MiR-10a in Pancreatic Juice as a Biomarker for Invasive Intraductal Papillary Mucinous Neoplasm by miRNA Sequencing.

Natsuhiko Kuratomi,Makoto Kadokura,Tatsuya Yamaguchi,Tetsuo Kondo,Hitomi Takada,Nobuyuki Enomoto,Ryoh Kato,Hiroshi Hayakawa,Ei Takahashi,Natsuko Nakakuki,Hiromichi Kawaida,Shinya Maekawa,Hiroshi Kono,Shinichi Takano,Yasuhiro Nakayama,Mitsuharu Fukasawa,Yoshimitsu Fukasawa,Hiroko Shindo,Sumio Hirose,Satoshi Kawakami,Daisuke Ichikawa,Taisuke Inoue

doi:10.3390/ijms22063221

Natsuhiko Kuratomi, Makoto Kadokura + Show 20 more

Open Access

https://doi.org/10.3390/ijms22063221

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Abstract

New biomarkers are needed to further stratify the risk of malignancy in intraductal papillary mucinous neoplasm (IPMN). Although microRNAs (miRNAs) are expected to be stable biomarkers, they can vary owing to a lack of definite internal controls. To identify universal biomarkers for invasive IPMN, we performed miRNA sequencing using tumor-normal paired samples. A total of 19 resected tissues and 13 pancreatic juice samples from 32 IPMN patients were analyzed for miRNA expression by next-generation sequencing with a two-step normalization of miRNA sequence data. The miRNAs involved in IPMN associated with invasive carcinoma were identified from this tissue analysis and further verified with the pancreatic juice samples. From the tumor-normal paired tissue analysis of the expression levels of 2792 miRNAs, 20 upregulated and 17 downregulated miRNAs were identified. In IPMN associated with invasive carcinoma (INV), miR-10a-5p and miR-221-3p were upregulated and miR-148a-3p was downregulated when compared with noninvasive IPMN. When these findings were further validated with pancreatic juice samples, miR-10a-5p was found to be elevated in INV (p = 0.002). Therefore, three differentially expressed miRNAs were identified in tissues with INV, and the expression of miR-10a-5p was also elevated in pancreatic juice samples with INV. MiR-10a-5p is a promising additional biomarker for invasive IPMN.

Highlights

Intraductal papillary mucinous neoplasm (IPMN) is a noninvasive mucin-producing epithelial neoplasm, which is grossly visible, predominantly papillary, and rarely flat and which grows in the main or branch pancreatic ducts [1,2]
After normalization of miRNA sequence reads by calculating the percentage of reads in the total sample for each miRNA, we further normalized the results for 194 miRNAs by calculating the ratio of the miRNA expression in the tumor tissue to the paired normal acinar tissue in 19 tumor-normal paired tissue samples
We showed that miR-10a and miR-221 were upregulated and that miR148a was downregulated in IPMN associated with invasive carcinoma by next-generation sequencing (NGS) using tumornormal paired resected tissues

Summary

Introduction

Intraductal papillary mucinous neoplasm (IPMN) is a noninvasive mucin-producing epithelial neoplasm, which is grossly visible, predominantly papillary, and rarely flat and which grows in the main or branch pancreatic ducts [1,2]. The prevalence of incidental findings of IPMN or pancreatic cyst increased to 4.3% with improved diagnostic imaging technologies [3,4]. IPMN, like pancreatic intraepithelial neoplasia (PanIN), is a lesion, which is a precursor of pancreatic ductal carcinoma, and shows a wide-ranging histological spectrum, from low-grade dysplasia (LGD) and high-grade dysplasia (HGD) to IPMN with an associated invasive carcinoma (INV) [1,5]. IPMN with INV exhibits a poor survival rate after resection when the tumor is accompanied by lymph node metastases or histological findings of tubular adenocarcinoma [6,7]. The five-year survival rate of INV after resection (30%) is much poorer than that of LGD and HGD (73% and 70%, respectively) [8]. Diagnosing INV without delay is extremely important

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