MicroRNA-224 Promotes Pancreatic Cancer Cell Proliferation and Migration by Targeting the TXNIP-Mediated HIF1α Pathway.

MicroRNAs (miRNAs) have been shown to participate in the development of pancreatic ductal adenocarcinoma (PDAC) by modulating multiple cellular processes. Increased miR-224 expression enhances proliferation and metastasis in human cancers. This study aimed to investigate the role of miR-224 and its underlying mechanism of action in PDAC. BrdU, MTT, and cell migration assays were performed to determine cell proliferation, viability, and migration, respectively. The binding sites of miR-224 were identified using a luciferase reporter system, whereas protein expression of target genes was determined by immunoblotting and immunofluorescence analyses. A BALB/c nude mouse xenograft model was used to evaluate the role of miR-224 in vivo. We demonstrated that miR-224 expression was enhanced in PDAC cells and tissues, and was related to migration and proliferation. Noticeably, miR-224 overexpression promoted the proliferation, migration, and metastasis of Panc1 cells, while miR-224 inhibition had the reverse effect on PDAC cells. Moreover, we found that thioredoxin-interacting protein (TXNIP) is a target of miR-224. The results also indicated that miR-224 inversely regulated TXNIP by binding directly to its 3'-untranslated region, which resulted in the activation of hypoxia-inducible factor 1α (HIF1α). Further, either TXNIP re-expression or HIF1α depletion abolished the effects of miR-224 on the proliferation and migration of PDAC cells in vitro and in vivo. Regarding the relationship of TXNIP and HIF1α, we found that TXNIP mediated the nuclear export of HIF1α and its degradation by forming a complex with HIF1α. The miR-224-TXNIP-HIF1α axis may be useful in developing novel therapies for PDAC.

Zhu G ，Zhou L ，Liu H ，Shan Y ，Zhang X ... -  《-》

Thioredoxin-interacting protein is a favored target of miR-125b, promoting metastasis and progression of pancreatic cancer via the HIF1α pathway.

MicroRNAs (miRs) are vital in the development of pancreatic cancer (PC) targeting several cellular processes. This study was aimed at evaluating the function of miR-125b and the mechanism involved in PC. Cell migration, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), and Bromodeoxyuridine/5-bromo-2'-deoxyuridine (BrdU) study was done to establish the migration capability, cell viability, and cell proliferation, respectively. Binding sites for miR-125b were recognized by luciferase assay, and the expression of protein by Western blot and immunofluorescence assay. In vivo study was done by BALB/c nude xenograft mice for evaluating the function of miR-125b. The study showed that expression of miR-125b was elevated in PC cells and tissues and was correlated to proliferation and migration of cells. Also, overexpression of miR-125b encouraged migration, metastasis, and proliferation of BxPC-3 cells, and suppression reversed it. We also noticed that thioredoxin-interacting protein (TXNIP) was the potential target of miR-125b. The outcomes also suggested that miR-125b governed the expression of TXNIP inversely via directly attaching to the three prime untranslated region (3'-UTR) activating hypoxia-inducible factor 1α (HIF1α). Looking into the relation between HIF1α and TXNIP, we discovered that TXNIP caused the degradation and export of HIF1α by making a complex with it. The miR-125b-TXNIP-HIF1α pathway may serve as a useful strategy for diagnosing and treating PC.

Wang P ，Zheng D ，Qi H ，Gao Q ... -  《-》

miR-125b enhances metastasis and progression of cancer via the TXNIP and HIF1α pathway in pancreatic cancer.

Wang P ，Zheng D ，Qi H ，Gao Q ... -  《-》

miR-124 Suppresses Pancreatic Ductal Adenocarcinoma Growth by Regulating Monocarboxylate Transporter 1-Mediated Cancer Lactate Metabolism.

