MicroRNA-21 Regulates Stemness in Pancreatic Ductal Adenocarcinoma Cells.

Maria Mortoglou,Francesc Miralles,Elif Damla Arisan,Sigrun Lange,Stipo Jurcevic,Pinar Uysal-Onganer,Alwyn Dart

doi:10.3390/ijms23031275

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most common and aggressive type of pancreatic cancer (PCa) with a low survival rate. microRNAs (miRs) are endogenous, non-coding RNAs that moderate numerous biological processes. miRs have been associated with the chemoresistance and metastasis of PDAC and the presence of a subpopulation of highly plastic “stem”-like cells within the tumor, known as cancer stem cells (CSCs). In this study, we investigated the role of miR-21, which is highly expressed in Panc-1 and MiaPaCa-2 PDAC cells in association with CSCs. Following miR-21 knockouts (KO) from both MiaPaCa-2 and Panc-1 cell lines, reversed expressions of epithelial–mesenchymal transition (EMT) and CSCs markers were observed. The expression patterns of key CSC markers, including CD44, CD133, CX-C chemokine receptor type 4 (CXCR4), and aldehyde dehydrogenase-1 (ALDH1), were changed depending on miR-21 status. miR-21 (KO) suppressed cellular invasion of Panc-1 and MiaPaCa-2 cells, as well as the cellular proliferation of MiaPaCa-2 cells. Our data suggest that miR-21 is involved in the stemness of PDAC cells, may play roles in mesenchymal transition, and that miR-21 poses as a novel, functional biomarker for PDAC aggressiveness.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the eighth primary source of cancerrelated deaths globally with a 5-year survival rate of 3–6% [1–4]
Using three different PDAC cell lines, we found that miR-21, miR-221, miR-155, and miR-126 expressions were significantly altered in MiaPaca-2, Panc-1, and BxPC3 PDAC cell lines, compared with normal pancreatic ductal epithelial cell lines (HPDE)
We found that miR-21 moderated the expression levels of several cancer stem cells (CSCs), including CD44

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the eighth primary source of cancerrelated deaths globally with a 5-year survival rate of 3–6% [1–4]. Cancer stem cells (CSCs) are involved in chemoresistance and play critical roles in the metastasis of several cancers, including PDAC [22–29]. Pancreatic CSCs (PCSCs) are less than 1% of all pancreatic cancer cells and are critical mediators of PDAC tumor growth, maintenance, metastasis, and chemoresistance [35]. E-cadherin downregulation is associated with poor prognosis, differentiation, and chemoresistance in PDAC [37–40]. Transcription marker Zeb suppresses E-cadherin through the repression of both miR-203 (an inhibitor of stemness) and miR-200 family members, which control the expression levels of stem cell factors [41]. Zeb overexpression is linked to advanced PDAC stages and poor malignancy outcome, migration, and invasion in response to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling [42–44]. Non-canonical Wnt-11 overexpression is associated with poor prognosis and tumor-node-metastasis (TNM) staging in PDAC [45–49]

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Results

Conclusion