Khare Sharad, Verma Mukesh
Hines Veterans Affairs Medical Center, Hines, IL, USA.
Methods Mol Biol. 2012;863:177-85. doi: 10.1007/978-1-61779-612-8_10.
Accumulation of genetic and epigenetic alterations transforms normal colonic epithelial cells to adenocarcinoma cells. Genetic alterations include mutations in tumor suppressor genes and oncogenes, whereas epigenetic mechanisms are defined as heritable alterations in gene expression that is independent of changes in the primary DNA sequence. Role of epigenetic mechanisms in development and maintenance of organ- and tissue-specific gene expression is now realized. Disturbances in epigenetic landscape can lead to malignant cellular makeover, and these heritable changes are maintained through various cycles of cell division that renders cells to have discrete identity with similar genetic information. Epigenetic alterations in colorectal cancer (CRC) that transform colonic epithelial cells into adenocarcinoma cells include aberrant DNA methylation, chromatin modifications, and noncoding RNAs, especially microRNA expression. CpG island DNA methylation and aberrant methylation of genes drive the initiation and progression of CRC. Histone modifications impinge on chromatin structure and gene expression and thus play an important role in gene silencing in CRC. DNA hypermethylation also leads to downregulation and inappropriate expression of certain microRNAs that act like tumor suppressor genes. Determining the causes and roles of epigenetic instability in CRC pathogenesis will lead to effective prevention and therapeutic strategies for patients with CRC. Epigenetic drugs that underscore the reversible nature of epigenetic events have led the possibility of epigenetic therapy as a treatment option in CRC.
遗传和表观遗传改变的积累将正常结肠上皮细胞转变为腺癌细胞。遗传改变包括肿瘤抑制基因和癌基因的突变，而表观遗传机制被定义为基因表达中的可遗传改变，其独立于初级DNA序列的变化。现在已经认识到表观遗传机制在器官和组织特异性基因表达的发育和维持中的作用。表观遗传格局的紊乱可导致恶性细胞改造，并且这些可遗传变化通过细胞分裂的各个周期得以维持，从而使细胞具有相似遗传信息的离散身份。将结肠上皮细胞转变为腺癌细胞的结直肠癌（CRC）中的表观遗传改变包括异常DNA甲基化、染色质修饰和非编码RNA，尤其是微小RNA表达。CpG岛DNA甲基化和基因的异常甲基化驱动CRC的起始和进展。组蛋白修饰影响染色质结构和基因表达，因此在CRC的基因沉默中起重要作用。DNA高甲基化还导致某些起肿瘤抑制基因作用的微小RNA的下调和异常表达。确定表观遗传不稳定性在CRC发病机制中的原因和作用将为CRC患者带来有效的预防和治疗策略。强调表观遗传事件可逆性的表观遗传药物使得表观遗传治疗成为CRC治疗选择的可能性。
