miR-204 mediated loss of Myeloid cell leukemia-1 results in pancreatic cancer cell death

Abstract

BackgroundPancreatic cancer is one of the most lethal human malignancies, with an all-stage 5-year survival of <5%, mainly due to lack of effective available therapies. Cancer cell survival is dependent upon up-regulation of the pro-survival response, mediated by anti-apoptotic proteins such as Mcl-1.ResultsHere we show that over-expression of Mcl-1 in pancreatic patient tumor samples is linked to advancement of the disease. We have previously shown that triptolide, a diterpene triepoxide, is effective both in vitro and in vivo, in killing pancreatic cancer cells. Decrease of Mcl-1 levels, either by siRNA or by treatment with triptolide results in cell death. Using pancreatic cancer cell lines, we have shown that miR-204, a putative regulator of Mcl-1, is repressed in cancer cell lines compared to normal cells. Over-expression of miR-204, either by a miR-204 mimic, or by triptolide treatment results in a decrease in Mcl-1 levels, and a subsequent decrease in cell viability. Using luciferase reporter assays, we confirmed the ability of miR-204 to down-regulate Mcl-1 by directly binding to the Mcl-1 3’ UTR. Using human xenograft samples treated with Minnelide, a water soluble variant of triptolide, we have shown that miR-204 is up-regulated and Mcl-1 is down-regulated in treated vs. control tumors.ConclusionTriptolide mediated miR-204 increase causes pancreatic cancer cell death via loss of Mcl-1.

Transformer 2β and miR-204 regulate apoptosis through competitive binding to 3′ UTR of BCL2 mRNA

“…[37][38][39][40][41] Decreased expression of miR-204 results in overexpression of its target, myeloid cell leukemia sequence 1 (Mcl-1) mRNA, and induces anti-apoptotic signaling in pancreatic cancers. 42 miR-204 also regulates expression of an oncogene, neurotrophic receptor tyrosine kinase B, and promotes metastasis in endometrial carcinoma. 43 Imam et al 44 showed that the genomic locus encoding miR-204 is frequently lost in multiple cancers, including breast and ovarian cancers, and pediatric renal tumors.…”

miR-204-5p Inhibits Proliferation and Invasion and Enhances Chemotherapeutic Sensitivity of Colorectal Cancer Cells by Downregulating RAB22A

“…For example, miR-204 inhibited tumor growth in renal clear cell carcinoma (17) and pancreatic cancer (32) and suppressed invasion in endometrial cancer (23), glioma (21), gastric cancer (16), intrahepatic cholangiocarcinoma (16), and head and neck tumor (18). In addition, miR-204 could affect chemoresistance in neuroblastoma and gastric cancer cells by targeting BCL2 (22,33).…”

Developments in Mirna Gene Signaling Pathways in Pancreatic Cancer

“…As previously described, overexpression of miR-204 either by an miR-204 mimic or by triptolide treatment, downregulates MCL1 by directly binding to the 3′UTR of the gene and causes a subsequent decrease in cell viability and pancreatic cancer cell death [114]. In addition, transfection of lentivirus containing miR-137 mimic inhibits cancer cell invasion, increases sensitivity to Fluorouracil and suppresses tumor growth in vivo [115].…”

“…Tumor suppressor miRNA mimic Inhibition of invasive growth [112] miR-148b Tumor suppressor miRNA mimic and lentiviral system Remarkably suppresses growth and invasion and enhances chemosensitivity/inhibits tumorigenicity in nude mice [113] miR-204 Tumor suppressor miRNA mimic or triptolide treatment Decrease in cell viability and cell death [114] miR-137 Tumor suppressor Lentiviral system Inhibits cell invasion/increases sensitivity to Fluorouracil/suppresses tumor growth in vivo [115] miR-216a Tumor suppressor miRNA mimic Inhibition of the JAK2/STAT3 signaling pathway and xenograft tumor growth in vivo [116] miR-135a Tumor suppressor Lentiviral system Reduced proliferation and clonogenicity/ induced G1 arrest and apoptosis [117] miR-218 Tumor suppressor miRNA mimic and lentiviral system Attenuation of cell migration/invasion [118] miR-663 Tumor suppressor Lentiviral system Antiproliferative, anti-invasive and pro-apoptotic effects in vivo and in vitro [119] The oncogenic or tumor-suppressive effect of miRNA-based targeting is denoted in several pancreatic adenocarcinoma settings. ASO: Antisense oligonucleotide; EMT: Epithelial-mesenchymal transition; HCC: Hepatocellular carcinoma cell.…”