中国人前列腺癌血清exosome miRNA诊断标记的鉴定和功能研究

Prostate cancer is one of the major threats for men’s life worldwide. The conventional strategy for early diagnosis and the treatment options still bear intrinsic defectiveness. Exosomes, secreted by almost all kinds of cells, are capable of messengers for cell-cell communication. Owing to their embedded functional genetic material, studies on exosomes are emerging as one of the increasingly important research areas aiming at early diagnosis of complex diseases and tumor-targeted therapy. Previously we used prostate cancer serum from Mayo Clinic and identified several exosomal miRNA biomarkers with advantages when compared with traditional evaluations, as evidenced by the superior sensitivity and specificity for prognosis of prostate cancer. We propose here that in Chinese prostate cancer patients’ circulation, there possibly are similar or unique exosomal miRNAs which not only can discriminate prostate cancer at early stage, but also can modulate the biological activities of recipient cells via transfusionally regulating the expression of the target genes, thereafter elicit impacts on the tumor progression. To test our hypothesis, we are planning to further screen and validate exosomal miRNAs in serum as diagnostic markers using prostate cancer serum collected from Chinese patients, and to advance the privileges of the biomarkers for early diagnosis in other independently collected large samples. Next, facilitated by multiple cell and molecular biology approaches such as RNAi and overexpression, we will explore the functions of the miRNA biomarkers and exosome embedded miRNA biomarkers in vitro and in vivo and elucidate the mechanisms by which exosomal miRNA biomarkers are involved in the progress of prostate cancer. The proposed study is an extension of the project we have previously accomplished. Once granted, we will possibly provide experimental references for non-invasive diagnosis of prostate cancer in early stage, as well as for the anti-tumor biotherapy with exosomes as vehicles.

前列腺癌严重威胁男性生命，传统的早期诊断和治疗手段仍有内在不足。由细胞分泌至体液的exosome作为细胞间通讯的信使能够保护其内含的遗传物质，使之免受降解而稳定转入靶细胞，因此是近年来疾病诊断和肿瘤个体化治疗的研究热点。在鉴定了西方人前列腺癌血浆exosome miRNA标记后，我们推测国人前列腺癌患者血清中可能存在类似或特异的exosome miRNA，这些分子不仅可用作肿瘤的早期诊断标记，且可经exosome介导而调控受体细胞的生物学行为。为验证推断，计划在独立收集的中国前列腺癌血清样本中用已建立的技术流程继续筛选国人特异的exosome miRNA诊断标记并验证其诊断优势，再综合利用细胞和分子生物学手段，研究miRNA标记及exosome携带的miRNA标记参与前列腺癌进程的机制。本研究是前期研究的深入和拓展，会为前列腺癌的早期非侵入性诊断和以exosome为载体的抗肿瘤治疗提供依据

前列腺癌严重威胁男性生命，传统的早期诊断和治疗手段仍有内在不足。由细胞分泌至体液的exosome作为细胞间通讯的信使能够保护其内含的遗传物质，使之免受降解而稳定转入靶细胞，因此是近年来疾病诊断和肿瘤个体化治疗的研究热点。在鉴定了西方人前列腺癌血浆exosome miRNA标记后，我们推测国人前列腺癌患者血清中可能存在类似或特异的exosome miRNA，这些分子不仅可用作肿瘤的早期诊断标记，且可经exosome介导而调控受体细胞的生物学行为。因此计划在继续筛选国人特异的exosome miRNA诊断标记并验证其诊断优势，再综合利用细胞和分子生物学手段，研究miRNA标记及exosome携带的miRNA标记参与前列腺癌进程的机制。有赖于资金资助，本课题共计发表了4篇与项目直接相关的SCI收录文章，均按照要求格式标注了基金号。已经提前完成对于SCI文章的发表目标。建立并优化了适用于临床检验的血清exosome miRNA性质和含量的检测方法。在前列腺癌相关exosome miRNA标记与其靶基因之间的调控关系研究方面：标记性miRNA参与前列腺癌调控的分子机制方面的研究已经得到了初步结果，目前正在进行体内实验，预计明年整理形成研究论文并发表。在结直肠癌、胃癌及甲状腺结节中，我们发现一系列血浆外泌体miRNA分子具备早诊、诊断或者鉴别诊断的意义。以上这些重要发现，为我国常见的恶性肿瘤的早期诊断提供了有价值的参考。如果能够有进一步的资金支撑，在更大量的临床样本中加以验证，尤其是在多中心加以验证，将对恶性肿瘤的无创性早期临床诊断及鉴别诊断提供重要的选项，临床应用前景广阔。.