scholarly journals Inhibition of DCLK1 kinase reverses epithelial-mesenchymal transition and restores T-cell activity in pancreatic ductal adenocarcinoma

2022 ◽  
Vol 17 ◽  
pp. 101317
Author(s):  
Yang Ge ◽  
Heshu Liu ◽  
Yuanyuan Zhang ◽  
Jian Liu ◽  
Rui Yan ◽  
...  
Oncogene ◽  
2021 ◽  
Vol 40 (17) ◽  
pp. 3164-3179
Author(s):  
Yang Liu ◽  
Tianchi Tang ◽  
Xiaosheng Yang ◽  
Peng Qin ◽  
Pusen Wang ◽  
...  

AbstractPancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies and rapidly progressive diseases. Exosomes and long noncoding RNAs (lncRNAs) are emerging as vital mediators in tumor cells and their microenvironment. However, the detailed roles and mechanisms of exosomal lncRNAs in PDAC progression remain unknown. Here, we aimed to clarify the clinical significance and mechanisms of exosomal lncRNA 01133 (LINC01133) in PDAC. We analyzed the expression of LINC01133 in PDAC and found that exosomal LINC01133 expression was high and positively correlated with higher TNM stage and poor overall survival rate of PDAC patients. Further research demonstrated that Periostin could increase exosome secretion and then enhance LINC01133 expression. In addition, Periostin increased p-EGFR, p-Erk, and c-myc expression, and c-myc could bind to the LINC01133 promoter region. These findings suggested that LINC01133 can be regulated by Periostin via EGFR pathway activity. We also observed that LINC01133 promoted the proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) of pancreatic cancer cells. We subsequently evaluated the effect of LINC01133 on the Wnt/β-catenin pathway and confirmed that LINC01133 can interact with Enhancer Of Zeste Homolog 2 (EZH2) and then promote H3K27 trimethylation. This can further silence AXIN2 and suppress GSK3 activity, ultimately activating β-catenin. Collectively, these data indicate that exosomal LINC01133 plays an important role in pancreatic tumor progression, and targeting LINC01133 may provide a potential treatment strategy for PDAC.


2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Dawei Jiang ◽  
Xiangfei Yuan ◽  
Jianqi Ni ◽  
Lan Shen ◽  
Min Cai ◽  
...  

Background. One of the microRNAs (miRNAs) known to be associated with cancer development is miR-607. The aim of this study is to investigate the clinical significance and diagnostic and prognostic value of miR-607 and to explore its potential role in pancreatic ductal adenocarcinoma (PDAC). Methods. The expression levels of miR-607 were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). The correlation between miR-607 expression and clinical characteristics was analyzed by the Chi-square test. Overall survival (OS) and progression-free survival (PFS) were evaluated via the Kaplan–Meier method, and the association between miR-607 expression and OS was investigated by the Cox proportional hazard analysis. The diagnostic value was estimated via receiver operating characteristic (ROC) curve analysis. The effect of miR-607 overexpression on cell migration, invasion, and epithelial-mesenchymal transition (EMT) was determined by wound-healing, Transwell invasion, and Western blotting assays. Results. miR-607 levels were downregulated in PDAC tumor tissues compared with normal tissues. Also, low miR-607 levels were observed in serum samples from PDAC patients than that in healthy controls. The miR-607 level was found to be closely correlated with lymphatic metastasis and liver metastasis, perineural invasion, and OS and PFS, and the low miR-607 level was an independent prognostic factor for the poor OS of PDAC patients. Furthermore, the area under the curve (AUC) of serum miR-607 for discriminating PDAC patients was 0.785 with a sensitivity of 0.647 and a specificity of 0.772, which was better than those for CA19-9 (AUC: 0.702, sensitivity: 0.607, specificity: 0.736) and CEA (AUC: 0.648, sensitivity: 0.542, specificity: 0.670). The AUC (0.863), sensitivity (0.766), and specificity (0.831) of their combination in the diagnosis of PDAC were better than those for alone. Moreover, ectopic overexpression of miR-607 could inhibit cell migration and invasion of BxPc-3 and PANC-1 cells by decreasing EMT ability. Conclusions. Low serum miR-607 level may serve as a potential diagnostic and prognostic biomarker through regulation of tumor metastasis in PDAC patients.


Author(s):  
Rui Huang ◽  
Lin Yang ◽  
Zhiwen Zhang ◽  
Xiaoding Liu ◽  
Yi Fei ◽  
...  

Although RNA m6A regulators have been implicated in the tumorigenesis of several different types of tumors, including pancreatic cancer, their clinical relevance and intrinsic regulatory mechanism remain elusive. This study analyzed eight m6A regulators (METTL3, METTL14, WTAP, FTO, ALKBH5, and YTHDF1-3) in pancreatic ductal adenocarcinoma (PDAC) and found that only RNA m6A demethylase ALKBH5 serves as an independent favorable prognostic marker for this tumor. To better understand the molecular mechanism underlying the protective effect conferred by ALKBH5 against pancreatic tumorigenesis, we performed a transcriptome-wide analysis of m6A methylation, gene expression, and alternative splicing (AS) using the MIA PaCa-2 stable cell line with ALKBH5 overexpression. We demonstrated that ALKBH5 overexpression induced a reduction in RNA m6A levels globally. Furthermore, mRNAs encoding ubiquitin ligase FBXL5, and mitochondrial iron importers SLC25A28 and SLC25A37, were identified as substrates of ALKBH5. Mechanistically, the RNA stabilities of FBXL5 and SLC25A28, and the AS of SLC25A37 were affected, which led to their upregulation in pancreatic cancer cell line. Particularly, we observed that downregulation of FBXL5 in tumor samples correlated with shorter survival time of patients. Owing to FBXL5-mediated degradation, ALKBH5 overexpression incurred a significant reduction in iron-regulatory protein IRP2 and the modulator of epithelial-mesenchymal transition (EMT) SNAI1. Notably, ALKBH5 overexpression led to a significant reduction in intracellular iron levels as well as cell migratory and invasive abilities, which could be rescued by knocking down FBXL5. Overall, our results reveal a previously uncharacterized mechanism of ALKBH5 in protecting against PDAC through modulating regulators of iron metabolism and underscore the multifaceted role of m6A in pancreatic cancer.


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