM. 10 µL of TCEP and 2 µL of each strand were successively added into 82 µL TM buffer. The resulting mixture was then heated to 95 °C for 2 min, followed by cooling to 4 °C over 30 s. Construction of FNA microarray. An FNA microarray was constructed inside a glass capillary following a previously reported procedure40. Briefly, 1 µM FNAs was added into the glass capillary, in which the droplets were shuttled back and forth. 7



Then, the glass capillary was incubated overnight for immobilizing FNAs on the inner wall of the aldehyde-modified glass capillary. In order to perform the analysis of multiplex miRNAs, droplets containing different FNAs were added one by one by using a stepping motor. Thereafter, the glass capillary was reduced by 65.8 mM NaBH4 for 45 min after rinsing with immobilizing buffer. Finally, a block step was carried out using 5% BSA. Detection of miRNAs. A “sandwich-like” assay was performed for the miRNA detection. First, the miRNA-helper was heated to 95 °C for 4 min and cooled on ice for 10 min, followed by mixing with target miRNAs in 1× SPSC buffer to reach a final concentration of 500 nM. The mixture was then added into the glass capillary and incubated for 2 h under 37 °C, followed by washing with PBS buffer for 3 times, then, the glass capillary was incubated with a mixture of H1-1 and H1-2 (H2-1 and H2-2, H3-1 and H3-2) for the HCR. After another 2 h of reaction, the glass capillary was rinsed to be ready for the fluorescence imaging. In this assay, Typhoon 9210 scanner was used to collect the fluorescence signal for the evaluation of FNA efficiency and the quantification of miRNAs. RESULTS AND DISCUSSION The past decades have witnessed the enormous development of DNA nanotechnology41. Based on their intrinsic Watson-Crick base pairing rules, DNA molecules are exploited to construct DNA nanoarchitectures with well-defined sizes, shapes, and geometries42-45. Among them, tetrahedral DNA nanostructures have been 8


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demonstrated to be an excellent rigid scaffold for the oriented anchoring of DNA probes (e.g., DNA tetrahedron-structured probes)46-49 which can be used for precise engineering of the biosensing interface50-51. Here, we designed four FNAs with different sizes: FNA-7, FNA-13, FNA-17, and FNA-26, by gradually extending the length of their edges from 7, 13, 17 to 26 base pairs, respectively. Meantime, the FNA was appended with a pendant DNA probe at one vertex and 3 amino groups at the other vertices, enabling ready and firm anchoring onto the inner surface of a glass capillary via the interaction between amino group and carboxyl group.

Figure 2. (a) The fluorescence signal collected after it reached the equilibrium, when the FNA size was gradually increased. (b) The hybridization efficiency varies with the size of FNAs. (c) Continuous fluorescence analysis during the hybridization time between 1~120 min. FL represents fluorescence. Based on the aforementioned design, fluorescence assay was firstly carried out to quantify the surface density of the FNAs with different sizes immobilized on the inner wall of the glass capillary. To this goal, each pendant DNA probe was labeled with a fluorophore. As shown in Figure 2a, the surface density of FNAs decreased with the increasing of FNA size, this is probably because the FNAs with larger size produced 9



longer lateral distance between the probes and resulted in lower surface density38. Given that the sensitivity is closely related to the surface hybridization capability, we then studied the hybridization efficiency and the kinetics of our FNA microarray. As shown in Figure 2b, the hybridization efficiency of FNA-7 was as low as ∼14%. When the FNA size was increased, the hybridization efficiency was increased monotonously until saturated at ∼81% for FNA-17, which is almost 5-time higher than FNA-7. There results suggested that the increased lateral distance between probes with increasing FNA size could effectively improve the accessibility and reactivity of hybridization probes38. Similarly, the hybridization kinetics significantly improved with increase of the probe distance. As displayed in Figure 2c, we observed fast signal increase of FNA-17 which finally saturated at ∼40 min, whereas, a relatively slower hybridization process was observed using ssDNA probes which reached the saturation at ∼80 min, which again, indicated the importance of the distance regulation of the DNA probes for the DNA hybridization process. Having demonstrated that FNA-17 achieved dramatically improved hybridization efficiency and kinetics, that are two most important factors for the sensitivity of biosensor, we constructed an optimized FNA microarray using FNA-17 in all the following miRNA analysis. Next, we evaluated the biosensing capability of our FNA microarray after exploring the distance-dependent hybridization process. Chu group has previously reported that miRNA-627, miRNA-629 and miRNA-652 are very much sensitive for early

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diagnosis of gastric cancer, even compared with convertional tumor markers (e.g., carcinoem-bryonic antigen)52. Inspired by their work, miRNA-627, miRNA-629 and miRNA-652 were selected as the targets in our work. As the test bed, the FNA-17 was integrated with a well-established sandwich assay, in which helper DNAs with hairpin structure were introduced to immobilize on the FNAs. Thereafter, the presence of target miRNAs would open the hairpin structrue of helper DNA and initiate the HCR, leading to the signal amplification. Then we challenged the FNA microarray with miRNA samples with concentrations from 100 fM to 1 µM, the fluorescence signal increased monotonically with the concentration of target miRNA-652 (Figure 3a), and finally, our FNA microarray achieved an ultrahigh detection limit of 100 fM with a dynamic detection range spanning nearly 5 orders of magnitude (from 100 fM to 5 nM) when using the HCR amplification strategy (Figure 3a). Addtionally, the detection limit of our method based on HCR amplification is lower than or comaprable to the previously reported methods for simultaneous multiplexed detection of miRNAs31, 53-57 (Table 1). The FNA microarray using HCR amplification strategy achieved a significantly improved signal (∼100-fold) compared to traditional hybridization method based on the 1:1 binding event without signal amplification (LOD= 10 pM, Figure 3b). It is worthwhile to point out that this FNA microarray based on HCR amplification also exhibited excellent sensitivity toward miRNA-627 and miRNA-629 with a remarkable detection limit of 100 fM. Taken together, these results indicate that the FNA microarray realized highly sensitive detection of various miRNAs on the basis of HCR amplification. 11



