Shao Huilin, Zhang Yue, Yan Jie, Ban Xinchao, Fan Xiaojie, Chang Xiaoyan, Lu Zhaohui, Wu Yan, Zong Liju, Mo Shengwei, Yu Shuangni, Chen Jie
Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, People's Republic of China.
Onco Targets Ther. 2021 Mar 25;14:2163-2175. doi: 10.2147/OTT.S288936. eCollection 2021.
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.
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.
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.
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.
迫切需要开发用于早期胰腺癌诊断的有效非侵入性生物标志物。微小RNA（miRNA）是有前景的候选物，可在外周血中检测到，并可作为“液体活检”生物标志物。miR-483-3p在胰腺导管腺癌的肿瘤组织中过表达，但其作为非侵入性生物标志物的潜力尚不清楚。
我们对107例胰腺导管腺癌（PDAC）患者的存档组织进行了miR-483-3p的锁核酸原位杂交（LNA-ISH）。我们还使用免疫组织化学评估SMAD4的表达，SMAD4是推测的miR-483-3p靶基因。还使用定量实时PCR（qRT-PCR）评估了63例PDAC患者和22名健康个体的血清及血清外泌体样本中miR-483-3p的表达水平。
LNA-ISH显示，与正常胰腺导管细胞相比，miR-483-3p在PDAC和胰腺上皮内瘤变（PanIN）组织中过表达。miR-483-3p表达水平与PanIN病变等级的增加相关。在PDAC和PanIN组织中，miR-483-3p表达与Smad4表达呈负相关（γ=-0.770，p<0.0001）。与健康对照相比，PDAC患者血清和血清外泌体中循环miR-483-3p水平显著升高（分别为p<0.0001和p<0.01）。具体而言，血清miR-483-3p水平能够区分早期（≤2cm）PDAC患者与健康对照，曲线下面积（AUC）为0.83[95%置信区间（CI），0.70-0.96]。血清外泌体miR-483-3p水平较高预示着PDAC患者预后较差，血清外泌体miR-483-3p也被证明是PDAC的独立预后因素（风险比=3.307；95%CI=1.104至9.903；p=0.033）。体外研究还表明，miR-483-3p促进胰腺癌细胞迁移和侵袭。
miR-483-3p过表达在PDAC发生早期出现，并存在于癌前PanIN病变中。血清miR-483-3p可能作为早期PDAC诊断生物标志物，血清外泌体miR-483-3p可能是PDAC预后生物标志物。
