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Background. Mounting evidence has shown circular RNAs (circRNAs) play an important role in the initiation and progression of pancreatic cancer (PC). Meanwhile, circRNAs may serve as the biomarkers for the diagnosis, treatment, and prognosis of PC. Therefore, it is urgent to elucidate the function and underlying mechanism of circRNAs in the development of PC. Methods. The Cancer-Specific CircRNA Database (CSCD), Circular RNA Interactome database (circinteractome database), and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were used to verify the expression level of circRNF13 in PC cell lines. Fluorescence in situ hybridization (FISH) and RNase protection assay were used to detect the localization and structure of circRNF13. Then, cell functional experiments were employed to estimate the proliferated, migrated, and invasive abilities in PC. Furthermore, bioinformatic tools, luciferase dual reporter assay, and RT-qPCR were used to investigate the interaction among circRNF13, miR-139-5p, and IGF1R. Eventually, the rescue functional experiments were employed to confirm that circRNF13 targeted the miR-139-5p/IGF1R axis to participate in the development of PC. Results. CircRNF13 was overexpressed in PC cell lines compared with the normal pancreatic duct cell line. Additionally, inhibition of circRNF13 impaired the proliferation, migration, and invasion of PC cells. CircRNF13 could serve as the molecular sponge of miR-139-5p to inhibit its association with IGF1R that eventually accelerated the malignant progression of PC. Conclusion. CircRNF13 serves as a competitive endogenous RNA of IGF1R to inhibit the function of miR-139-5p that eventually reinforces the malignant phenotype of PC. [ABSTRACT FROM AUTHOR]

Introduction: Malignant proliferation and metastasis are some of the causes of high mortality in pancreatic cancer. MicroRNAs have been a hot spot in cancer research and are involved in tumor formation and metabolic stress responses. However, the biology function and underlying mechanism of miRNA regulating pancreatic cancer progress is remained uncleared. Methods: RNA-seq analysis the glycolysis associated miRNAs and verified miRNA-489-3p was involving in glycolysis. We used RNA in situ hybridization (ISH) and qRT-PCR to analyze the differential expression of miR-489-3p in pancreatic cancer tissues and adjacent tissues and cell lines. Then the function assay of in vivo and in vitro were used to evaluated the role of miR-489-3p in the proliferation, metastasis and glucose metabolism of pancreatic cancer. Furthermore, dual luciferase reporter and rescue experiments were performed to explore the mechanism underlying in the role of miRNA-489-3p. Results: We determined that glycolysis associated miRNA miR-489-3p was downregulated in pancreatic cancer tissues and cell lines. The gain and loos of function experiments confirmed that miR-489-3p could inhibit the proliferation, metastasis and glucose metabolism of pancreatic cancer. Further, we found that miR-489-3p could target regulating LDHA and PKM through the luciferase report experiment. Finally, in vivo experiment confirmed that highly expressed miR-489-3p inhibited the growth of pancreatic cancer. Conclusion: In short, this study identified miR-489-3p as a novel therapy target for pancreatic cancer which was involving in the proliferation, metastasis and glycolysis, but its diagnostic value deserves further study. [ABSTRACT FROM AUTHOR]

Circular RNAs (circRNAs) play key roles in many malignant tumors, including pancreatic cancer (PC); however, whether circular RNA hsa_circ_0006117, a newly identified circRNA, has a role in PC has not been investigated. Here, in order to elucidate the role and potential molecular mechanisms of circRNAs, we utilized bioinformatic tolls to screen the differentially expressed circRNAs in PC. Subsequently, circular RNA hsa_circ_0006117 was identified as being highly expressed in PC tissues in a screen of two GEO datasets, which was further verified in PC cell lines and tissues. Then, its molecular characteristics were investigated using methods such as Sanger sequencing and fluorescence in situ hybridization (FISH). Functional experiments subsequently indicated that circular RNA hsa_circ_0006117 facilitated the malignant behaviors of PC cells, prompting that it plays an oncogenic role in PC. Moreover, we found that circular RNA hsa_circ_0006117 exerts its PC-promoting effects via activating the KRAS/mitogen-activated protein kinase (MAPK) signaling pathway. Through bioinformatics exploration and dual-luciferase reporter assays, miR-96-5p was identified as a downstream target of circular RNA hsa_circ_0006117. A series of assays confirmed that circular RNA hsa_circ_0006117 acted as a miR-96-5p sponge, thereby promoting the malignant features of PC in a miR-96-5p/KRAS axis-dependent manner. Taken together, our study indicated, for the first time, that the specifically highly expressed circular RNA hsa_circ_0006117 facilitates PC progression via the modulation of the miR-96-5p/KRAS/MAPK signaling pathway and might be a hopeful therapeutic target for PC. [ABSTRACT FROM AUTHOR]

