The miR-217 microRNA functions as a potential tumor suppressor in pancreatic ductal adenocarcinoma by targeting KRAS

Abstract

Aberrantly expressed microRNA (miRNA) is frequently associated with a variety of cancers, including pancreatic ductal adenocarcinoma (PDAC). In this study, we investigated the expression and possible role of miR-217 in PDAC. Data obtained by locked nucleic acid in situ hybridization and real-time quantitative polymerase chain reaction showed that miR-217 was downregulated in 76.2% (16/21) of PDAC tissues and in all tested PDAC cell lines when compared with the corresponding normal pancreatic tissue. Overexpression of miR-217 in PDAC cells inhibited tumor cell growth and anchorage-independent colony formation and miR-217 decreased tumor cell growth in nude mouse xenografts in vivo. Using in silico predictions, KRAS was defined as a potential direct target of miR-217. Data from the dual-luciferase reporter gene assay showed that KRAS was a direct target of miR-217. Upregulation of miR-217 could decrease KRAS protein levels and reduce the constitutive phosphorylation of downstream AKT. Downregulation of miR-217 expression in PDAC cells could increase cell anchorage-independent colony formation and KRAS protein levels. Furthermore, miR-217 expression was observed to be negatively correlated with KRAS protein expression in PDAC cell lines. We conclude that the frequently downregulated miR-217 can regulate KRAS and function as a tumor suppressor in PDAC. Therefore, miR-217 may serve as a useful therapeutic agent for miRNA-based PDAC therapy.

Regulation of Complement-Dependent Cytotoxicity by MicroRNAs miR-200b, miR-200c, and miR-217

“…Decreased miR-200b expression in lung adenocarcinoma appears to lead to resistance to docetaxel therapy and to poor prognosis (56). miR-217 was also shown to act as a tumor suppressor in pancreatic ductal adenocarcinoma (57), lung cancer (58), osteosarcoma (59), and esophageal squamous cell carcinoma (60), and accordingly its expression level is reduced in these tumors. In contrast, miR-217 was found to be overexpressed in breast cancer and to enhance tumor proliferation via promoting cell cycle progression (61).…”

MicroRNA expression profiles associated with pancreatic adenocarcinoma and ampullary adenocarcinoma

“…21,39 Over-expression of miR-217 in pancreatic adenocarcinoma cells inhibits tumor cell growth in vivo and in vitro. 41 Expression of miR-217 is negatively related to KRAS expression. Up-regulation of miR-217 decreases KRAS protein level and reduces the constitutive phosphorylation of AKT in the downstream PI3K-AKT pathway involved in cell growth, differentiation, proliferation and survival.…”

“…Up-regulation of miR-217 decreases KRAS protein level and reduces the constitutive phosphorylation of AKT in the downstream PI3K-AKT pathway involved in cell growth, differentiation, proliferation and survival. 41 Down-regulation of miR-148a is an early marker of pancreatic adenocarcinoma and is already decreased in pre-neoplastic PanIN lesions. 42 At least 27 target genes are known for miR-148a, including bladder cancer associated protein.…”

Developments in miRNA gene signaling pathways in pancreatic cancer

“…Data obtained by locked nucleic acid in situ hybridization (LNA-ISH) and realtime quantitative PCR showed that miR-217 is frequently downregulated in PDAC tissues. Manipulation of miR-217 expression provides evidence for its role as a tumor suppressor that exerts its function by specifically targeting the KRAS oncogene [36]. Another study identified miR-96 as a potent regulator of KRAS signaling.…”

“…A preclinical in vivo experiment has been described, according to Oncogenic Anti-miRNA Significant increase in cell apoptosis [71] miR-21/mir-221 Oncogenic ASO Increases cell apoptosis/cell cycle arrest [92] miR-21 Oncogenic HIV-1-based lentiviral vectors Inhibits pancreatic cancer tumor growth both in vitro and in vivo [104] miR-27a Oncogenic Anti-miRNA Suppresses growth, colony formation and migration [105] miR-371-5p Oncogenic Anti-miRNA Proliferative inhibition [106] miR-21/miR-23a/miR-27a Oncogenic Anti-miRNA Synergistic effects in reducing cell proliferation both in vivo and in vitro [107] miR-200 and let-7 families Downregulated in gemcitabineresistant cells miRNA mimic or isoflavone Reversal of EMT phenotype leading to epithelial morphology [26] ↑ miR-22 and ↓ miR-199a -miRNA mimic or curcumin Suppressed expression SP1 transcription factor and ESR1 [60] Let-7 Tumor suppressor Plasmid-based synthetic miRNAs or by lentiviral transduction Strongly diminishes cell proliferation [108] miR-34a Tumor suppressor Lentiviral system Inhibits clonogenic cell growth and invasion and induces apoptosis and cell cycle arrest at G1 and G2/M phase [27] miR-217 Tumor suppressor miRNA-expressing plasmids Suppresses tumor cell growth in vivo [36] miR-20a Tumor suppressor Lentiviral system Inhibits proliferation and metastasis [65] miR-96 Tumor suppressor miRNA mimic and miRNA-expressing plasmid…”