RASAL2 mediated the enhancement of YAP1/TIAM1 signaling promotes malignant phenotypes of pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a high incidence of metastasis and dismal prognosis. As a member of Gas-Gap gene, RASAL2 is involved in the hydrolysis of RAS-GTP to RAS-GDP and abnormal expression in human cancers. Here we firstly described the function of RASAL2 on PDAC to enrich the knowledge of RAS family.We interestingly observed that RASAL2 expression was upregulated in PDAC at both mRNA and protein levels, and high expression of RASAL2 predicted a poor prognosis in PDAC patients. Additionally, RASAL2 promoted malignant behaviors of PDAC in vitro and in vivo. To determine the mechanistic roles of RASAL2 signaling and its potential as a therapeutic target in PDAC, we clarified that RASAL2 could accumulate the TIAM1 expression in different level through inhibiting YAP1 phosphorylation, increased TIAM1 mRNA expression and suppressed ubiquitination of TIAM1 protein. In conclusion, RASAL2 enhances YAP1/TIAM1 signaling and promotes PDAC development and progression.     

High expression of diffuse panbronchiolitis critical region 1 gene promotes cell proliferation,migration and invasion in pancreatic ductal adenocarcinoma

Diffuse panbronchiolitis critical region 1 (DPCR1) is located in the major histocompatibility complex (MHC) class I. It was reported to be downregulated in invasive pituitary adenoma compared with that in non-invasive tumors, but upregulated in the precursor of gastric carcinogenesis. However, the direct effect of DPCR1 on cancer cells has rarely been reported, and the role DPCR1 in pancreatic ductal adenocarcinoma (PDAC) remains unclear. The clinical sample validation and public data analysis of the present study demonstrated that DPCR1 was upregulated markedly in PDAC and this high expression was negatively correlated with the patient prognosis. Functionally, knocking down DPCR1 in PDAC cell lines inhibited cell proliferation, migration and invasion in vitro. Tumor xenograft experiments further showed that suppression of DPCR1 inhibited tumor growth in vivo. In addition, the results of RNA deep sequencing and qRT-PCR assay showed that DPCR1 participated in PADC progression by regulating nuclear factor-kappa B signaling pathway, suggesting that it might be a novel oncogene in tumor progression and a potential therapeutic target in PDAC as well.     

Fibroblast heterogeneity in pancreatic ductal adenocarcinoma: Perspectives in immunotherapy

Cancer-associated fibroblasts (CAFs), the key component in pancreatic tumor microenvironment (TME), originate from many sources and are naturally heterogeneous in phenotype and function. Numerous studies have identified their crucial role in promoting tumorigenesis through many routes including fostering cancer proliferation, angiogenesis, invasion, and metastasis. Conversely, research also indicates that subsets of CAFs express anti-tumor activity. These dual effects reflect the complexity of CAF heterogeneity and their interactions with other cells and factors in pancreatic TME. A critical component in this environment is infiltrated immune cells and immune mediators, which can communicate with CAFs. The crosstalk occurs via the production of various cytokines, chemokines, and other mediators and shapes the immunological state in TME. Comprehensive studies of the crosstalk between CAFs and tumor immune environment, particularly internal mechanisms interlinking CAFs and immune effectors, may provide new approaches for pancreatic ductal adenocarcinoma (PDAC) treatments. In this review, we explore the characteristics of CAFs, describe the interplay among CAFs, infiltrated immune cells, other mediators, and provide an overview of recent CAF-target therapies, their limitations, and potential research directions in CAF in the context of PDAC.     