Hypoxia is involved in the development of pancreatic cancer (PC). The responses of hypoxia‐associated genes and their regulated mechanisms are largely unknown. In this study, through bioinformatic analysis and quantitative real‐time polymerase chain reaction, the YEATS domain containing 2 (YEATS2) was determined to be a key hypoxia‐associated gene. It was increased in PC cells under hypoxia, upregulated in PC tissues, and predicted poor outcome. YEATS2 inhibition decreased the proliferation and migration of PC cells under both normoxia and hypoxia in vitro as well as proliferation and metastasis in vivo. We found that hypoxia‐inducible factor 1α (HIF1α) regulated the expression of YEATS2 via binding to the hypoxia response element (HRE) of YEATS2 and coexpressed with YEATS2 in PC tissues. Overexpression of YEATS2 blocked the inhibitory effects of HIF1α silence on PC cell proliferation and migration under hypoxia. Collectively, our study revealed that YEATS2 is a target gene of HIF1α and promotes PC development under hypoxia. [ABSTRACT FROM AUTHOR]

Increasing evidence indicated that tripartite motif containing 37 (TRIM37) was involved in the tumorigenesis of several cancer types. However, its expression pattern and biological functions in pancreatic ductal adenocarcinoma (PDAC) remained unknown. In this study, real-time PCR, Western blot and immunohistochemistry was performed to examine the expression of TRIM37 in the pancreatic cancerous tissues. Colony formation assay and cell migration assay were performed to study the functions of TRIM37 in pancreatic cancer cells. Dual-luciferase assay was performed to study the regulation of TRIM37 on beta-catenin/TCF signaling. It was found that the expression level of TRIM37 was significantly higher in pancreatic cancerous tissues compared with the adjacent normal tissues. Function analysis indicated that overexpression of TRIM37 promoted the growth and migration of the pancreatic cancer cells, while knocking down the expression of TRIM37 inhibited the growth and migration of the pancreatic cancer cells. The molecular mechanism study suggested that TRIM37 interacted with beta-catenin and activated the transcriptional activity of beta-catenin/TCF complex as well as the expression of its downstream target genes. Taken together, our study showed the oncogenic roles of TRIM37 in pancreatic cancer, and TRIM37 might be a promising target for pancreatic cancer treatment. [ABSTRACT FROM AUTHOR]

Recent studies have shown that cancer stem cells (CSCs) play an important role in the development of pancreatic cancer. Multiple oncogenes and signaling pathways have been confirmed to participate in the stemness maintenance and tumorigenicity of CSCs, including sex-determining region Y-box 2 (SOX2) and signal transduction and activation of transcription 3 (STAT3), which may provide novel therapeutic targets on pancreatic cancer. Here, we reported in pancreatic cancer tissues and cells that miR-1181 expression was markedly downregulated, and the low miR-1181 expression was associated with poorer overall survival and disease-free survival in pancreatic cancer patients. Furthermore, overexpression of miR-1181 inhibited, whereas downregulation of miR-1181 promoted, CSCs-like phenotypes in vitro and tumorigenicity in vivo in pancreatic cancer cells. Moreover, we demonstrated that miR-1181 directly suppressed SOX2 and STAT3 expression, resulting in downregulation of SOX2 and inhibition of the STAT3 pathway. Hence, our results suggest that miR-1181 plays a vital role in inhibiting the CSCs-like phenotypes in pancreatic cancer and might represent a potential target for anti-pancreatic cancer. [ABSTRACT FROM AUTHOR]

