Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer
Telomere Maintenance-Associated PML Is a Potential Specific Therapeutic Target of Human Colorectal Cancer
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DOI：
10.1016/j.tranon.2019.05.010
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发表时间：
2019-09-01
影响因子：
5
通讯作者：
Liu, Lin
中科院分区：
文献类型：
--
作者：
Gong, Peng;Wang, Hua;Liu, Lin
端粒长度的维持对于细胞增殖是必不可少的，这在癌症中特别突出。我们证实，原发性结直肠肿瘤表现出不同的端粒长度，但大多数（90%）短端粒相对于正常组织。有趣的是，相对较短的端粒与肿瘤恶性程度相关，如低分化状态所示，这些肿瘤含有更多的癌症干细胞样细胞（CSLC），这些细胞通过几种常用的标记物CD44，EPHB 2或LGR 5鉴定。此外，早幼粒细胞白血病（PML）和ALT相关的PML核小体（APB）经常在端粒短和高度增殖的肿瘤中发现。相反，远处的正常组织很少或仅最低限度地表达PML。ATR抑制剂对PML和APB的抑制降低了CSLC和类器官的增殖，表明了对进行性结直肠肿瘤的潜在治疗靶点。总之，肿瘤进展下的端粒维持与CSLC有关。
Telomere length maintenance is essential for cell proliferation, which is particularly prominent in cancer. We validate that the primary colorectal tumors exhibit heterogeneous telomere lengths but mostly (90%) short telomeres relative to normal tissues. Intriguingly, relatively short telomeres are associated with tumor malignancy as indicated by poorly differentiated state, and these tumors contain more cancer stem-like cells (CSLCs) identified by several commonly used markers CD44, EPHB2 or LGR5. Moreover, promyelocytic leukemia (PML) and ALT-associated PML nuclear bodies (APBs) are frequently found in tumors with short telomeres and high proliferation. In contrast, distant normal tissues rarely or only minimally express PML. Inhibition of PML and APBs by an ATR inhibitor decreases proliferation of CSLCs and organoids, suggesting a potential therapeutic target to progressive colorectal tumors. Together, telomere maintenance underling tumor progression is connected with CSLCs.