|Year : 2017 | Volume
| Issue : 2 | Page : 53-57
Circulating micrornas and long noncoding rnas: Liquid biomarkers in thoracic cancers
Pablo Reclusa1, Anna Valentino1, Rafael Sirera2, Martin Frederik Dietrich3, Luis Estuardo Raez3, Christian Rolfo1
1 Department of Oncology, Phase I - Early Clinical Trials Unit, Antwerp University Hospital, Center for Oncological Research, Antwerp University, Antwerp, Belgium
2 Department of Oncology, Phase I - Early Clinical Trials Unit, Antwerp University Hospital, Center for Oncological Research, Antwerp University, Antwerp, Belgium; Department of Biotechnology, Universitat Politecnica de Valencia, Valencia, Spain
3 Department of Thoracic Oncology, Memorial Cancer Institute, Pembroke Pines, FL, USA
|Date of Submission||01-Aug-2016|
|Date of Acceptance||22-Dec-2016|
|Date of Web Publication||27-Apr-2017|
Phase I - Early Clinical Trials Unit, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem
Source of Support: None, Conflict of Interest: None
Thoracic cancers are the leading causes of cancer-related deaths worldwide. Recent advances in genome and transcriptome analysis have allowed for the identification of numerous classes of noncoding RNAs (ncRNAs) that play important roles either in a biological process or human disease. microRNAs (miRNAs) are small, 19–22 nucleotides, ncRNAs that regulate posttranscriptional gene expression by binding to the 3' untranslated region (3'UTR) of their target mRNA. Conversely, long noncoding RNAs (lncRNAs) are a novel class of transcripts longer than 200 nucleotides that do not encode any proteins. Some lncRNAs can interact with miRNAs and act as repressors, impeding them to bind to their protein-coding targets. There is cumulative evidence that these ncRNAs contribute to the tumorigenic process regulating cell growth, apoptosis, and metastasis, and may serve as biomarkers in various types of tumors. In this review, we have summarized the important role of ncRNAs as promising biomarkers in liquid biopsy for the diagnosis and prognosis of thoracic malignancies such as lung cancer, mesothelioma, and thymoma.
Keywords: Liquid biopsy, long noncoding RNA, microRNA, thoracic cancers
|How to cite this article:|
Reclusa P, Valentino A, Sirera R, Dietrich MF, Raez LE, Rolfo C. Circulating micrornas and long noncoding rnas: Liquid biomarkers in thoracic cancers. Cancer Transl Med 2017;3:53-7
|How to cite this URL:|
Reclusa P, Valentino A, Sirera R, Dietrich MF, Raez LE, Rolfo C. Circulating micrornas and long noncoding rnas: Liquid biomarkers in thoracic cancers. Cancer Transl Med [serial online] 2017 [cited 2017 May 28];3:53-7. Available from: http://www.cancertm.com/text.asp?2017/3/2/53/202226
| Introduction|| |
While it is estimated that more than 70% of the human genome is transcribed into primary RNA, approximately, only 2% of human DNA encodes for proteins. A particular family of RNA, noncoding RNAs (ncRNAs), can be divided into two major groups according to their transcript lengths: (1) the long noncoding RNAs (lncRNAs) which are longer than 200 bp, and (2) small ncRNAs, which are shorter than 200 bp. In this second group, there are: (a) the piwi-interacting RNAs, which is the largest class of small ncRNAs molecules expressed in animal cells and involved in epigenetic and posttranscriptional gene silencing; (b) the small nucleolar RNAs, which guide chemical modifications of other RNAs; and (c) the microRNAs (miRNAs), which also function in the posttranscriptional regulation of gene expression. Small ncRNAs are implicated in the regulation of genome expression; they play important roles in a wide range of biological processes, including modulation of cellular development, differentiation, apoptosis, and carcinogenesis.
