2013年11月21日讯 /生物谷BIOON/--从汕头大学获悉汕大医学院肿瘤研究中心和附属肿瘤医院科研团队首次在食管癌中发现具有标志特征的嵌合RNA。
据课题组负责人张灏教授介绍,融合基因及其产物在肿瘤诊断和靶向治疗中的作用日益凸显。而此前在食管癌中尚未有这方面的研究报道。张灏教授回国后针对国内特别是当地食管癌高发并且无理想分子标志物和治疗靶点的特点,开展了从食管癌分子机制到转化的研究。课题组根据前期转录组测序和生物信息分析,筛选出一批在食管癌中异常表达的嵌合RNA。进一步分析发现了在食管癌标本和细胞中特征性表达的嵌合RNA GOLM1-MAK10。研究人员发现这种RNA不是染色体转位所致的融合基因产物,而是由不同染色体上各自的RNA在转录水平切割和错读所导致的嵌合RNA。大样本检测分析发现这种嵌合RNA与食管癌恶性进展高度相关。进一步研究发现这一嵌合RNA可以翻译成分泌性蛋白产物并可以在细胞分泌液中检查到。这一发现为食管癌发病和进展提供一个新的层面分子机制。其转化的意义不仅在于可以用常规的方法在RNA和蛋白水平检测这一标志物,而且类似于融合基因可以做为分子治疗靶点。这一成果发表在国际癌症学术期刊《Oncotarget》上。这项课题是和美国Baylor Medical College(贝勒医学院)的研究人员合作完成。
鉴于食管癌预后非常差,目前尚无早期筛查诊断标志物和理想分子治疗靶点,课题组将对这种嵌合RNA的功能,以及作为食管癌早期诊断分子标志物和治疗靶点的临床转化进一步研究和开发。
生物谷推荐英文摘要:
Oncotarget PMID:24243830
Aberrant chimeric RNA GOLM1-MAK10 encoding a secreted fusion protein as a molecular signature for human esophageal squamous cell carcinoma.
Zhang H, Lin W, Kannan K, Luo L, Li J, Chao PW, Wang Y, Chen YP, Gu J, Yen L.
It is increasingly recognized that chimeric RNAs may exert a novel layer of cellular complexity that contributes to oncogenesis and cancer progression, and could be utilized as molecular biomarkers and therapeutic targets. To date yet no fusion chimeric RNAs have been identified in esophageal cancer, the 6th most frequent cause of cancer death in the world. While analyzing the expression of 32 recurrent cancer chimeric RNAs in esophageal squamous cell carcinoma (ESCC) from patients and cancer cell lines, we identified GOLM1-MAK10, as a highly cancer-enriched chimeric RNA in ESCC. In situ hybridization revealed that the expression of the chimera is largely restricted to cancer cells in patient tumors, and nearly undetectable in non-neoplastic esophageal tissue from normal subjects. The aberrant chimera closely correlated with histologic differentiation and lymph node metastasis. Furthermore, we demonstrate that chimera GOLM1-MAK10 encodes a secreted fusion protein. Mechanistic studies reveal that GOLM1-MAK10 is likely derived from transcription read-through/splicing rather than being generated from a fusion gene. Collectively, these findings provide novel insights into the molecular mechanism involved in ESCC and provide a novel potential target for future therapies. The secreted fusion protein translated from GOLM1-MAK10 could also serve as a unique protein signature detectable by standard non-invasive assays. These observations are critical as there is no clinically useful molecular signature available for detecting this deadly disease or monitoring the treatment response.