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. 2021 Mar 22;22(6):3221.
doi: 10.3390/ijms22063221.

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

Natsuhiko Kuratomi  1 , Shinichi Takano  1 , Mitsuharu Fukasawa  1 , Shinya Maekawa  1 , Makoto Kadokura  1 , Hiroko Shindo  1 , Ei Takahashi  1 , Sumio Hirose  1 , Yoshimitsu Fukasawa  1 , Satoshi Kawakami  1 , Hiroshi Hayakawa  1 , Hitomi Takada  1 , Natsuko Nakakuki  1 , Ryoh Kato  1 , Tatsuya Yamaguchi  1 , Yasuhiro Nakayama  1 , Hiromichi Kawaida  2 , Hiroshi Kono  2 , Taisuke Inoue  1 , Tetsuo Kondo  3 , Daisuke Ichikawa  2 , Nobuyuki Enomoto  1
Affiliations

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

Natsuhiko Kuratomi et al. Int J Mol Sci. .

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.

Keywords: formalin-fixed paraffin-embedded samples; intraductal papillary mucinous neoplasm; miRNA; next-generation sequencing; pancreatic juice.

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Conflict of interest statement

There are no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Volcano plots of next-generation sequencing data show differential miRNA expressions in intraductal papillary mucinous neoplasm (IPMN) between tumor tissue and its paired normal acinus tissue. (a) All IPMN cases (n = 19). (b) Cases with low-grade dysplasia (LGD) (n = 4). (c) Cases with high-grade dysplasia (HGD) (n = 9). (d) Cases with invasive carcinoma (INV) (n = 6). Orange dots show significantly upregulated miRNAs (fold-change > 2, p < 0.05), and blue dots show significantly downregulated miRNAs (fold-change < 0.5, p < 0.05).
Figure 2
Figure 2
Heatmap of miRNA expressions stratified by pathological grades of intraductal papillary mucinous neoplasm (IPMN). The expressions of each miRNA in the IPMN tissues are shown as a heatmap. The expression levels of miRNAs are shown on a green-red scale in the center panel where the green and red should be interpreted as a low and high expression, respectively. The right panel shows the p-values by a Kruskal–Wallis test comparing three pathological grades (bold p value < 0.05). The left and upper panels show miRNAs and patients that were arranged according to an unsupervised hierarchical clustering, which was performed using a one minus Pearson’s correlation as the distance measure and an average linkage as the agglomerative method. LGD, low-grade dysplasia; HGD, high-grade dysplasia; INV, invasive carcinoma. MiRNAs with underlines show significant differential expressions between INV and non-INV (LGD and HGD) patients.
Figure 3
Figure 3
Candidate biomarker miRNAs in intraductal papillary mucinous neoplasm (IPMN) tissues to differentiate invasive IPMNs from noninvasive IPMNs. (a,d) MiR-10a-5p and (b,e) miR-221-3p were significantly upregulated in invasive carcinoma (INV) compared to low-grade dysplasia (LGD) and high-grade dysplasia (HGD). (c,f) MiR-148-3p was downregulated in INV compared to LGD and HGD. Gray dots indicate all other normalized read numbers of miRNA for each grade.
Figure 4
Figure 4
The miRNA expression of candidate biomarkers in intraductal papillary mucinous neoplasm (IPMN) pancreatic juice samples. (a) MiR-10a-5p was significantly upregulated in invasive IPMN compared to noninvasive IPMN, and (b) miR-221-5p showed a similar tendency. INV, invasive carcinoma.
Figure 5
Figure 5
A flowchart of the study. The microRNA expression in intraductal papillary mucinous neoplasm (IPMN) was analyzed in tissue samples (Step 1) and pancreatic juice samples (Step 2).
See this image and copyright information in PMC

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