| Noncoding Rna|| |
The miRNAs are described as a subgroup of small ncRNAs (19–24 nucleotides) that regulate targets at a posttranscriptional level [Figure 1]. They either inhibit mRNA translation or facilitate mRNA destruction by base pairing to partially complementary sites predominately in the untranslated region of the messenger. miRNA networks are highly conserved among species, and contribute to the regulation of several cellular functions, including cellular proliferation and differentiation, apoptosis, signal transduction, organ development, and immune response. miRNAs are transcribed by RNA polymerase II and cleaved by RNase III (Drosha) to a pre-miRNA of about 70–90 nucleotides. This pre-miRNA is exported from the nucleus into the cytoplasm by exportin 5 and cleaved again by Dicer, another RNase. This yields a mature miRNA of about 18–21 nucleotides which can bind target mRNAs to form RNA-induced silencing complex, leading to translation, inhibition, or mRNA degradation [Figure 2]. In addition, miRNAs have several interesting characteristics such as stability, tissue specificity, easy detection, and manipulation. Most cancers have deregulated miRNAs, which represent potential diagnostic and therapeutic targets, and can be used to assess the effect of chemotherapy.
lncRNAs are mainly located in the nucleus, where they are transcribed by the RNA polymerase II. They interact with nucleic acids and proteins, participating in the epigenetic regulation of gene expression and guiding chromatin-modifying complexes., In addition, they can interact with splicing regulatory proteins in the cytoplasm to affect the alternative splicing of mRNA, and interact with translational factors to influence the stability of mRNAs. It has also been demonstrated that lncRNAs sequester miRNA molecules and prevent them from binding their targets., Only a fraction of the lncRNAs have been characterized experimentally. The LNCipedia 4.0 (http://www.lncipedia.org/), is a database that contains 118,777 human annotated lncRNAs with information about secondary structures, protein coding potential and miRNA binding sites. Cancer-associated lncRNAs may serve as diagnostic or predictive biomarkers of cancer, and in the future might also help to provide new therapeutic strategies. Both lncRNA and miRNA are considered potential cancer biomarkers with potential clinical therapeutic applications.
| Noncoding Rnas in Liquid Biopsy|| |
Biopsy is still the current source for tumor information, however, information about tumor location, size, and heterogeneity are not easy to obtain. To rid this problem, liquid biopsy has become one of the most promising tools for the identification, prediction and prognosis of tumors. Some potential advantages of liquid biopsy are its minimal invasiveness and the vast amount of information that can be obtained from unconventional sources such as urine, saliva, or the blood. Three main components have been studied in regards to liquid biopsy: (1) circulating tumor cells, (2) exosomes, and (3) circulating tumor nucleic acids, including circulating tumor DNA and circulating tumor RNA (ctRNA), which comprises lncRNAs and miRNA., In general, RNA is a very labile molecule with a short half-life in standard conditions. However, different reports demonstrate unconventional stability levels of RNA in the blood and after incubation at room temperature for 24 h or incubation with RNase A for 3 h.,, The reason for this stability is the association of ctRNA with other components in the liquid biopsy such as lipids, phospholipids, apoptotic bodies, or DNA in nucleosomes.,,,
In the last years, due to advances in different techniques, the detection of this circulating ncRNAs with a low yield has improved dramatically,,, making it possible to get crucial information through microarrays or deep-sequencing (DeepSeq) with a small amount of material. The real time quantitative polymerase chain reaction is still the most used method to analyze these molecules due to its specificity and affordability,,,, providing a feasible tool in a clinical setting [Figure 3].
|Figure 3: LncRNAs and microRNAs as biomarkers and therapeutic targets in thoracic|
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| Noncoding Rnas in Liquid Biopsy from Lung Cancer Patients|| |
Circulating ncRNAs have been shown to play a crucial role in tumor initiation, progression and metastasis. It is known that tumorigenesis is frequently associated with an over-expression of oncogenes, as well as a down-regulation of tumor-suppressor genes. ncRNAs can act as either oncogenes or tumor-suppressor genes, and several studies in lung cancer patients have found them to be deregulated in the tissue and in the plasma. miRNAs in liquid biopsy have several advantages such as tissue specific expression and relatively easy detection, thus they may be considered as potential biomarkers for diagnosis, prognosis, and personalized therapy.
