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Background Pancreatic cancer is one of the most lethal human cancers. N 6 -methyladenosine (m 6 A), 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 m 6 A levels in pancreatic cancer and normal tissues. Bioinformatics analysis, real-time PCR, immunohistochemistry, and western blotting were used to identify the role of m 6 A 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 m 6 A levels were elevated in approximately 70% of the pancreatic cancer samples. Furthermore, we demonstrated that METTL14 is the major enzyme that modulates m 6 A 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 m 6 A-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 m 6 A modification, promoting the growth and metastasis of pancreatic cancer; therefore METTL14 is a potential therapeutic target for its treatment.

Background Accumulation evidence indicates the vital role of long non-coding RNAs (lncRNAs) in tumorigenesis and the progression of malignant tumors, including pancreatic cancer (PC). However, the role and the molecular mechanism of long non-coding RNA 00976 is unclear in pancreatic cancer. Methods In situ hybridization (ISH) and qRT-PCR was performed to investigate the association between linc00976 expression and the clinicopathological characteristics and prognosis of patients with PC. Subsequently, linc00976 over-expression vector and shRNAs were transfected into PC cells to up-regulate or down-regulate linc00976 expression. Loss- and gain-of function assays were performed to investigate the role of linc00976 in proliferation and metastasis in vitro and vivo. ITRAQ, bioinformatic analysis and rescue assay were used to illustrate the ceRNA mechanism network of linc00976/miR-137/OTUD7B and its downstream EGFR/MAPK signaling pathway. Results linc00976 expression was overexpressed in PC tissues and cell lines and was positively associated with poorer survival in patients with PC. Function studies revealed that linc00976 knockdown significantly suppressed cell proliferation, migration and invasion in vivo and in vitro, whereas its overexpression reversed these effects. Based on Itraq results and online database prediction, Ovarian tumor proteases OTUD7B was found as a downstream gene of linc00976, which deubiquitinated EGFR mediates MAPK signaling activation. Furthermore, Bioinformatics analysis and luciferase assays and rescue experiments revealed that linc00976/miR137/OTUD7B established the ceRNA network modulating PC cell proliferation and tumor growth. Conclusion The present study demonstrates that linc00976 enhances the proliferation and invasion ability of PC cells by upregulating OTUD7B expression, which was a target of miR-137. Ultimately, OTUD7B mediates EGFR and MAPK signaling pathway, suggesting that linc00976/miR-137/OTUD7B/EGFR axis may act as a potential biomarker and therapeutic target for PC.

Gemcitabine is the first-line treatment for patients with pancreatic cancer (PC), yet most patients develop resistance to gemcitabine. Recent studies showed that circular RNAs (circRNAs) have important regulatory roles in PC progression and chemoresistance. In this study, the ability of circRNA circ_0092367 to enhance gemcitabine efficacy was tested and the underlying molecular mechanism of circ_0092367 was investigated. The expression levels of circ_0092367, miR-1206, and ESRP1 were measured using qRT-PCR experiments. The effects of circ_0092367, miR-1206, and ESRP1 on PC cell lines exposed to gemcitabine were examined by CCK-8 assays. We performed luciferase assays to determine the relationship between circ_0092367 and miR-1206 and between miR-1206 and ESRP1. We demonstrated that circ_0092367 was significantly downregulated in PC tissues and cell lines, and a high expression of circ_0092367 was associated with improved survival in patients with PC. Gain- and loss-of-function assays revealed that circ_0092367 inhibited epithelial–mesenchymal transition (EMT) phenotypes and sensitized PC cells to gemcitabine treatment in vitro and in vivo. Cytoplasmic circ_0092367 could directly repress the levels of miR-1206 and thus upregulate the expression of ESRP1, thereby inhibiting EMT and enhancing the sensitivity of PC cells to gemcitabine treatment. Our findings show that circ_0092367 plays a crucial role in sensitizing PC cells to gemcitabine by modulating the miR-1206/ESRP1 axis, highlighting its potential as a valuable therapeutic target in PC patients.

Dysfunction in long noncoding RNAs (lncRNAs) is reported to participate in the initiation and progression of human cancer; however, the biological functions and molecular mechanisms through which lncRNAs affect pancreatic cancer (PC) are largely unknown. Here, we report a novel lncRNA, LINC01111, that is clearly downregulated in PC tissues and plasma of PC patients and acts as a tumor suppressor. We found that the LINC01111 level was negatively correlated with the TNM stage but positively correlated with the survival of PC patients. The overexpression of LINC01111 significantly inhibited cell proliferation, the cell cycle, and cell invasion and migration in vitro, as well as tumorigenesis and metastasis in vivo. Conversely, the knockdown of LINC01111 enhanced cell proliferation, the cell cycle, and cell invasion and migration in vitro, as well as tumorigenesis and metastasis in vivo. Furthermore, we found that high expression levels of LINC01111 upregulated DUSP1 levels by sequestering miR-3924, resulting in the blockage of SAPK phosphorylation and the inactivation of the SAPK/JNK signaling pathway in PC cells and thus inhibiting PC aggressiveness. Overall, these data reveal that LINC01111 is a potential diagnostic biomarker for PC patients, and the newly identified LINC01111/miR-3924/DUSP1 axis can modulate PC initiation and development.

