2013年11月21日訊 /生物谷BIOON/--從汕頭大學(xué)獲悉汕大醫(yī)學(xué)院腫瘤研究中心和附屬腫瘤醫(yī)院科研團(tuán)隊(duì)首次在食管癌中發(fā)現(xiàn)具有標(biāo)志特征的嵌合RNA,。
據(jù)課題組負(fù)責(zé)人張灝教授介紹,，融合基因及其產(chǎn)物在腫瘤診斷和靶向治療中的作用日益凸顯,。而此前在食管癌中尚未有這方面的研究報(bào)道,。張灝教授回國(guó)后針對(duì)國(guó)內(nèi)特別是當(dāng)?shù)厥彻馨└甙l(fā)并且無(wú)理想分子標(biāo)志物和治療靶點(diǎn)的特點(diǎn),，開(kāi)展了從食管癌分子機(jī)制到轉(zhuǎn)化的研究,。課題組根據(jù)前期轉(zhuǎn)錄組測(cè)序和生物信息分析,，篩選出一批在食管癌中異常表達(dá)的嵌合RNA,。進(jìn)一步分析發(fā)現(xiàn)了在食管癌標(biāo)本和細(xì)胞中特征性表達(dá)的嵌合RNA GOLM1-MAK10,。研究人員發(fā)現(xiàn)這種RNA不是染色體轉(zhuǎn)位所致的融合基因產(chǎn)物,，而是由不同染色體上各自的RNA在轉(zhuǎn)錄水平切割和錯(cuò)讀所導(dǎo)致的嵌合RNA。大樣本檢測(cè)分析發(fā)現(xiàn)這種嵌合RNA與食管癌惡性進(jìn)展高度相關(guān),。進(jìn)一步研究發(fā)現(xiàn)這一嵌合RNA可以翻譯成分泌性蛋白產(chǎn)物并可以在細(xì)胞分泌液中檢查到,。這一發(fā)現(xiàn)為食管癌發(fā)病和進(jìn)展提供一個(gè)新的層面分子機(jī)制。其轉(zhuǎn)化的意義不僅在于可以用常規(guī)的方法在RNA和蛋白水平檢測(cè)這一標(biāo)志物,，而且類(lèi)似于融合基因可以做為分子治療靶點(diǎn),。這一成果發(fā)表在國(guó)際癌癥學(xué)術(shù)期刊《Oncotarget》上。這項(xiàng)課題是和美國(guó)Baylor Medical College（貝勒醫(yī)學(xué)院）的研究人員合作完成,。
鑒于食管癌預(yù)后非常差,，目前尚無(wú)早期篩查診斷標(biāo)志物和理想分子治療靶點(diǎn)，課題組將對(duì)這種嵌合RNA的功能,，以及作為食管癌早期診斷分子標(biāo)志物和治療靶點(diǎn)的臨床轉(zhuǎn)化進(jìn)一步研究和開(kāi)發(fā),。
生物谷推薦英文摘要：
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.
