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近日來自南方醫(yī)科大學(xué)的研究人員在鼻咽癌細(xì)胞系中發(fā)現(xiàn)并確定一類特殊的干細(xì)胞樣細(xì)胞亞群的特征,他們認(rèn)為這些細(xì)胞可能是導(dǎo)致鼻咽癌放療后復(fù)發(fā)及治療耐受的重要原因。研究發(fā)現(xiàn)發(fā)表在國際權(quán)威腫瘤學(xué)雜志 Cancer Research上。
領(lǐng)導(dǎo)這一研究的是南方醫(yī)科大學(xué)教授、中國科學(xué)院院士姚開泰。他是我國鼻咽癌研究的主要奠基人之一,長期從事分子腫瘤病理學(xué)研究,在腫瘤(尤其鼻咽癌)的流行病學(xué)、病因?qū)W、實(shí)驗(yàn)病理學(xué)、分子生物學(xué)方面有較深的造詣。
鼻咽癌是一種發(fā)生于鼻咽粘膜的惡性腫瘤。占頭頸部惡性腫瘤的78.08%。占上呼吸道癌腫的92.99%。其具有原發(fā)部位隱蔽,不易被早期發(fā)現(xiàn),病理分化差,惡性程度高,易呈浸潤性生長及早期轉(zhuǎn)移的特點(diǎn)。我國是鼻咽癌發(fā)病率最高的國家,而廣東、廣西、海南等地都是高發(fā)區(qū),發(fā)病率比其他大部分國家、地區(qū)高100倍以上,因此鼻咽癌有“廣東癌”之稱。當(dāng)前鼻咽癌的治療以放療為主,但療效上不理想,約55%的鼻咽癌在放療后5年會出現(xiàn)復(fù)發(fā)轉(zhuǎn)移。
癌癥干細(xì)胞(CSC)是一類具有永生或無限自我更新能力的細(xì)胞,它們的數(shù)目相對恒定,有強(qiáng)的遷徙、浸潤和轉(zhuǎn)移能力;具有多分化潛能,能分化為不同表型的腫瘤細(xì)胞;在發(fā)育期間能夠通過對稱性分裂以擴(kuò)增數(shù)量,或者通過非對稱性分裂進(jìn)行自我更新和產(chǎn)生更多不同分化類型的祖細(xì)胞;這些細(xì)胞具有治療抵抗特性,能夠耐受傳統(tǒng)的細(xì)胞毒化療和放射治療。許多學(xué)者認(rèn)為,腫瘤復(fù)發(fā)、轉(zhuǎn)移以及對治療的耐受等均與癌癥干細(xì)胞相關(guān)。
在這篇文章中,研究人員利用標(biāo)記保留(label retention)技術(shù)在鼻咽癌細(xì)胞系中發(fā)現(xiàn)了一種干細(xì)胞樣細(xì)胞亞群PKH26+。(PKH26+)細(xì)胞是一些能夠聚集生成克隆,形成細(xì)胞球的側(cè)群細(xì)胞(side-population cell),對放療耐受。利用基因組方法,研究人員證實(shí)原癌基因c-Myc (MYC)通過直接結(jié)合Chk1 (CHEK1)和Chk2 (CHEK2)啟動(dòng)子,轉(zhuǎn)錄激活Chk1和Chk2細(xì)胞周期檢測點(diǎn)激酶,從而調(diào)控了放療耐受。在PKH26+亞細(xì)胞群中過表達(dá)c-Myc,可導(dǎo)致Chk1和Chk2表達(dá)增高,隨后激活DNA損傷檢測點(diǎn)反應(yīng),導(dǎo)致抗輻射性。而Chk1和Chk2表達(dá)喪失則可以逆轉(zhuǎn)體內(nèi)外PKH26+細(xì)胞的抗輻射性。
這項(xiàng)研究闡明了c-Myc-Chk1/Chk2軸在調(diào)控DNA損傷檢測點(diǎn)反應(yīng)中的作用,以及PKH26+亞細(xì)胞群的干細(xì)胞特征。此外,這些數(shù)據(jù)提供了一條通過抑制c-Myc-Chk1/Chk2信號通路來逆轉(zhuǎn)抗輻射性的潛在治療策略。
MYC regulation of CHK1 and CHK2 promotes radioresistance in a stem cell-like population of nasopharyngeal carcinoma cells
Kai-Tai Yao1,*, Wen-Jun Wang1, Si-Pei Wu1, Jin-Bin Liu2, Yong-Sheng Shi3, Xue Huang1, and Qian-Bing Zhang1
Radiotherapy is the most successful nonsurgical treatment for nasopharyngeal carcinoma (NPC). Despite this, the prognosis remains poor. Although NPCs initially respond well to a full course of radiation, recurrence is frequent. The cancer stem cell (CSC) hypothesis provides a framework for explaining the discrepancy between the response of NPC to therapy and the poor survival rate. In this study, a stem cell-like subpopulation (PKH26+) was identified in NPC cell lines using a label retention technique. PKH26+ cells were enriched for clonogenicity, sphere-formation, side-population cells, and resistance to radiotherapy. Using genomic approaches, we show that the proto-oncogene c-Myc (MYC) regulates radio-tolerance through transc**tional activation of Chk1 (CHEK1) and Chk2 (CHEK2) checkpoint kinases through direct binding to the Chk1 and Chk2 promoters. Overexpression of c-Myc in the PKH26+ subpopulation leads to increased expression of Chk1 and Chk2 and subsequent activation of the DNA damage checkpoint response, resulting in radioresistance. Furthermore, loss of Chk1 and Chk2 expression reverses radioresistance in PKH26+ (c-Myc high expression) cells in vitro and in vivo. This study elucidates the role of the c-Myc-Chk1/Chk2 axis in regulating DNA damage checkpoint responses and stem cell characteristics in the PKH26+ subpopulation. Furthermore, these data reveal a potential therapeutic application in reversal of radioresistance through inhibition of the c-Myc-Chk1/Chk2 pathway.
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