Mir34a constrains pancreatic carcinogenesis

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.

Therapeutic Approaches for Metastases from Colorectal Cancer and Pancreatic Ductal Carcinoma

“…In metastasis, miR-34a is found downregulated since it is a direct target of TP53 to reduce pro-inflammatory cytokines. Its restoration could be key in tumor suppression [ 97 , 98 ]. CXCL1/2-expressing tumor cells can recruit CD11b+ Gr1+ bone marrow cells and CXCL1/2 expression promotes lung metastasis and may contribute to metastatic niche formation after tumor cell dissemination [ 67 ].…”

Mitochondrial DNA and MitomiR Variations in Pancreatic Cancer: Potential Diagnostic and Prognostic Biomarkers

“…[70, [74][75][76][77][78][79][80] miR-491-5p Bcl-XL Human PDAC cell lines SW1990, MiaPaCa-2, Capan-1, and AsPC-1 + 1 normal pancreas…”

“…Preclinical studies support the therapeutic potential of miR-34a in combination therapy: in mice bearing PDAC tumors, amphiphilic nanocarrier delivery of miR-34a mimics, together with PLK1 siRNA, ameliorated the therapeutic response [ 78 ]. Furthermore, a mouse model of pancreatic conditional deletion of miR-34a ( Kras G12D ; Mir34a Δ/Δ ) revealed the presence of preneoplastic lesions and PDAC development earlier than in Kras G12D control mice [ 79 ]. This protumorigenic effect was accompanied by an early increase in normal pancreatic acinar cells of TNF-α and interleukin-6, two proinflammatory cytokines, and by recruitment of immune cells in the microenvironment [ 79 ].…”

“…Furthermore, a mouse model of pancreatic conditional deletion of miR-34a ( Kras G12D ; Mir34a Δ/Δ ) revealed the presence of preneoplastic lesions and PDAC development earlier than in Kras G12D control mice [ 79 ]. This protumorigenic effect was accompanied by an early increase in normal pancreatic acinar cells of TNF-α and interleukin-6, two proinflammatory cytokines, and by recruitment of immune cells in the microenvironment [ 79 ]. In addition, miR-34a restoration in pancreatic cancer cell lines reduced the number of cancer stem cells, tumorsphere formation in vitro, and tumor development in vivo [ 80 ], further confirming that miR-34a represents a PDAC tumor suppressor.…”

Csf1r mediates enhancement of intestinal tumorigenesis caused by inactivation of Mir34a

“…The miR-34a gene is frequently inactivated by epigenetic silencing in CRCs and other tumor entities 11 , 12 . Whereas, inactivation of the Mir34a and/or Mir34b/c genes in mice does not increase the rate of tumor formation, combination of Mir34 loss with other pro-tumorigenic lesions or treatments promotes tumor formation and progression in mouse models of prostate 13 , pancreatic 14 and lung cancer 15 as well as in sporadic 16 , colitis-associated 17 and inherited colon cancer mouse models 18 . Since loss of Mir34a did not promote lymphoma formation in Eµ-Myc mice 19 and the ability of miR-34a to inhibit proliferation may depend on high levels of expression, the definition of miR-34a as bona fide tumor suppressor has been subject to debates 20 .…”