基因组不稳定与肿瘤

基因组不稳定与肿瘤细胞有丝分裂时染色体分离错误导致子细胞中整条染色体非整倍体突变，或者DNA损伤引起染色体结构改变，造成的基因易位、缺失、反转、断裂等统称为基因组不稳定（genomic instability ）1-2。染色体不稳定导致某些基因的拷贝数增加或者缺失，改变细胞的命运。有丝分裂检控点缺陷、中心体复制或者姐妹染色单体分裂错误等是染色体非整倍体突变形成的主要原因。整条染色体的不稳定性可能导致原癌基因的拷贝数增加、肿瘤抑制基因的缺失，使得细胞更容易适应周围环境的改变，最终形成肿瘤细胞3-7。细胞代谢异常或者外界因素如紫外照射等造成DNA损伤，当DNA损伤应答和修复机制受损或缺陷时，会导致某些基因的突变或失活，进而导致细胞死亡或者成为肿瘤细胞8-9。事实上所有肿瘤细胞都伴随基因组不稳定，比如2/3的人类肿瘤在细胞分裂过程中获得额外的或者丢失整条染色体1。肿瘤中染色体分离相关基因极少发生突变，此种突变主要与原癌基因诱导的有丝分裂相关10。原癌基因的激活与抑癌基因的失活直接或间接的影响了有丝分裂并调控了染色体的分离。如人类肿瘤通常高表达Ras，导致中心体复制，在有丝分裂后期形成多极纺锤体，染色体错误分配形成微核或双核细胞11。同样CDK4、Ras下游原癌基因、B-Raf异常表达都会导致基因组不稳定12-14。而肿瘤抑制基因Rb和P53的突变也通过影响中心体、染色体、纺锤体等导致有丝分裂异常15-16。DNA损伤修复相关功能或者DNA损伤应答机制缺陷会造成染色体结构改变。如DNA损伤应答信号通路中的激酶ATM和CHK2功能缺陷会导致DNA损伤修复的缺失2。目前以基因组不稳定为切入点治疗肿瘤也取得了一定进展。高水平的染色体非整倍体突变会导致细胞死亡，通过增加染色体非整倍体突变根除肿瘤细胞的已经在体外得到验证；肿瘤细胞中心粒复制频率较高，用灰黄霉素或有丝分裂相关蛋白HSET和HC1的干扰RNA可以有效抑制中心粒高复制的肿瘤细胞的增殖；针对肿瘤细胞染色体非整倍体的特性，有三种药可以抑制三倍体的小鼠胚胎纤维细胞和非整倍体人细胞的增殖；一些肿瘤中获得或缺失的染色体是特定的，如肿瘤中常缺失7号染色体，50%的子宫腺癌缺失22号染色体，可以以此为切入点进行治疗；染色体结构大量突变也会导致细胞死亡，5-FU和奥沙利铂通过诱导DNA损伤有效的治疗结肠癌17-22。或许在不久的将来能够根据基因组不稳定的特性找到更有效的治疗肿瘤的方案。参考文献1. Duijf PHG , Benezra R . The cancer biology of whole-chromosome instability . Oncogene 2013 ; 32 : 4727 36 .2. Heijink AM , Krajewska M , van Vugt MATM . The DNA damage response during mitosis . Mutat Res 2013 ; 750 : 45 55 .3. Holland AJ, Cleveland DW. Boveri revisited: chromosomal instability, aneuploidy and tumorigenesis. Nat Rev Mol Cell Biol 2009; 10: 478487.4. Schvartzman JM, Sotillo R, Benezra R. Mitotic chromosomal instability and cancer: mouse modelling of the human disease. Nat Rev Cancer 2010; 10: 102115.5. Thompson SL, Bakhoum SF, Compton DA. Mechanisms of chromosomal instability. Curr Biol 2010; 20: R285R295.6. Ricke RM, Van Ree JH, Van Deursen JM. Whole chromosome instability and cancer: a complex relationship. Trends Genet 2008; 24: 457466.7. Gordon DJ, Resio B, Pellman D. Causes and consequences of aneuploidy in cancer. Nat Rev Genet 2012; 13: 189203.8. S.P. Jackson, J. Bartek, The DNA-damage response in human biology and disease, Nature 461 (2009) 10711078.9. L. Zou, S.J. Elledge, Sensing DNA damage through ATRIP recognition of RPAssDNA complexes, Science 300 (2003) 15421548.10. Sherr CJ, McCormick F. The RB and p53 pathways in cancer. Cancer Cell 2002; 2: 103112.11. Saavedra HI, Fukasawa K, Conn CW, Stambrook PJ. MAPK mediates RAS-induced chromosome instability. J Biol Chem 1999; 274: 3808338090.12. Nelsen CJ, Kuriyama R, Hirsch B, Negron VC, Lingle WL, Goggin MM et al. Short term cyclin D1 overexpression induces centrosome amplification, mitotic spindle abnormalities, and aneuploidy. J Biol Chem 2005; 280: 768776.13. Kamata T, Hussain J, Giblett S, Hayward R, Marais R, Pritchard C. BRAF inactivation drives aneuploidy by deregulating CRAF. Cancer Res 2010; 70: 84758486.14. Cui Y, Borysova MK, Johnson JO, Guadagno TM. Oncogenic B-Raf(V600E) induces spindle abnormalities, supernumerary centrosomes, and aneuploidy in human melanocytic cells. Cancer Res 2010; 70: 675684.15. Manning AL, Longworth MS, Dyson NJ. Loss of pRB causes centromere dysfunction and chromosomal instability. Genes Dev 2010; 24: 13641376.16. Fukasawa K, Choi T, Kuriyama R, Rulong S, Vande Woude GF. Abnormal centrosome amplification in the absence of p53. Science 1996; 271: 17441747. 17.Rebacz B, Larsen TO, Clausen MH, Ronnest MH, Loffler H, Ho AD et al. Identification of griseofulvin as an inhibitor of centrosomal clustering in a phenotype based screen. Cancer Res 2007; 67: 63426350.18. Karna P, Rida PC, Pannu V, Gupta KK, Dalton WB, Joshi H et al. A novel microtubule modulating noscapinoid triggers apoptosis by inducing spindle multi-polarity via centrosome amplification and declustering. Cell Death Differ 2011;18: 632644.19. Kwon M, Godinho SA, Chandhok NS, Ganem NJ, Azioune A, Thery M et al. Mechanisms to suppress multipolar divisions in cancer cells with extra centrosomes. Genes Dev 2008; 22: 21892203.20. Wu G, Qiu XL, Zhou L, Zhu J, Chamberlin R, Lau J et al. Small molecule targeting the Hec1/Nek2 mitotic pathway suppresses tumor cell growth in culture and in animal. Cancer Res 2008; 68: 83938399.21. Tang YC, Williams BR, Siegel JJ, Amon A. Identification of aneuploidy-sele