Immune-Related Circulating miR-125b-5p and miR-99a-5p Reveal a High Recurrence Risk Group of Pancreatic Cancer Patients after Tumor Resection

Abstract

Clinical follow-up aided by changes in the expression of circulating microRNAs (miRs) may improve prognostication of pancreatic ductal adenocarcinoma (PDAC) patients. Changes in 179 circulating miRs due to cancer progression in the transgenic KrasG12D/+; Trp53R172H/+; P48-Cre (KPC) animal model of PDAC were analyzed for serum miRs that are altered in metastatic disease. In addition, expression levels of 250 miRs were profiled before and after pancreaticoduodenectomy in the serum of two patients with resectable PDAC with different progression free survival (PFS) and analyzed for changes indicative of PDAC recurrence after resection. Three miRs that were upregulated ≥3-fold in progressive PDAC in both mice and patients were selected for validation in 26 additional PDAC patients before and after resection. We found that high serum miR-125b-5p and miR-99a-5p levels after resection are significantly associated with shorter PFS (HR 1.34 and HR 1.73 respectively). In situ hybridization for miR detection in the paired resected human PDAC tissues showed that miR-125b-5p and miR-99a-5p are highly expressed in inflammatory cells in the tumor stroma, located in clusters of CD79A expressing cells of the B-lymphocyte lineage. In conclusion, we found that circulating miR-125b-5p and miR-99a-5p are potential immune-cell related prognostic biomarkers in PDAC patients after surgery.

miRNAs in pancreatic cancer progression and metastasis

“…Increasing amounts of evidence suggest that several miRNAs are also altered after surgical resection, and/or chemotherapy, and are typically associated with risk of recurrence. In a cohort of 26 PDAC patients who underwent pancreaticoduodenectomy, serum miR-99a-5p and miR-125b-5p were upregulated following surgery and significantly associated with shorter progression-free survival [ 152 ]. A risk score developed incorporating expression of miR-181b/d and miR-575 was validated for use in assessing the risk of locoregional recurrence and worse overall survival in PDAC patients receiving different treatments [ 153 ].…”

Clinical Value of Circulating miRNA in Diagnosis, Prognosis, Screening and Monitoring Therapy of Pancreatic Ductal Adenocarcinoma–A Review of the Literature

“…In a study by Gablo et al [ 82 ], a panel consisting of down-regulated miR-99a-5p, miR-365a-3p and up-regulated miR-200c-3p had been proven to identify patients with poor prognosis after surgical resection with the sensitivity of 85% and specificity of 80%. According to the study by Vietsch et al [ 86 ], two up-regulated miRNAs (miR-99a-5p and miR-125b-5p) are significantly associated with a shorter progression free survival (PFS).…”