| Prostate is important reproduction organ in males,likes a small walnut-shaped gland that produces the seminal fluid that nourishes and transports sperm.Prostate Cancer(PCa)is one of the most common types of cancer in men in the western countries.The morbidity of PCa in our country is 60,300,ranking sixth in the morbidity of malignancies in males[1].It was reported that the rise in the incidence of prostate cancer may be related to the gradually popularization of prostate specific antigen(PSA)screening and the increasing accuracy of prostate biopsy.Although clinical diagnosis is improved obviously,the proportion of patients with advanced prostate cancer in China is significantly higher than that in the western countries.The patients with advanced prostate cancer has lost chance to receive radical surgery or radiotherapy,and must be treated with hormonal therapy.However,the disease easily gains hormone independency,called castration resistance,then the patients only have a 15-months median survival time.As a result,prostate cancer has been a severe genitourinary malignant disease which do harm to males in our country.Prostate cancer usually grows slowly and initially remains confined to the prostate gland,where it may not cause serious harm.While some types of prostate cancer grow slowly and may need minimal or no treatment,other types are aggressive and can spread quickly such as advanced prostate cancer in castration resistant prostate cancer.And this kind of PCa is resistant to androgen deprivation therapy,even if a neoadjuvant hormonal therapy,such as abiraterone,apalutamide,still can't completely cure CRPC.s There will be an important implication for molecular mechnisms of transdifferentiation from prostate cancer with luminal phenotype to neuroendocrine phenotype to guide eraly intervention and individualized treatment.The notion of precision medicine means medical care designed to optimize efficiency or therapeutic benefit for particular groups of patients,especially by using genetic or molecular profiling.Furthermore,it can also help classify patients according for the molecular genetic changes to enhance the efficacy of prevention and treatment.However,the high-throughput sequencing are well used in the prostate cancer research,especially in the high risk prostate cancer.Therefore,we sequenced 50 high risk prostate cancer tissues and 10 adjacent tissues.And using matching seminal vesicle as the germline reference,we mapped the transcription spectrum Chinese people at high risk of prostate cancer.Part ? Transcription spectrum characteristic analysis of Chinese high risk prostate cancer based on the high-throughput sequencingProstate Cancer(PCa)is one of the most common types of cancer in men in the western countries.The morbidity of PCa in our country is ranking sixth in the morbidity of malignancies in males.More and more researches are focusing on mechanism of prostate cancer tumorigenesis and the the majority of castration resistant prostate cancer are progressed from high-risk prostate cancer.So to investgate the mechanism of high risk of prostate cancer tumorigenesis is paramount.With the next generation of sequencing technology,we can understand the molecular classification of tumors better.And it also can be used for tumor clinical practice such as diagnosis,prognosis and treatment decision.We use 50 high risk prostate cancer tissues and 10 adjacent tissues from September2010 to May 2013 for the next generation high-throughput sequencing.Then we selected 24 prostatic candidate genes for the transcriptome sequencing data analysis of single nucleotide mutation analysis,differentially expressed genes and fusion genes.We found that the 17 cases of single nucleotide mutation,including FOXA1 mutation rate is as high as 16%(8/50),3 cases of fusion genes,20 cases SPINK1over-expression.Then we used the tumor tissues and seminal vesicle tissues to comfirm somatic FOXA1 mutation.Comparing to FOXA1-mutant differentially expressed genes in The Cancer Genome Atlas(TCGA),we found that 108 FOXA1 mutation specificity differentially expressed genes in Chinese high risk prostate cancer,and pathway enrichment analysis showed that the 108 differentially expressed genes were enriched in 17 biological processes.So we summarize these Chinese people at high risk of prostate cancer transcriptome characteristics,combined with clinical data and experiments in vivo and in vitro,which will help the future study of prostate cancer treatment.Part ? TRIM36,a novel androgen-responsive gene,enhances anti-androgen efficacy against prostate cancer by inhibiting MAPK/ERK signaling pathwayHormone therapy drugs,such as bicalutamide and enzalutamide,directed against prostate cancer focus on androgen receptor(AR)signaling and are initially effective,but the disease progresses to lethality as resistance to these drugs develops.A method to prolong the drug response time and improve the drug efficacy is still unavailable.We early used of microarray assay to screen the differentially expressed genes in prostate cancer and adjacent tumor tissues.We found TRIM36 m RNA increased in prostate tissue by using real-time quantitative polymerase chain reaction(q RT-PCR)in 24 pairs for prostate cancer and adjacent tumor tissues.And 20 cases(83.3%)TRIM36 m RNA expression level in prostate cancer tissues was higher than that in adjacent tumor tissues.And in the PCa with higher Gleason score,TRIM36 expression level is lower(P < 0.05).we found that63.4%(64/95)of PCa in TMA expressed the TRIM36 protein.Interestingly,patients with negative TRIM36 expression had a shorter biochemical recurrence-free survival.TRIM36 expression was significantly associated with the Gleason score(P = 0.005),delayed prostate cancer cell cycle progression and inhibited cell proliferation in vitro and in vivo,and these effects were mediated via inhibition of the MAPK/ERK phosphorylation pathway.Remarkably,we found that rescuing the expression of TRIM36 during anti-androgen therapy could improve the drug efficacy.Collectively,TRIM36 is a novel androgen-responsive gene,and it dramatically enhanced the efficacy of anti-androgen drugs against prostate cancer. |
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