| Prostate cancer is one of the urinary system tumors with high incidence in Western countries and China.In our country,even though its incidence is slightly lower than digestive and respiratory cancer,the incidence of prostate cancer shows a significant increase with the diet structure adjustment and acceleration of aging society in recent years.It is more and more important to carry out the reach of specific pathogenesis of prostate cancer.Early diagnosis of prostate cancer has been greatly improved with the development of ultrasound,CT and MRI as well as other diagnostic techniques and indicators;nevertheless,there are still lots of patients with advanced prostate cancer losing the most effective curing time because of no obvious clinical symptoms in the early stages.Nowadays,the incidence rate of prostate ranks first and the mortality rate ranks second among all tumors in western countries,therefore prostate cancer attracts more attention of many researchers all the time.Although the current incidence of prostate cancer is relatively low in China,it is increasing gradually with the change of environments and lifestyles and the researches of pathogenesis of prostate cancer are becoming hot.The current studies suggest that risk factors for prostate cancer include age,race,and family history of cancer.Like other cancers,prostate cancer is the interaction result of environmental factors and genetic factors.Previous studies have found that a large number of related gene mutation and genetic abnormality which cause abnormal gene function and related biological cell abnormalities are involved indevelopment of prostate cancer.With the intensive study of the molecular genetic mechanisms of cancer,researchers gradually discovered the important role of epigenetic mechanisms in the development of malignancies.So far,epigenetic mechanisms which have been widely studied includes histone modification,chromatin remodeling,DNA methylation and regulatory non-coding RNA.As the human genome project development,a large number of studies have found that genetic variations in the key positions of genes will have an important impact on the gene structure,expression of protein and regulation of molecular function,and further cause thechange of the biological regulatory functions in body.Single nucleotide polymorphisms(SNPs)are the most common genetic variation.Numerous studies show that genetic variations determine the genetic susceptibility of individuals suffering from cancer.SNPs are able to change the structure or expression of genes and affect the regulation of genes in the body.In recent years,researches about SNPs and genetic susceptibility of diseases are no longer confined to protein-coding genes,but extend to non-coding genes which have important regulatory roles.resea;rches on the non-coding gene will help understand its role in the development and possible biological mechanism of diseases,and also put forward new ideas about genetic predisposition to diseases.The following study based on literature reviews filters correspond:ing tagSNPs in HapMap database and use a case-control study to analyze the association between IncRNA PCAT1 gene SNPs and risk of prostate cancer.We explore the influence of IncRNA PC AT1 on prostate cancer cell line malignant phenotype by over-expression of RNA technology,CCK8,Transwell,flow cytometry and other methods and analyze the differentially expressed genes which may interact with PCAT1 and its molecular pathways on the basis of bioinformatics IPA(Ingenuity Pathway Anaylsis)technology.The study is expected to provide a theoretical basis for further study of the development and its possible biological mechanisms of IncRNAs in prostate cancer and in favor of etiological study,early prevention and screening of prostate cancer.The first part:The association between IncRNA PC AT1 genetic variants and prostate cancer riskBackground:As the highest incidence of malignant tumor in the western developed country,prostate cancer is the result of the genetic factors interact with environmental factors.And the risk tendency of individuals suffering from prostate cancer is decided to the related gene genetic variation.The oncogenic IncRNA PCAT-1 play an important role in the development of prostate cancer mainly through its combination with the 3'UTR BRCA2,which,in turn affecting DNA repair within the BRCA2 gene post-transcription regulation,interfering with the genome DNA damage repair process.Methods and Results:Molecular epidemiology case-control study methods was performed on 823 prostate cancer cases and 858 cases of healthy controls in this study to analyze the risk between the candidate IncRNA PCAT1 four TagSNPs with prostate cancer.We found that single nucleotide mutation at loci rs1902432 is closely related to the occurrence of prostate cancer,and person who carried the CC allele have a higher risk of prostate cancer relative to the TT individuals(OR=1.391,95%CI:1.051-1.856).Conclusion:Our findings confirm a significant association between the risk of prostate cancer with PCAT1 rs190243 in Chinese people.And it has the potential to be an important susceptibility biomarkers in the early detection and treatment of prostate cancer.The second part:The mechanism of IncRNA PC ATI involved in prostate cancer etiologyBackground:Emerging evidences studies have confirmed that although the IncRNA lacked reading frame without protein-coding ability and expressed in low abundance in cells,it can interact with key proteins involving in gene regulation element system,showing significant tissue and cell-specific,and promoting cell phenotypic changes in proliferation,invasion and metastasis.All of these indicate IncRNA's important biological functions in epigenetic mechanisms.Methods and Results:In this study,we constructed the PC ATI overexpression plasmids and then transfected it to prostate cancer cells by transient transfection to build PCAT1 overexpressing cell lines,which was used to evaluate the effect of PC ATI on prostate cancer cell line malignant behavior including proliferation,invasion,migration,apoptosis and cell cycle.We found that overexpression PCAT1 could significantly promote the proliferation,migration and invasion of prostate cancer cells,and it could significantly inhibit apoptosis and promote cell from G2 phase to S phase progression,thereby promoting cell growth and playing oncogene-like effect.On this basis,this study uses microarray technology to explore the molecular effects of PCATI on cell lines in the genome-wide level.The volcano plot found that after PC ATI interfering prostate cancer cells,it could affect many differentially expressed genes.KEGG enrichment analysis and IPA enrichment analysis results strongly suggest that,PCAT1 could significantly change the Toll-like receptor pathway activity,of which the genes were mainly involved in cell death,survival and growth.In addition,the upstream regulatory analysis found that in the PCAT1 stimulated prostate cancer cells,the transcription factor NR3C1 may play an important biological effects in regulating downstream target gene activity,and thus promoting cell proliferation and other biological behaviors.Conclusion:This study mainly focused on the PCAT1 effect on biological behavior of malignant cells and its possible molecular mechanisms.The results from this study confirm cell phenotype and molecular level angle to each other.From the perspective of epigenetics,we systematically expounded PC AT1 molecular mechanisms involved in the development of prostate cancer.All these provided important experimental basis that PC AT1 could serve as the potential biomarkers of prostate cancer diagnosis and treatment. |
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