Figure 3. Comparison of the sensor performance using (a) the HCR amplification strategy and (b) the traditional hybridization method. The fluorescent images corresponding to serial concentrations are shown as insets in Figure 3a. The concentration of FNA-miR-652 was 500 nM, and the reaction time was 2 h. The miRNA assay plays an important role in early diagnostic of gastric cancer. However, distinguishing the miRNA family members with high sequence homology remains a great challenge. Based on well-demonstrated sensing capability of the FNA microarray, we then investigated the specificity of the biosensor. As depicted in Figure 4a, there are negligible fluorescence responses in the presence of other analytes or blank in contrast with the target miRNA-652. Here, the helper DNA1 with hairpin structure works as a molecular beacon (MB) that enables selective differentiation of one-base mismatched target. As a result, only the presence of miRNA-652 that is perfectly complementary to the loop of the helper DNA1, can open its hairpin structure and subsequently trigger the HCR amplification. Similarly, only analytes (e.g., miRNA-627 and miRNA-629) well-matched with their corresponding FNAs can give rise to distinctly improved fluorescence signal (Figure 12


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4b and Figure 4c). In summary, in view of its high sensitivity and selectivity, our FNA microarray is functional as a rapid and sensitive platform for multiplex miRNA assay and clinical diagnostics.

Figure 4. Speciﬁcity investigations of the FNA microarray for the detection of (a) FNA-miR-652, (b) FNA-miR-627, and (c) FNA-miR-629. Error bars were calculated from three independent experiments. The analysis results of 3 different microRNAs in this work were obtained simultaneously. Table 1. Comparison of different methods for multiplexed detection of miRNAs Detection

Detection

Signal amplification

target

method

strategy

Linear range 100 pM to 100

miRNA-141

LOD

100 fM

DSN-assisted signal

nM

amplification





let-7d





miRNA-20a

0.05 to 0.75 nM

23 pM

0.05 to 0.75 nM

23 pM

miRNA-21

miRNA-20b

Fluorescence

Fluorescence



31

miRNA-21

0.05 to 0.75 nM

21 pM

miRNA-21

0 to 1000 nM

10 pM.

0 to 1000 nM

10 pM.

miRNA-96

0 to 1000 nM

10 pM.

miRNA-155

50 fM to 30 pM

12 fM

miRNA-125b

miNAR-10b

Fluorescence



Electrochemical

ligase chain reaction

method

amplification

SERS



miRNA-21 miRNA122 miRNA-223

50 fM to 1050 pM

31 fM

10 pM to 10 nM

2.72 pM

10 pM to 10 nM

0.24 pM

10 pM to 10 nM

2.68 pM

13


Ref.

53

54

55

56


miRNA-155 miRNA-182

FRET



miRNA-197

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0.02 to 10 nM

18 pM



12 pM



11 pM

miRNA-141

Electrochemical

DSN-assisted signal

5.0 fM to 50 pM

3.0 fM

miRNA-21

method

amplification

5.0 fM to 50 pM

4.2 fM

miRNA-21

Electrochemical

miRNA-141

method

miRNA-652 miRNA-627

Fluorescence

miRNA-629



hybridization chain reaction amplification

0.02–150 pM

6.3 fM

0.03–150 pM

8.6 fM



100 fM



100 fM



100 fM

57

58

59

This work

CONCLUSION In summary, we developed an efficient and convenient analytical platform based on FNA60-61 microarray and HCR amplification, which realized rapid, sensitive, and selective detection of multiplex miRNAs62-63. Compared with previous miRNA biosensors, our detection platform offers several distinct advantages: First, the FNA had well-demonstrated solid conformation with 3 amino groups, and thus could readily and firmly assemble the probes on the inner surface of the glass capillary, toward the facile construction of an FNA microarray. Second, the surface density, hybridization efficiency and kinetics can be effectively regulated by tuning the size of FNA. Finally, by the application of FNAs inside the glass capillary and HCR amplification strategy, it showed great potential as a rapid, ultrasensitive, and selective analytical platform for simultaneous and multiplexed detection of miRNA biomarkers for gastric cancer. Given these advantages, we believe this platform based on FNA microarray will become a promising tool for simultaneous multiplexed quantitative analysis of miRNAs, and hold great promise for biomedial reserarch and clinical early diagnosis of gastric cancer. 14


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ASSOCIATED CONTENT Supporting Information. This material is available free of charge on the ACS Publications website. This material includes the sequences of FNAs (Table S1), the sequences of DNA and miRNAs in the miRNA assay (Table S2) (PDF). AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]. Tel.: (+86) 021-54340134. *E-mail: [email protected]. Tel.: (+86) 021-38839800-35324.

Author Contributions #

The authors have equal contribution to this work.

Notes The authors declare no competing financial interest. ACKNOWLEDGMENT This work was supported by the National Natural Science Foundation of China (grant numbers 21722502, 21505045, 21705048, 21775104), the Shanghai Pujiang Talent Project (16PJ1402700), and the National Quality Infrastructure Program of China (2017YFF0204605, 2017YFF0204603). 15



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Patterns

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Stereocontrolled

Plasmonic

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TOC Graphic

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Framework Nucleic Acid-Mediated Pull-Down MicroRNA Detection

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