NDRG4基因的表达调控及生物学效应研究进展

NDRG是近年来发现的新的基因家族,被认为与细胞分化和肿瘤形成有关。其中NDRG4基因在心脑组织中特异性高表达,并且参与正常心脑功能的维持。此外,NDRG4基因的异常表达与某些肿瘤的发生发展关系密切,因此备受关注。就NDRG4基因的调控机制、生物学效应以及与肿瘤的关系作一综述,为人们对其进一步探索提供帮助。     

Cardiac mitochondrial biogenesis in endotoxemia is not accompanied by mitochondrial function recovery

Mitochondrial biogenesis emerges as a compensatory mechanism involved in the recovery process in endotoxemia and sepsis. The aim of this work was to analyze the time course of the cardiac mitochondrial biogenesis process occurring during endotoxemia, with emphasis on the quantitative analysis of mitochondrial function. Female Sprague-Dawley rats (45 days old) were ip injected with LPS (10 mg/kg). Measurements were performed at 0–24 h after LPS administration. PGC-1α and mtTFA expression for biogenesis and p62 and LC3 expression for autophagy were analyzed by Western blot; mitochondrial DNA levels by qPCR, and mitochondrial morphology by transmission electron microscopy. Mitochondrial function was evaluated as oxygen consumption and respiratory chain complex activity. PGC-1α and mtTFA expression significantly increased in every time point analyzed, and mitochondrial mass was increased by 20% (P<0.05) at 24 h. p62 expression was significantly decreased in a time-dependent manner. LC3-II expression was significantly increased at all time points analyzed. Ultrastructurally, mitochondria displayed several abnormalities (internal vesicles, cristae disruption, and swelling) at 6 and 18 h. Structures compatible with fusion/fission processes were observed at 24 h. A significant decrease in state 3 respiration was observed in every time point analyzed (LPS 6 h: 20%, P<0.05). Mitochondrial complex I activity was found decreased by 30% in LPS-treated animals at 6 and 24 h. Complex II and complex IV showed decreased activity only at 24 h. The present results show that partial restoration of cardiac mitochondrial architecture is not accompanied by improvement of mitochondrial function in acute endotoxemia. The key implication of our study is that cardiac failure due to bioenergetic dysfunction will be overcome by therapeutic interventions aimed to restore cardiac mitochondrial function.     

HDAC2 promotes loss of primary cilia in pancreatic ductal adenocarcinoma

Loss of primary cilia is frequently observed in tumor cells, including pancreatic ductal adenocarcinoma (PDAC) cells, suggesting that the absence of this organelle may promote tumorigenesis through aberrant signal transduction and the inability to exit the cell cycle. However, the molecular mechanisms that explain how PDAC cells lose primary cilia are still ambiguous. In this study, we found that inhibition or silencing of histone deacetylase 2 (HDAC2) restores primary cilia formation in PDAC cells. Inactivation of HDAC2 results in decreased Aurora A expression, which promotes disassembly of primary cilia. We further showed that HDAC2 controls ciliogenesis independently of Kras, which facilitates Aurora A expression. These studies suggest that HDAC2 is a novel regulator of primary cilium formation in PDAC cells.     

A small molecule FAK kinase inhibitor,GSK2256098, inhibits growth and survival of pancreatic ductal adenocarcinoma cells

Focal adhesion kinase (FAK) hyperactivation is common in pancreatic ductal adenocarcinoma (PDAC). A small molecule, GSK2256098 (GlaxoSmithKline), has been developed to inhibit FAK activity through targeting the phosphorylation site of FAK, tyrosine (Y) 397. We sought to determine whether GSK2256098 inhibition of FAK Y397 phosphorylation attenuates PDAC-associated cell proliferation, motility and survival. Cultured PDAC cells were used as cellular models of GSK2256098-impaired abnormal growth. Western blot analysis, cell viability analysis, clonogenic survival, soft-agar and wound healing assays were performed. The responses of 6 PDAC cell lines in regards to FAK Y397 phosphorylation or activity to GSK2256098 treatments (0.1–10 μM) ranged from low (less than 20% inhibition) to high (more than 90% inhibition). The least and most sensitive cell lines (PANC-1 and L3.6P1) were selected for further analysis. GSK2256098 inhibition of FAK Y397 phosphorylation correlated with decreased levels of phosphorylated Akt and ERK in L3.6P1 cells. GSK2256098 decreased cell viability, anchorage-independent growth, and motility in a dose dependent manner. Current studies demonstrate that small molecule kinase inhibitors targeting FAK Y397 phosphorylation can inhibit PDAC cell growth. Assessments of FAK Y397 phosphorylation in biopsies may be used as a biomarker to select the subgroup of responsive patients and/or monitor the effects of GSK2256098 on FAK-modulated tumor growth during treatment.     