The present data suggest the potential value of miRNAs as diagnostic blood-based markers for early detection of lung cancer. miR-21 was the first miRNA with oncogenic function found in serum and plasma significantly higher in nonsmall cell lung cancer patients than in healthy controls. Furthermore, plasma levels of miR-155, miR-197, and miR-182 were significantly increased in plasma of lung cancer patients with stage I compared to controls with high specificity and sensitivity. Powrózek et al. investigated the role of miR-944 and miR-3662 as biomarkers and described a higher expression profile in lung cancer patients. Conversely, other studies have indicated that miR-361-3p, miR-625, and miR-375 were significantly decreased in serum of NSCLC patients compared to benign disease and healthy individuals. In addition, miR-625 was lower in serum from smoking patients compared with nonsmoking patients. Expanding the analytical capability of miRNAs, a set of 6 miRNAs (miR-429, miR-205, miR-200b, miR-203, miR-125b, and miR-34b) have been found significantly higher in the serum of NSCLC patients in early stages with a high sensitivity and specificity. In this regard, Geng et al. tested 12 candidate miRNAs in plasma samples of both lung cancer patients and controls and found that all miRNAs were up-regulated but only 5 (miR-20a, miR-223, miR-21, miR-221, and miR-145) resulted significantly increased in the early stage of NSCLC patients compared to healthy controls. These miRNAs showed better diagnostic value in smokers relative to nonsmokers. Several other studies have analyzed the potential diagnostic role of miRNAs in different types of biological samples such as sputum and pleural effusion in lung cancer. In particular, miR-21 and miR-210 were found to be the most deregulated miRNAs in sputum of NSCLC patients, whereas miR-30d, miR-24, and miR-26a were higher in malignant effusions compared to normal effusions.
Regarding the association with clinically relevant pathological variables in NSCLC patients, miR-21 expression was not related to age, sex, smoking status, pathology, lymph node metastasis, but it was associated with pathological TMN stage. In addition, miR-145 and miR-146 augmented circulating levels failed to associate with pathological characteristics of the patients, while serum miR-125b were associated with clinical stages, lymph node, epidermal growth factor receptor mutation and smoking status in NSCLC patients. Other studies have shown that plasma levels of let-7c and miR-152 are related with pathological features such as histological classification, differentiation status, lymph node metastasis and stage. miRNAs expression profiles can be evaluated after surgery, in fact, let-7c and miR-152 in the postoperative plasmas are significantly increased compared to the preoperative plasmas as well as miR-361-3p is up-regulated after surgery. While contrarily, other studies have demonstrated that miR-205 is selectively found in exosomes and its levels decrease after lung cancer removal. Petriella et al. confirmed that several miRNAs can be deregulated in both serum and tissues. miR-486-5p has a higher expression in tumor serum than in tumor tissues, whereas miR-29c* showed a lower expression in tumor tissues than in tumor serum. These studies may suggest the need to monitor both serum and tissues samples to search for altered expression of specific miRNAs in NSCLC patients. Circulating miR-142-3p and miR-29b have been found up-regulated in lung adenocarcinomas  and associated with the risk of recurrence. Patients with metastatic NSCLC presented with lower levels of miR-375 than those with nonmetastatic disease. In addition, low expression of miR-375 in plasma was an independent predictor of poor prognosis for NSCLC patients, and high miR-142-3p serum levels may be valuable to predict a worse response in patients who received adjuvant therapy.
Despite efforts in the field, not many lncRNAs have been described in liquid biopsies from lung cancer patients. One of the most studies is MALAT1, which binds to unmethylated Polycomb 2 protein, promoting the relocation of growth control genes in response to mitogenic signals. It seems that MALAT1 enhances the metastatic capacity of the tumor because it has been described that patients with metastatic lung cancer have higher MALAT1 levels in peripheral blood than those without metastasis.