Background: Pancreatic cancer is one of the most lethal human cancers. N6-methyladenosine (m6A), a common eukaryotic mRNA modification, plays critical roles in both physiological and pathological processes. However, its role in pancreatic cancer remains elusive. Methods: LC/MS was used to profile m6A levels in pancreatic cancer and normal tissues. Bioinformatics analysis, real-time PCR, immunohistochemistry, and western blotting were used to identify the role of m6A regulators in pancreatic cancer. The biological effects of methyltransferase-like 14 (METTL14), an mRNA methylase, were investigated using in vitro and in vivo models. MeRIP-Seq and RNA-Seq were used to assess the downstream targets of METTL14. Results: We found that the m6A levels were elevated in approximately 70% of the pancreatic cancer samples. Furthermore, we demonstrated that METTL14 is the major enzyme that modulates m6A methylation (frequency and site of methylation). METTL14 overexpression markedly promoted pancreatic cancer cell proliferation and migration both in vitro and in vivo, via direct targeting of the downstream PERP mRNA (p53 effector related to PMP-22) in an m6A-dependent manner. Methylation of the target adenosine lead to increased PERP mRNA turnover, thus decreasing PERP (mRNA and protein) levels in pancreatic cancer cells. Conclusions: Our data suggest that the upregulation of METTL14 leads to the decrease of PERP levels via m6A modification, promoting the growth and metastasis of pancreatic cancer; therefore METTL14 is a potential therapeutic target for its treatment. [ABSTRACT FROM AUTHOR]

Application of oxaliplatin for the treatment of pancreatic cancer (PC) is restricted owing to its toxic side effects and drug resistance. We investigated how withaferin A (WA), a bioactive component isolated from the medicinal plant Withania somnifera , acts synergistically with oxaliplatin on human PC in vitro and in vivo . We found that WA enhanced oxaliplatin-induced growth suppression and apoptosis in PC cells dramatically through a mechanism involving mitochondrial dysfunction and inactivation of the PI3K/AKT pathway. Combination treatment resulted in significant accumulation of intracellular reactive oxygen species (ROS). Pretreatment of cells with the ROS scavenger N-acetylcysteine completely blocked the apoptosis induced by combination treatment, and recovered expression of AKT inactivation, which revealed the important role of ROS in apoptosis and AKT regulation. In vivo , combination therapy showed the strongest anti-tumor effects compared with single agents, without obvious additional toxicity. These results support the notion that combination treatment with oxaliplatin and WA could facilitate development of an effective strategy for PC treatment. [ABSTRACT FROM AUTHOR]

Inflammatory molecules and exosomes are crucial for signal transduction between tumor-associated macrophages and tumor cells. IL-6, a key inflammatory molecule secreted by M2 macrophages after polarization, can mediate malignant progression of pancreatic cancer (PC). However, the functions and mechanisms of IL-6 and tumor-derived exosomes in tumor-associated macrophages and PC remain unclear. Transcriptome chip and quantitative reverse transcription PCR experiments indicated that FGD5-AS1 induced IL-6 and high FGD5-AS1 expression correlated with the poor prognosis in PC patients. RNA pulldown, mass spectrometry, and dual luciferase reporter assays were used to identify the mechanism of exosomal FGD5-AS1 in promoting PC progression and M2 macrophage polarization. FGD5-AS1 exerted cancer-promoting functions when co-cultured with M2 macrophages. PC-derived exosomal FGD5-AS1 stimulated M2 macrophage polarization by activating STAT3/NF-κB pathway. FGD5-AS1 interacts with p300, resulting in STAT3 acetylation, thus promoting nuclear localization and transcriptional activity of STAT3/NF-κB. These data indicated that PC cells generate FGD5-AS1-rich exosomes, which cause M2 macrophage polarization to promote the malignant behaviors of PC cells. Targeting exosomal FGD5-AS1 may provide a potential diagnosis and treatment strategy for PC. [ABSTRACT FROM AUTHOR]