NDRG1 的功能及其与癌症的关系

细胞生长、分化和多种应激的情况都可以影响NDRG1(N-myc downstream-regulated gene 1)蛋白的表达水平。NDRG1在许多细胞的正常生理功能中起着重要作用,NDRG1的缺乏可能导致多种疾病,如4D型CMTD(夏-马-图三氏病进行性神经性肌萎缩,Charcot-Marie-Tooth disease)的发生与施万细胞中NDRG1的缺失有关。在多种癌细胞系中,NDRG1的转录和翻译与肿瘤的分化和转移有关。在缺氧环境中,NDRG1的表达水平上调,而且在许多肿瘤细胞中都存在缺氧的现象,这使得NDRG1与缺氧和癌症之间存在着复杂的关系。NDRG1与癌症的关系使得NDRG1可能作为肿瘤演进的标识和癌症诊断的辅助工具。     

Candidate agents for pancreatic ductal adenocarcinoma identified by a sub-pathway based method

Aim

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death worldwide. This study aims to explore the molecular mechanism of PDAC and identify biologically active small molecules capable of targeting the sub-pathways which were dysregulated in the development of PDAC.

Methods

The gene expression profile of GSE28735 microarray data (including 45 matching pairs of pancreatic tumor and adjacent non-tumor tissues) was downloaded from GEO (Gene Expression Omnibus) database. Differentially expressed genes (DEGs) between pancreatic tumor tissues and non-tumor tissues were identified, and then the sub-pathway enrichment analysis was performed. Moreover, an approach based on targeting sub-pathways was used to reveal potential agents for PDAC.

Results

A total of 5315 DEGs were identified between pancreatic tumor tissues and non-tumor tissues with a false discovery rate of 0.01. Genes of collagen family and integrin receptor family which were involved in pathways of focal adhesion and ECM-receptor interaction respectively were differentially expressed in the pancreatic tumor tissue. Besides, a total of 85 small molecules including fludrocortisone, latamoxef and metronidazole were revealed by bioinformatics analysis.

Conclusion

This study proposed the use of an approach based on targeting sub-pathways to identify potential agents for PDAC. The sub-pathways and small molecules discovered in this study were not only related to PDAC but also play a role in perturbing the development of PDAC.     

Bone morphogenetic protein-4 induced by NDRG2 expression inhibits MMP-9 activity in breast cancer cells

In the current study, we examined the function of N-myc downstream-regulated gene 2 (NDRG2) expression in breast cancer cells, especially focusing on the role of bone morphogenetic protein-4 (BMP-4) induced by NDRG2. NDRG2 expression in MDA-MB-231 cells inhibited the mRNA expression of several matrix metalloproteinases (MMPs) and the gelatinolytic activity of MMP-9. Interestingly, a specific induction of active BMP-4 was exclusively observed in MDA-MB-231-NDRG2 cells but not in MDA-MB-231-mock cells. Neutralization of BMP-4 in MDA-MB-231-NDRG2 cells resulted in the rescue of MMP-9 mRNA expression and migration capacity. In addition, treatment with recombinant BMP-4 dramatically suppressed MMP-9 mRNA expression, gelatinolytic MMP-9 activity, migration, and invasion capacity both in MDA-MB-231 and PMA-treated MCF-7 cells. Collectively, our data show that BMP-4 induced by NDRG2 expression inhibits the metastatic potential of breast cancer cells, especially via suppression of MMP-9 activity.     