Background Pancreatic ductal adenocarcinoma is one of the most aggressive cancers, with a 5-year survival rate of less than 8%. The complicated tumor microenvironment, particularly TGF-β, provides possible convenience for the progression of PC cells. TGF-β regulates critical cellular processes, including autophagy. However, the mechanism and effects of TGF-β-mediated autophagy are still poorly understood. Methods Bioinformatics analysis, western blot, transmission electron microscopy and confocal microscopy were used to identify that TFEB is the key factors in TGF-β-induced autophagy. The biological effects of TFEB-driven autophagy were investigated in vitro using transwell and wound healing assays and in vivo using liver metastasis and LSL-KrasG12D/Pdx1-Cre mice models. Luciferase assays and motif analysis were used to assess regulation of RAB5A gene promoter activity by TGF-β-induced TFEB. TFEB levels were measured by real-time PCR, western blot and immunohistochemical staining in clinical pancreatic ductal adenocarcinoma tissues. Results We demonstrated that TGF-β induces TFEB expression via the canonical smad pathway in Smad4-positive PC cells and facilitates TFEB-mediated autophagic activation. TFEB-driven autophagy caused by TGF-β regulates RAB5A-dependent endocytosis of Itgα5 and promotes progression of PC cells. We further showed that enhanced TFEB expression and its direct target RAB5A both predict poor prognosis in PC patients. Conclusions Our findings reveal TFEB-driven autophagy is required for TGF-β induced migration and metastasis of PC cells by promoting endocytosis of Itgα5β1 and focal adhesion disassembly through the TGF-β-TFEB-RAB5A axis. Our results highlight the potential utility of suppressing TFEB-driven autophagy to block PC metastasis.

Background Cancer stem cells (CSCs) play an important role in the development of pancreatic cancer. We previously showed that the microRNA miR-137 is downregulated in clinical samples of pancreatic cancer, and its expression negatively regulates the proliferation and invasiveness of pancreatic cancer cells. Methods The stemness features of pancreatic cancer cells was detected by flow cytometry, immunofluorescence and sphere formation assay. Xenograft mouse models were used to assess the role of miR-137 in stemness features of pancreatic cancer cells in vivo. Dual-luciferase reporter assays were used to determine how miR-137 regulates KLF12. Bioinformatics and Chromatin immunoprecipitation analysis of KLF12 recruitment to the DVL2 promoters. Involvement of the Wnt/β-catenin pathways was investigated by western blot and Immunohistochemistry. Results miR-137 inhibits pancreatic cancer cell stemness in vitro and vivo. KLF12 as miR-137 target inhibits CSC phenotype in pancreatic cancer cells. Suppression of KLF12 by miR-137 inhibits Wnt/β-catenin signalling. KLF12 expression correlates with DVL2 and canonical Wnt pathway in clinical pancreatic cancer. Conclusion Our results suggest that miR-137 reduces stemness features of pancreatic cancer cells by Targeting KLF12-associated Wnt/β-catenin pathways and may identify new diagnostic and therapeutic targets in pancreatic cancer.

Background Pancreatic ductal adenocarcinoma is prone to metastasis, resulting in short survival and low quality of life. LncRNAs are pivotal orchestrators that participate in various tumor progress. The underlying role and mechanism of lncRNA FAM83H-AS1 is still unknown in PDAC progression. Methods To address this issue, firstly, we profiled and analyzed the aberrant lncRNA expression in TCGA database and identified FAM83H-AS1 as the most effective one in promoting the migration of pancreatic cancer cells. Then, the expression levels of FAM83H-AS1 in patient’s serum, tumor tissues and PDAC cells were detected using RT-qPCR, and FAM83H-AS1 distribution in PDAC cells was determined by performing FISH and RT-qPCR. Next, a series of in vivo and in vitro functional assays were conducted to elucidate the role of FAM83H-AS1 in cell growth and metastasis in PDAC. The regulatory relationship between FAM83H-AS1 and FAM83H (the homologous gene of FAM83H-AS1) was verified by performing protein and RNA degradation assays respectively. Co-IP assays were performed to explore the potential regulatory mechanism of FAM83H to β-catenin. Rescue assays were performed to validate the regulation of the FAM83H-AS1/FAM83H/β-catenin axis in PDAC progression. Results FAM83H-AS1 was highly expressed in the tumor tissues and serum of patients with PDAC, and was correlated with shorter survival. FAM83H-AS1 significantly promoted the proliferation, invasion and metastasis of PDAC cells, by protecting FAM83H mRNA from degradation. Importantly, FAM83H protein manifested the similar malignant functions as that of FAM83H-AS1 in PDAC cells, and could bind to β-catenin. Specifically, FAM83H could decrease the ubiquitylation of β-catenin, and accordingly activated the effector genes of Wnt/β-catenin signaling. Conclusions Collectively, FAM83H-AS1 could promote FAM83H expression by stabilizing its mRNA, allowing FAM83H to decrease the ubiquitylation of β-catenin, thus resulted in an amplified FAM83H-AS1/FAM83H/β-catenin signal axis to promote PDAC progression. FAM83H-AS1 might be a novel prognostic and therapeutic target for combating PDAC.

