Mir34a constrains pancreatic carcinogenesis

Ana Hidalgo-Sastre,Roland M Schmid,Jens T Siveke,Suyang Zhong,Roland Rad,Clara Lubeseder-Martellato,Judit Desztics,Heiko Hermeking,Katja Steiger,Rupert Öllinger,Thomas Engleitner,Guido Von Figura

doi:10.1038/s41598-020-66561-1

Abstract

Several studies have shown that over 70 different microRNAs are aberrantly expressed in pancreatic ductal adenocarcinoma (PDAC), affecting proliferation, apoptosis, metabolism, EMT and metastasis. The most important genetic alterations driving PDAC are a constitutive active mutation of the oncogene Kras and loss of function of the tumour suppressor Tp53 gene. Since the MicroRNA 34a (Mir34a) is a direct target of Tp53 it may critically contribute to the suppression of PDAC. Mir34a is epigenetically silenced in numerous cancers, including PDAC, where Mir34a down-regulation has been associated with poor patient prognosis. To determine whether Mir34a represents a suppressor of PDAC formation we generated an in vivo PDAC-mouse model harbouring pancreas-specific loss of Mir34a (KrasG12D; Mir34aΔ/Δ). Histological analysis of KrasG12D; Mir34aΔ/Δ mice revealed an accelerated formation of pre-neoplastic lesions and a faster PDAC development, compared to KrasG12D controls. Here we show that the accelerated phenotype is driven by an early up-regulation of the pro-inflammatory cytokines TNFA and IL6 in normal acinar cells and accompanied by the recruitment of immune cells. Our results imply that Mir34a restrains PDAC development by modulating the immune microenvironment of PDAC, thus defining Mir34a restauration as a potential therapeutic strategy for inhibition of PDAC development.

Highlights

Several studies have shown that over 70 different microRNAs are aberrantly expressed in pancreatic ductal adenocarcinoma (PDAC), affecting proliferation, apoptosis, metabolism, EMT and metastasis
The acinar to ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions from KrasG12D; Mir34aΔ/Δ mice were not more proliferative (Supplementary Fig. 2D,E) nor apoptotic (Supplementary Fig. 2D,F) compared to those from the KrasG12 control mice. These results show that KrasG12D; Mir34aΔ/Δ mice present an acceleration in the development of ADM and PanIN pancreatic lesions, compared to KrasG12D mice
Many studies showed that plenty of microRNAs are deregulated in PDAC, among them MicroRNA 34a (Mir34a) is often downregulated and is a promising biomarker with prognostic value that correlates with diagnosis[39,40,41]

Summary

Introduction

Several studies have shown that over 70 different microRNAs are aberrantly expressed in pancreatic ductal adenocarcinoma (PDAC), affecting proliferation, apoptosis, metabolism, EMT and metastasis. KrasG12D expression in epithelial cells leads to activation of inflammatory pathways and results in paracrine signalling with the surrounding stroma This promotes formation and maintenance of a desmoplastic, fibro-inflammatory microenvironment, which favours the step-wise progression of normal exocrine pancreas into pre-invasive precursor acinar to ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) lesions and PDAC development[5]. There are two main mechanisms to inactivate tumour suppressor genes: transcriptional silencing by methylation of CpG islands and genomic loss Evidence of both mechanisms have been reported for miR-34: previous studies showed how the CpG islands in the Mir34a promoter are methylated (correlating with Mir34a silencing) in different solid tumours, including pancreatic cancer[16,22]; and, genomic loss of the chromosomal region (1p36) of Mir34a has been reported in neuroblastoma[20,23]. In vitro studies revealed that MIR34a is downregulated in human pancreatic cancer cells[26], where it modulates Notch[1] signalling, Bcl[2], and EMT27–31

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Conclusion