Tumor-specific CD4 T cells instruct monocyte fate in pancreatic ductal adenocarcinoma

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LncRNA PWAR6 regulates proliferation and migration by epigenetically silencing YAP1 in tumorigenesis of pancreatic ductal adenocarcinoma

Long non-coding RNAs (lncRNAs) are a novel class of regulators in multiple cancer biological processes. However, the functions of lncRNAs in pancreatic ductal adenocarcinoma (PDAC) remain largely unknown. In this study, we identified PWAR6 as a frequently down-regulated lncRNA in PDAC samples as well as a panel of pancreatic cancer cell lines. Down-regulated PWAR6 was associated with multiple clinical outcomes, including advanced tumour stage, distant metastasis, and overall survival of PDAC patients. In our cell-based assays, ectopic expression of PWAR6 dramatically repressed PDAC cells proliferation, invasion and migration, accelerated apoptosis, and induced cell cycle arrest at G0/G1 phase. In contrast, depletion of PWAR6 mediated by siRNA exhibited opposite effects on PDAC cell behaviours. In vivo study further validated the anti-tumour role of PWAR6 in PDAC. By taking advantage of available online sources, we also identified YAP1 as a potential PWAR6 target gene. Negative correlation between YAP1 and PWAR6 expressions were observed in both online database and our PDAC samples. Notably, rescue experiments further indicated that YAP1 is an important downstream effector involved in PWAR6-mediated functions. Mechanistically, PWAR6 could bind to methyltransferase EZH2, a core component of Polycomb Repressive Complex 2 (PRC2) in regulating gene expression, and scaffold EZH2 to the promoter region of YAP1, resulting in epigenetic repression of YAP1. In conclusion, our data manifest the vital roles of PWAR6 in PDAC tumorigenesis and underscore the potential of PWAR6 as a promising target for PDAC diagnosis and therapy.     

Hyperforin promotes mitochondrial function and development of oligodendrocytes

St. John's wort has been found to be an effective and safe herbal treatment for depression in several clinical trials. However, the underlying mechanism of its therapeutic effects is unclear. Recent studies show that the loss and malfunction of oligodendrocytes are closely related to the neuropathological changes in depression, which can be reversed by antidepressant treatment. In this study, we evaluated the effects of hyperforin, a major active component of St. John's wort, on the proliferation, development and mitochondrial function of oligodendrocytes. The study results revealed that hyperforin promotes maturation of oligodendrocytes and increases mitochondrial function without affecting proliferation of an oligodendrocyte progenitor cell line and neural stem/progenitor cells. Hyperforin also prevented mitochondrial toxin-induced cytotoxicity in an oligodendrocyte progenitor cell line. These findings suggest that hyperforin may stimulate the development and function of oligodendrocytes, which could be a mechanism of its effect in depression. Future in vitro and in vivo studies are required to further characterize the mechanisms of hyperforin.     

Long noncoding RNA DLEU1 aggravates pancreatic ductal adenocarcinoma carcinogenesis via the miR-381/CXCR4 axis

Recent evidence has highlighted that long noncoding RNAs (lncRNA) are associated with many diseases, particularly cancer. However, current understanding of the lncRNA deleted in lymphocytic leukemia 1 (DLEU1) in pancreatic ductal adenocarcinoma (PDAC) remains limited. Our studies indicated that the DLEU1 expression level was upregulated in PDAC tissue samples compared with adjacent normal tissue. Moreover, the aberrant overexpression of DLEU1 indicated poor prognosis of patients with PDAC. Loss-of-function experiments revealed that DLEU1 knockdown inhibited the proliferation, migration, and invasion of PDAC cells in vitro and decreased tumor growth in vivo. Bioinformatics analysis predicted that miR-381 potentially targeted the DLEU1 3′-untranslated region (UTR), suggesting an interaction between miR-381 and DLEU1. Furthermore, miR-381 also targeted the chemokine receptor-4 (CXCR4) messenger RNA 3′-UTR, which was validated by luciferase reporter assay. Taken together, our study demonstrated the oncogenic role of DLEU1 in clinical PDAC specimens and cellular experiments, showing the potential involvement of DLEU1/miR-381/CXCR4 pathway. These results provide novel insight into PDAC tumorigenesis.