Pancreatic cancer is the seventh leading cause of cancer death worldwide, which is demonstrated with remarkable resistance to radiotherapy and chemotherapy. The identification of prognosis signature and novel prognostic markers will facilitate patient stratification and an individualized precision therapy strategy. In this study, TCGA-PAAD was used to screen prognostic E3 ubiquitin ligases and establish prognostic signatures, and GEO database was used to verify the accuracy of prognostic signatures. Functional analysis, in vitro experiments and clinical cohort studies were used to analyze the function and prognostic efficacy of the target gene. An E3 ligase-based signature of 9 genes and the nomogram were developed, and the signature was proved to accurately predict the prognosis of patients with pancreatic cancer. WDR37 might be the most prognostic E3 ubiquitin ligase in pancreatic cancer, and the clinical cohort analyses suggested a tumor‐suppressive role. The results of functional analysis and in vitro experiments indicated that WDR37 may promote the degradation of TCP1 complex to inhibit tumor and improve immune cell infiltration. The E3 ligase-based signature accurately predicted the prognosis of patients with pancreatic cancer, so it can be used as a decision-making tool to guide the treatment of patients with pancreatic cancer. At the same time, WDR37, the main gene in E3PMP signature, can be used as the most prognostic E3 ubiquitin ligase in the treatment of pancreatic cancer.

Purpose. This study was aimed at investigating the roles of plasma miR-181b, miR-196a, and miR-210 in the diagnosis of pancreatic cancer (PC). Methods. Plasma samples were isolated from 40 patients with PC and 40 healthy individuals, respectively. The expression of miR-181b, miR-196a, and miR-210 was detected by qRT-PCR. The level of carbohydrate antigen 199 (CA199) was measured by an electrochemiluminescence (ECL) assay. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic value of miR-181b, miR-196a, miR-210, CA199, and their combinations in PC. Results. The expression of plasma miR-181b, miR-196a, and miR-210 was significantly upregulated in PC patients. The plasma level of CA199 was also significantly increased in PC patients. The expression of miR-181b, miR-196a, and miR-210 was closely associated with lymph node metastasis, clinical stage, and vascular invasion but not correlated with age, gender, and tumor size. miR-181b, miR-196a, and miR-210 have lower AUC than CA199 in the diagnosis of PC. miR-181b+miR-210 and miR-196a+miR-210 also have lower AUC than CA199. It is worth noting that miR-181b+miR-196a+miR-210 has a higher AUC than CA199 in the diagnosis of PC. Conclusion. The combination of plasma miR-181b, miR-196a, and miR-210 had a good diagnostic value for PC.

Purposes To establish a scoring model for the risk of postoperative pancreatic fistula (POPF) following pancreatoduodenectomy (PD). Methods PD Patients from 7 institutions in 2 independent sets: developmental ( n  = 457) and validation cohort ( n  = 152) were retrospectively enrolled and analyzed. Pancreatic Fibrosis (PF) and Pancreatic Steatosis (PS) were assessed by pathological examination of the pancreatic stump. Results Stepwise univariate and multivariate analysis indicated that pancreatic duct diameter ≤ 3 mm, increased PS and decreased PF were independent risk factors for POPF and Clinically Relevant Postoperative Pancreatic Fistula (CR-POPF). Based on the relative weight and odds ratio of each factor in the POPF, a simplified scoring model was developed. And patients were stratified into high-risk group (22~28 points), medium-risk group (15~21 points) and low-risk group (8~14 points). The receiver operating characteristic curve demonstrated that the Area under the curve for the predictive model was 0.868 and 0.887 in the model design group and the external validation group. Conclusions This study establishes a simplified scoring model based on accurately and quantitatively measuring the PS, PF and pancreatic duct diameter. The scoring model accurately predicted the risk of POPF.