Protein arginine methyltransferases(PRMTs) catalyze the methylation of a variety of protein substrates, many of which have been linked to the development, progression and aggressiveness of different types of cancer. M...Protein arginine methyltransferases(PRMTs) catalyze the methylation of a variety of protein substrates, many of which have been linked to the development, progression and aggressiveness of different types of cancer. Moreover, aberrant expression of PRMTs has been observed in several cancer types. While the link between PRMTs and cancer is a relatively new area of interest, the functional implications documented thus far warrant further investigations into its therapeutic potential. However, the expression of these enzymes and the regulation of their activity in cancer are still significantly understudied. Currently there are nine main members of the PRMT family. Further, the existence of alternatively spliced isoforms for several of these family members provides an additional layer of complexity. Specifically, PRMT1, PRMT2, CARM1 and PRMT7 have been shown to have alternative isoforms and others may be currently unrealized. Our knowledge with respect to the relative expression and the specific functions of these isoforms is largely lacking and needs attention. Here we present a review of the current knowledge of theknown alternative PRMT isoforms and provide a rationale for how they may impact on cancer and represent potentially useful targets for the development of novel therapeutic strategies.展开更多
BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is the fourth leading cause of death among cancers,it is characterized by poor prognosis and strong chemoresistance.In the PDAC microenvironment,stromal cells release d...BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is the fourth leading cause of death among cancers,it is characterized by poor prognosis and strong chemoresistance.In the PDAC microenvironment,stromal cells release different extracellular components,including CXCL12.The CXCL12 is a chemokine promoting the communication between tumour and stromal cells.Six different splicing isoforms of CXCL12 are known(α,β,γ,δ,ε,θ)but their role in PDAC has not yet been characterized.AIM To investigate the specific role ofα,β,andγCXCL12 isoforms in PDAC onset.METHODS We used hTERT-HPNE E6/E7/KRasG12D(Human Pancreatic Nestin-Expressing)cell line as a pancreatic pre-tumour model and exposed it to theα,β,andγCXCL12 isoforms.The altered expression profiles were assessed by microarray analyses and confirmed by Real-Time polymerase chain reaction.The functional enrichment analyses have been performed by Enrichr tool to highlight Gene Ontology enriched terms.In addition,wound healing assays have been carried out to assess the phenotypic changes,in terms of migration ability,induced by theα,β,andγCXCL12 isoforms.RESULTS Microarray analysis of hTERT-HPNE cells treated with the three different CXCL12 isoforms highlighted that the expression of only a few genes was altered.Moreover,theαandβisoforms showed an alteration in expression of different genes,whereasγisoform affected the expression of genes also common withαandβisoforms.Theβisoform altered the expression of genes mainly involved in cell cycle regulation.In addition,all isoforms affected the expression of genes assay confirmed that CXCL12 enhanced the migration ability of hTERT-HPNE cells.Among the CXCL12 splicing isoforms,theγisoform showed higher induction of migration thanαandβisoforms.CONCLUSION Our data suggests an involvement and different roles of CXCL12 isoforms in PDAC onset.However,more investigations are needed to confirm these preliminary observations.展开更多
CXCL12 expression was significantly lower in tumor samples than in corresponding normal samples.CXCL12 expression was significantly positively related to the infiltration levels of T cells,dendritic cells(DCs),immatur...CXCL12 expression was significantly lower in tumor samples than in corresponding normal samples.CXCL12 expression was significantly positively related to the infiltration levels of T cells,dendritic cells(DCs),immature DCs,cytotoxic cells,Tfh cells,mast cells,B cells,Th1 cells,natural killer(NK)cells,pDCs,neutrophils,and T helper cells(Spearman correlation coefficient>0.5,P<0.001)and negatively correlated with the infiltration level of NK CD56bright cells.In addition,pancreatic hTERT-HPNE cells treated with three diverse CXCL12 isoforms exhibited changes mainly in the regulation of the epithelialmesenchymal transition activation pathway.展开更多
Hepatocellular carcinoma(HCC) is one of the most prevalent malignancies worldwide and the second leading cause of death among all cancer types. Deregulation of the networks of tissue-specific transcription factors(TFs...Hepatocellular carcinoma(HCC) is one of the most prevalent malignancies worldwide and the second leading cause of death among all cancer types. Deregulation of the networks of tissue-specific transcription factors(TFs) observed in HCC leads to profound changes in the hepatic transcriptional program that facilitates tumor progression. In addition, recent reports suggest that substantial aberrations in the production of TF isoforms occur in HCC. In vitro experiments have identified distinct isoform-specific regulatory functions and related biological effects of liver-specific TFs that are implicated in carcinogenesis, which may be relevant for tumor progression and clinical outcome. This study reviews available data on the expression of isoforms of liver-specific and ubiquitous TFs in the liver and HCC and their effects, including HNF4α, C/EBPs, p73 and TCF7 L2, and indicates that assessment of the ratio of isoforms and targeting specific TF variants may be beneficial for the prognosis and treatment of HCC.展开更多
基金Supported by Cancer projects in the C télab are funded through the Cancer Research Society,Canadian Research Institutes of Health Research and Canadian Breast Cancer Foundation
文摘Protein arginine methyltransferases(PRMTs) catalyze the methylation of a variety of protein substrates, many of which have been linked to the development, progression and aggressiveness of different types of cancer. Moreover, aberrant expression of PRMTs has been observed in several cancer types. While the link between PRMTs and cancer is a relatively new area of interest, the functional implications documented thus far warrant further investigations into its therapeutic potential. However, the expression of these enzymes and the regulation of their activity in cancer are still significantly understudied. Currently there are nine main members of the PRMT family. Further, the existence of alternatively spliced isoforms for several of these family members provides an additional layer of complexity. Specifically, PRMT1, PRMT2, CARM1 and PRMT7 have been shown to have alternative isoforms and others may be currently unrealized. Our knowledge with respect to the relative expression and the specific functions of these isoforms is largely lacking and needs attention. Here we present a review of the current knowledge of theknown alternative PRMT isoforms and provide a rationale for how they may impact on cancer and represent potentially useful targets for the development of novel therapeutic strategies.