Recently, a study analyzing a microarray of more than 800 deregulated lncRNAs in the plasma of 11 lung cancer patients and 9 healthy controls has allowed further validation of three lncRNAs: RP11-397D12, AC0074031, and ERICH1-AS1. A similar study, where 21 lncRNAs were examined in the blood of 20 lung cancer patients and 20 healthy donors, found three different lncRNA signatures: SPRY-IT1, ANRIL, and NEAT1. This study was eventually validated with a larger cohort of fifty lung cancer patients and fifty healthy donors.
| Noncoding Rna in Liquid Biopsy from Malignant Pleural Mesothelioma and Thymoma Patients|| |
Malignant pleural mesothelioma (MPM) and thymoma are two cancers with a very low prevalence in both genders, making the material available for the studies limited. However, in recent years, the feasibility of studying different aspects of liquid biopsy has permitted the discovery of some new aspects about miRNAs from both mesothelioma and thymoma tumors. Until now, no lncRNAs have been analyzed in liquid biopsy from these tumors.
One of the biggest studies in liquid biopsy was carried by Gayosso-Gómez et al., in which a wide screen of miRNAs was analyzed in serum from 11 MPM patients, 36 adenocarcinoma NSCLC patients and 45 healthy donors. After DeepSeq and both computational and differential expression analysis, they found three miRNAs related to the p38 pathway: miR-1271, miR-96-5p, and miR-409-5p differentially upregulated. p38 downregulation is associated with cell proliferation and tumorigenesis. In other publications, miR-126 has been described to be highly downregulated in serum samples from patients with MPM compared to NSCLC patients and healthy donors., miR-625-3p was the first miRNA described to be significantly upregulated in patients with MPM, compared to healthy donors. The degree of methylation of miR-34b/c plays a key role in the pathogenesis of MPM, and correlates with the presence of MPM compared to benign asbestos pleurisy and healthy donors. In addition, it also correlates with the stage of MPM.
The aberrant lncRNAs implicated in thymoma development still remain unknown, and only one study has been carried out measuring miRNAs in liquid biopsy. miR-21-5p and miR-148a-3p were significantly up-regulated in plasma from thymoma and thymic carcinoma patients, compared to healthy donors. Furthermore, the expression levels of these on co-miRNAs appeared significantly reduced during follow-up, emphasizing their potential role as biomarkers not only for diagnosis but also to evaluate complete resection and response to treatment. Clearly, more studies are required to identify and validate new ncRNA as diagnostic, prognostic, and therapeutic biomarkers, however, due to new technology, there may be more information in the coming years.
| Conclusion|| |
Deregulated transcriptional profiles found in tumors suggest that ncRNAs may represent effective biomarkers in thoracic tumors with diagnostic, prognostic, and predictive utility. Based on the development of studies related to cfDNA, preliminary consideration has been given to ncRNA as a feasible tool for daily clinical practice. In our opinion, analysis of ncRNA will soon be used to diagnose, predict and improve treatment of patients. Exosomes are arising as a very promising tool to improve the quality of life of patients through better diagnosis and prediction of their disease. They could also potentially replace traditionally invasive biopsies from daily clinical practice due to their better protection of genetic material and their high representation of cellular cargo. However, since there are still unknown aspects in regards to exosome production and interaction, more work still needs to be performed in the field of exosome research.
In recent years, research in ncRNA has been on the rise, and 140,000 ncRNAs have been described, including miRNAs and lncRNAs, many of which are currently being studied in different tumors. Many ncRNAs have already been detected with promising characteristics, however, validation of these profiles must be performed to bring ncRNAs to the clinical setting. The scientific community is making a huge effort to detect new useful molecules in cancer. In our opinion, in the future years, liquid biopsy will become a necessary complement to the tissue analysis both with cfDNA and exosomes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]