近日來自南方醫(yī)科大學的研究人員在鼻咽癌細胞系中發(fā)現(xiàn)并確定一類特殊的干細胞樣細胞亞群的特征，他們認為這些細胞可能是導致鼻咽癌放療后復發(fā)及治療耐受的重要原因,。研究發(fā)現(xiàn)發(fā)表在國際權威腫瘤學雜志《Cancer Research》（2011年IF為7.856）上,。
領導這一研究的是南方醫(yī)科大學教授、中國科學院院士姚開泰,。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研究，在腫瘤（尤其鼻咽癌）的流行病學,、病因?qū)W、實驗病理學,、分子生物學方面有較深的造詣,。
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。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)復發(fā)轉(zhuǎn)移,。
癌癥干細胞（CSC）是一類具有永生或無限自我更新能力的細胞,，它們的數(shù)目相對恒定，有強的遷徙,、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胞,；在發(fā)育期間能夠通過對稱性分裂以擴增數(shù)量,，或者通過非對稱性分裂進行自我更新和產(chǎn)生更多不同分化類型的祖細胞；這些細胞具有治療抵抗特性,，能夠耐受傳統(tǒng)的細胞毒化療和放射治療,。許多學者認為，腫瘤復發(fā),、轉(zhuǎn)移以及對治療的耐受等均與癌癥干細胞相關,。
在這篇文章中，研究人員利用標記保留（label retention）技術在鼻咽癌細胞系中發(fā)現(xiàn)了一種干細胞樣細胞亞群PKH26+,。(PKH26+)細胞是一些能夠聚集生成克隆,，形成細胞球的側(cè)群細胞（side-population cell），對放療耐受,。利用基因組方法,，研究人員證實原癌基因c-Myc (MYC)通過直接結(jié)合Chk1 (CHEK1)和Chk2 (CHEK2)啟動子，轉(zhuǎn)錄激活Chk1和Chk2細胞周期檢測點激酶,，從而調(diào)控了放療耐受,。在PKH26+亞細胞群中過表達c-Myc，可導致Chk1和Chk2表達增高,，隨后激活DNA損傷檢測點反應,，導致抗輻射性。而Chk1和Chk2表達喪失則可以逆轉(zhuǎn)體內(nèi)外PKH26+細胞的抗輻射性,。
這項研究闡明了c-Myc-Chk1/Chk2軸在調(diào)控DNA損傷檢測點反應中的作用,，以及PKH26+亞細胞群的干細胞特征,。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,。(生物谷Bioon.com)
doi: 10.1158/0008-5472.CAN-12-1408
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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 transcriptional 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.
