Upregulated MicroRNA-483-3p is an Early Event in Pancreatic Ductal Adenocarcinoma (PDAC) and as a Powerful Liquid Biopsy Biomarker in PDAC
Authors Shao H, Zhang Y, Yan J, Ban X, Fan X, Chang X, Lu Z, Wu Y, Zong L, Mo S, Yu S, Chen J
Received 27 October 2020
Accepted for publication 30 January 2021
Published 25 March 2021 Volume 2021:14 Pages 2163—2175
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 3
Editor who approved publication: Prof. Dr. Takuya Aoki
Huilin Shao, Yue Zhang, Jie Yan, Xinchao Ban, Xiaojie Fan, Xiaoyan Chang, Zhaohui Lu, Yan Wu, Liju Zong, Shengwei Mo, Shuangni Yu, Jie Chen
Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People’s Republic of China
Correspondence: Shuangni Yu; Jie Chen Tel +86 10 69159375
; +86 10 69159389
Email [email protected]; [email protected]
Background: There is an urgent need for the development of effective noninvasive biomarkers for early pancreatic cancer diagnosis. MicroRNAs (miRNAs) are promising candidates that can be identified in peripheral blood and can act as “liquid biopsy” biomarkers. miR-483-3p is overexpressed in the tumor tissue of pancreatic duct adenocarcinoma, but its potential as noninvasive biomarker remains unknown.
Methods: We conducted locked nucleic acid in situ hybridization (LNA-ISH) for miR-483-3p in archival tissues of 107 patients with PDAC. We also used immunohistochemistry to evaluate SMAD4 expression, the putative miR-483-3p target gene. miR-483-3p expression level was also assessed using quantitative real-time PCR (qRT-PCR) in serum and serum exosome samples from 63 patients with PDAC and 22 healthy individuals.
Results: LNA-ISH showed that miR-483-3p was overexpressed in PDAC and PanIN tissues compared to normal pancreatic duct cells. miR-483-3p expression levels correlated with increases in PanIN lesion grade. miR-483-3p expression negatively correlated with Smad4 expression (γ=− 0.770, p< 0.0001) in PDAC and PanIN tissues. Circulating miR-483-3p levels were significantly elevated in the serum and serum exosomes of PDAC patients compared to healthy controls (p< 0.0001 and p< 0.01, respectively). Specifically, serum miR-483-3p levels were able to distinguish patients with early stage (≤ 2cm) PDAC from healthy controls with an AUC of 0.83 [95% CI, 0.70– 0.96]. Higher serum exosomal miR-483-3p levels predicted worse survival in PDAC patients and serum exosomal miR-483-3p also proved to be an independent prognostic factor for PDAC (hazard ratio = 3.307; 95% CI=1.104 to 9.903; p=0.033). In vitro studies also showed that miR-483-3p promoted pancreatic cancer cell migration and invasion.
Conclusion: miR-483-3p overexpression occurs early in PDAC development and is present in premalignant PanIN lesions. Serum miR-483-3p may act as an early PDAC diagnostic biomarker and serum exosomal miR-483-3p may be a PDAC prognostic biomarker.
Keywords: pancreatic ductal adenocarcinoma, exosome, microRNA-483-3p, liquid biopsy, biomarker
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