Specific MAPK-Associated MicroRNAs in Serum Differentiate Pancreatic Cancer from Autoimmune Pancreatitis

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is difficult to distinguish from autoimmune pancreatitis (AIP) because of their clinical and radiological similarities, and therefore simple and minimally invasive surrogate markers for differential diagnosis would be useful. In our previous studies, we identified four microRNAs (miRNAs)–miR-7, miR-34a, miR-181d, and miR-193b –as MAPK-associated microRNAs whose expression was altered significantly with upregulation of the MAPK signaling pathway. Recently it has been reported that these miRNAs could be used as biomarkers in serum samples for accurate diagnosis of pancreatic lesions. The aim of the present study was to evaluate whether these MAPK-associated miRNAs in serum could be used as biomarkers for differentiating PDAC from AIP. We enrolled 69 patients with PDAC, 26 with intraductal papillary mucinous neoplasm (IPMN) and 15 with AIP. The expression of MAPK-associated miRNAs in serum was measured by quantitative real-time PCR. The 2-ΔCT method was used to quantify the expression of miRNAs, and the data were normalized using spiked-in synthetic cel-miR-39. Patients with PDAC or IPMN showed significantly higher amounts of serum MAPK-associated miRNAs than those with AIP (p<0.009 for miR-7, p<0.002 for miR-34a, p<0.001 for miR-181d, p<0.002 for miR-193b). ROC curve analysis demonstrated that these miRNAs had an area under the ROC curve (AUC) of 0.723–0.882 for differentiation between PDAC or IPMN from AIP. Furthermore, serum miR-181d was significantly associated with the presence of metastasis in patients with PDA (p = 0.014). Serum MAPK-associated miRNAs could be novel noninvasive biomarkers for differentiation between PDAC or IPMN and AIP.

miR-155-5p is Negatively Associated with Acute Pancreatitis and Inversely Regulates Pancreatic Acinar Cell Progression by Targeting Rela and Traf3

“…Nonetheless, miRNAs exert vital roles in the occurrence and development of AP. A great deal of evidence has illustrated that miRNAs' primary function is to suppress the expression of downstream target genes by interacting with the 3'UTR of their mRNA [21][22][23], and therefore, miRNAs play critical regulatory roles in AP. It has been reported that miR-29 contributes to apoptosis in AR42J cells by targeting TNFRSF1A [24]; miR-22 and miR-135a promotes the apoptosis of pancreatic acinar cells in acute edematous pancreatitis through ErbB3 and Ptk2 [25]; miR-141 plays an important role in the regulation of autophagy in L-arginine-induced acute pancreatitis by targeting HMGB1 [11].…”

“…And there was higher expression of miR-155 in tissues and synovial fibroblasts of patients with autoimmune disorders such as rheumatoid arthritis [38]. Actually, in the previous researches, they were focused on the correlation between higher expression of miR-155 and either chronic inflammation or autoimmune disorders in which it needed a relatively long time to maintain this state [14,22].…”

Serological characteristics of autoimmune pancreatitis and its differential diagnosis from pancreatic cancer by using a combination of carbohydrate antigen 19-9, globulin, eosinophils and hemoglobin

“…They not only provide for novel therapeutic options for pancreatic malignancy treatment, also the chance to aid in early diagnosis, disease monitoring and prognostic analysis[27, 29]. Recently, Manabu Akamatsu and his colleagues reported that four MAKP-associated miRNAs, miR-7, miR-34a, miR-181d, and miR-193b can be candidate biomarkers to differentiate pancreatic malignancy from AIP [30]. In this work, significantly higher amounts of serum miRNAs were detected in patients with pancreatic ductal adenocarcinoma (PDCA) than in those with AIP, and sensitivity of 72–79% together with specificity of 73–80% were obtained in ROC curve analysis [30].…”

“…Recently, Manabu Akamatsu and his colleagues reported that four MAKP-associated miRNAs, miR-7, miR-34a, miR-181d, and miR-193b can be candidate biomarkers to differentiate pancreatic malignancy from AIP [30]. In this work, significantly higher amounts of serum miRNAs were detected in patients with pancreatic ductal adenocarcinoma (PDCA) than in those with AIP, and sensitivity of 72–79% together with specificity of 73–80% were obtained in ROC curve analysis [30]. In recent work of Johansen and his colleagues, they analysed serum level of 34 miRNAs in patients with pancreatic cancer, chronic pancreatitis and healthy controls and developed a diagnostic panels based on 5 or 12 miRNAs (miR-16, -18a, -20a, -24, -25, -27a, -29c, -30a.5p, -191, -323.3p, -345 and miR-483.5p) to distinguish pancreatic cancer from pancreatitis.…”

<p>A Systemic Review on the Regulatory Roles of miR-34a in Gastrointestinal Cancer</p>

“…155 Furthermore, CpG methylation of miR-34a was also employed as a diagnostic indicator for the prognosis of patients with PC. 164 Akamatsu et al 165 found that the expression level of miR-34a in serum could be used as a biomarker to distinguish between PDAC and autoimmune pancreatitis (AIP). These studies indicate that miR-34a and its methylation levels may be used as indicators for diagnosis and prognosis in patients with PC.…”