Increasing evidence shows that reprogramming of energy metabolism is a hallmark of cancer. Considering the emergence of microRNAs as crucial modulators of cancer, this study aimed to better understand the molecular mechanisms of miR-124 in regulating glycolysis in human pancreatic cancer. RT-PCR was used to investigate the expression of monocarboxylate transporters (MCTs) in pancreatic ductal adenocarcinoma (PDAC) patient samples and the PANC-1 cell line. A public database and immunochemistry were used for comprehensive analysis of MCT1 expression. The targeting of MCT1 by miR-124 was predicted by software and validated for the MCT1 3'-UTR by dual-luciferase reporter analysis. Cell proliferation, apoptosis, migration, xenografting, and the intracellular pH and L-lactate levels were assessed. Hypoxia-inducible factor-α (HIF-1α) and lactate dehydrogenase A (LDH-A) expression levels were determined by RT-PCR and western blotting. MCT1 expression was higher in PDAC tissue than in normal tissue. Inhibition of MCT1 affected lactate metabolism, resulting in a higher intracellular pH and less proliferation of PANC-1 cells. MCT1 was the target gene of miR-124. In in vitro experiments, miR-124 inhibited the glycolytic activity of PANC-1 cells by targeting MCT1, further decreasing the tumor phenotype by increasing the intracellular pH through LDH-A and HIF-1α. In in vivo experiments, overexpression of miR-124 and silencing of MCT1 significantly inhibited tumor growth. miR-124 inhibits the progression of PANC-1 by targeting MCT1 in the lactate metabolic pathway. Our findings provide novel evidence for further functional studies of miR-124, which might be useful for future therapeutic approaches to PDAC.

Wu DH ，Liang H ，Lu SN ，Wang H ，Su ZL ，Zhang L ，Ma JQ ，Guo M ，Tai S ，Yu S ... -  《-》

miRNA-1290 Promotes Aggressiveness in Pancreatic Ductal Adenocarcinoma by Targeting IKK1.

MicroRNAs (miRNAs) are a group of non-coding RNAs that play diverse roles in pancreatic carcinogenesis. In pancreatic ductal adenocarcinoma (PDAC), NF-kB is constitutively activated in most patients and is linked to a mutation in KRAS via IkB kinase complex 1 (IKK1, also known as IKKa). We investigated the link between PDAC aggressiveness and miR-1290. We used miRCURYTM LNA Array and in situ hybridization to investigate candidate miRNAs and validated the findings with PCR. The malignant behavior of cell lines was assessed with Cell Counting Kit-8, colony formation, and Transwell assays. A dual-luciferase reporter assay was used to evaluate the interaction between miR-1290 and IKK1. Protein expression was observed by western blotting. In this study, 36 miRNAs were dysregulated in high-grade pancreatic intraepithelial neoplasia (PanIN) and PDAC tissues compared with low-grade PanIN tissues. The area under the curve values of miR-1290 and miR-31-5p were 0.829 and 0.848, respectively (95% confidence interval, 0.722-0.936 and 0.749-0.948, both P < 0.001). There was a significant correlation between miR-1290 and histological differentiation (P = 0.029), pT stage (P = 0.006), and lymph node metastasis (P = 0.001). In addition, the in vitro work showed that miR-1290 promoted PDAC cell proliferation, invasion, and migration. Western blotting and the dual-luciferase reporter assay showed that miR-1290 promoted cancer aggressiveness by directly targeting IKK1. The synergist effect of miR-1290 on the proliferation and metastasis of PDAC cells was attenuated and enhanced by IKK1 overexpression and knockdown, respectively. Consistent with the in vitro results, a subcutaneous tumor mouse model showed that miR-1290 functioned as a potent promoter of PDAC in vivo. MiR-1290 may act as an oncogene by directly targeting the 3'-untranslated region of IKK1, and the miR-1290/IKK1 pathway may prove to be a novel diagnostic and therapeutic target for PDAC.

Ta N ，Huang X ，Zheng K ，Zhang Y ，Gao Y ，Deng L ，Zhang B ，Jiang H ，Zheng J ... -  《-》