Altered Serum MicroRNA Profile May Serve as an Auxiliary Tool for Discriminating Aggressive Thyroid Carcinoma from Nonaggressive Thyroid Cancer and Benign Thyroid Nodules

Hindawi Disease Markers Volume 2019, Article ID 3717683, 11 pages https://doi.org/10.1155/2019/3717683 Research Article Altered Serum MicroRNA Profile May Serve as an Auxiliary Tool for Discriminating Aggressive Thyroid Carcinoma from Nonaggressive Thyroid Cancer and Benign Thyroid Nodules Aisen Zhang ,1,2 Cheng Wang ,1,3 Hui Lu ,4 Xi Chen ,1 Yi Ba ,5 Chunni Zhang ,1,3 and Chen-Yu Zhang 1 1 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing Advanced Institute for Life Sciences, School of Life Sciences, Jiangsu Engineering Research Center for MicroRNA Biology and Biotechnology, Nanjing University, Nanjing, China 2 Department of Gerontology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China 3 Department of Clinical Laboratory, Jinling Hospital, Nanjing University School of Medicine, Nanjing University, Nanjing, China 4 Department of General Surgery, The First Hospital Affiliated to Nanjing Medical University, Nanjing, China 5 Tianjin Medical University Cancer Institute and Hospital, Key Laboratory of Cancer Prevention and Therapy, Tianjin, China Correspondence should be addressed to Chunni Zhang; and Chen-Yu Zhang; Received 11 January 2019; Revised 20 March 2019; Accepted 30 August 2019; Published 15 September 2019 Academic Editor: Chiara Fenoglio Copyright © 2019 Aisen Zhang et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Thyroid cancers are the most common malignancy of the endocrine system; however, there is no reliable blood biomarkers for thyroid cancer diagnosis and even for aggressive and nonaggressive thyroid cancers as well as benign nodule discrimination. The present study is aimed at evaluating whether circulating microRNA (miRNA) can differentiate aggressive and nonaggressive thyroid cancer from benign thyroid nodules. In this study, we performed a multiphase, case-control study to screen serum miRNA expression profile in 100 patients with papillary thyroid cancer (PTC), 15 patients with aggressive medullary thyroid carcinoma (MTC), 91 patients with benign nodules, and 89 healthy controls using TaqMan low-density array followed by extensive reverse transcription quantitative real-time PCR validation. The results showed that the serum levels of miR-222-3p, miR-17-5p, and miR-451a were markedly increased, while miR-146a-5p, miR-132-3p, and miR-183-3p were significantly decreased in the PTC and benign nodule groups compared with the control group. There was no difference in the miRNA expression profile between the PTC group and the benign nodule group. Nevertheless, the serum levels of miR-222-3p and miR-17-5p were significantly increased in the MTC group than the benign nodule and control group. Moreover, receiver operating characteristic curve analyses demonstrated that the 2 miRNAs and their panel can accurately discriminate MTC from the benign nodule group and healthy controls. These findings indicated that the altered circulating miRNAs may discriminate PTC and benign thyroid nodules from controls, and serum miR-222-3p and miR-17-5p have the potential to serve as auxiliary tools for diagnosing more aggressive thyroid carcinomas, such as MTC. 1. Introduction Thyroid cancers are the most common malignancy in the endocrine system and comprise 1% of all cancers. Differentiated thyroid carcinomas (DTCs), which include papillary and follicular cancers, comprise the vast majority (90%) of total thyroid cancer cases [1]. In the past three decades, even with the progress made on diagnostic methods, the yearly incidence of thyroid cancer has increased nearly 3-fold in the United States and continues to rise [2]. The increase has been attributed to the higher incidence of papillary thyroid carcinomas (PTCs), especially small PTCs (2 cm or smaller) [1], which comprises over 80% of all cancer cases. Thyroid nodules have a prevalence of 4-50% based on the diagnostic methods and patients’ age. Most thyroid nodules are benign; only 5% are malignant [3], but suspicious thyroid nodules must be tested for malignancy. Currently, thyroid ultrasound 2 and the fine-needle aspiration (FNA) are the two most valuable diagnostic approaches. The ultrasound examination is noninvasive, but heavily dependent on the techniques and clinical experience of the operators. FNA is now the gold standard procedure for the differential diagnosis of thyroid nodules. However, there are still limitations, such as inadequate sampling and indeterminate results (10-40%) [4]. In these situations, repeat aspirations or diagnostic lobectomy are recommended [5], although more than 50% of the patients who underwent diagnostic lobectomy were finally found to be benign [4]. In addition, the FNA diagnostic procedure is invasive. All these reasons bring difficulties in differential diagnosis and result in patient suffering. Blood-based examination is ideal for clinical diagnosis as it is minimally invasive. Currently, no clinically routine blood test is available for thyroid cancer. Therefore, the identification of noninvasive biomarkers is urgently needed for the differentiation of aggressive thyroid carcinoma from nonaggressive thyroid cancer and benign thyroid nodules. MicroRNAs (miRNAs) are a class of endogenous, small, noncoding RNAs of 19–23 nt cleaved from larger hairpin precursors. By binding to the 3 ′ -untranslated region of target mRNA, miRNAs can cause a block of translation or mRNA degradation. They comprise one of the most abundant classes of gene regulatory molecules in multicellular organisms and take part in many biological processes, including proliferation, apoptosis, differentiation, and carcinogenesis [6]. Numerous studies have noted that expression of particular miRNAs is found in various human cancer tissues, including thyroid cancer [7–13], and several miRNAs (miR-221, miR-222, miR-146b, miR-181b, miR-155, miR183, and miR-223) were found to be upregulated in postoperative cancer tissues, formalin-fixed paraffin-embedded tissues, and FNA samples. Furthermore, researches indicated that these dysregulated miRNAs are helpful in distinguishing cancer from normal or benign nodule tissues [14–16]; however, the invasiveness of the procedures has limited its application. Our group and others have previously discovered that miRNAs are stably present at sufficient levels in circulating blood to be detected as blood-based biomarkers [17, 18]. Subsequent, researchers have identified distinct expression signatures of circulating miRNA in a variety of cancers, such as lung cancer, hepatocellular and renal carcinoma, esophagus cancer, and pancreatic cancer [19–23]. To date, a few studies have focused on the profile of circulating miRNA in thyroid tumors [24–29]. However, although differential miRNA expressions in thyroid carcinomas (most PTCs) have been reported, the results are highly inconsistent. In our present s (...truncated)