文摘BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is the fourth leading cause of death among cancers,it is characterized by poor prognosis and strong chemoresistance.In the PDAC microenvironment,stromal cells release different extracellular components,including CXCL12.The CXCL12 is a chemokine promoting the communication between tumour and stromal cells.Six different splicing isoforms of CXCL12 are known(α,β,γ,δ,ε,θ)but their role in PDAC has not yet been characterized.AIM To investigate the specific role ofα,β,andγCXCL12 isoforms in PDAC onset.METHODS We used hTERT-HPNE E6/E7/KRasG12D(Human Pancreatic Nestin-Expressing)cell line as a pancreatic pre-tumour model and exposed it to theα,β,andγCXCL12 isoforms.The altered expression profiles were assessed by microarray analyses and confirmed by Real-Time polymerase chain reaction.The functional enrichment analyses have been performed by Enrichr tool to highlight Gene Ontology enriched terms.In addition,wound healing assays have been carried out to assess the phenotypic changes,in terms of migration ability,induced by theα,β,andγCXCL12 isoforms.RESULTS Microarray analysis of hTERT-HPNE cells treated with the three different CXCL12 isoforms highlighted that the expression of only a few genes was altered.Moreover,theαandβisoforms showed an alteration in expression of different genes,whereasγisoform affected the expression of genes also common withαandβisoforms.Theβisoform altered the expression of genes mainly involved in cell cycle regulation.In addition,all isoforms affected the expression of genes assay confirmed that CXCL12 enhanced the migration ability of hTERT-HPNE cells.Among the CXCL12 splicing isoforms,theγisoform showed higher induction of migration thanαandβisoforms.CONCLUSION Our data suggests an involvement and different roles of CXCL12 isoforms in PDAC onset.However,more investigations are needed to confirm these preliminary observations.
文摘CXCL12 expression was significantly lower in tumor samples than in corresponding normal samples.CXCL12 expression was significantly positively related to the infiltration levels of T cells,dendritic cells(DCs),immature DCs,cytotoxic cells,Tfh cells,mast cells,B cells,Th1 cells,natural killer(NK)cells,pDCs,neutrophils,and T helper cells(Spearman correlation coefficient>0.5,P<0.001)and negatively correlated with the infiltration level of NK CD56bright cells.In addition,pancreatic hTERT-HPNE cells treated with three diverse CXCL12 isoforms exhibited changes mainly in the regulation of the epithelialmesenchymal transition activation pathway.
基金Supported by Russian Foundation for Basic Research,contract No.18-34-00816\18
文摘Hepatocellular carcinoma(HCC) is one of the most prevalent malignancies worldwide and the second leading cause of death among all cancer types. Deregulation of the networks of tissue-specific transcription factors(TFs) observed in HCC leads to profound changes in the hepatic transcriptional program that facilitates tumor progression. In addition, recent reports suggest that substantial aberrations in the production of TF isoforms occur in HCC. In vitro experiments have identified distinct isoform-specific regulatory functions and related biological effects of liver-specific TFs that are implicated in carcinogenesis, which may be relevant for tumor progression and clinical outcome. This study reviews available data on the expression of isoforms of liver-specific and ubiquitous TFs in the liver and HCC and their effects, including HNF4α, C/EBPs, p73 and TCF7 L2, and indicates that assessment of the ratio of isoforms and targeting specific TF variants may be beneficial for the prognosis and treatment of HCC.
