He Shanshan, Liang Chengyu
a Department of Molecular Microbiology and Immunology, University of Southern California ; Los Angeles , CA USA.
Autophagy. 2015;11(10):1939-40. doi: 10.1080/15548627.2015.1086523.
Colorectal cancer (CRC) ranks as the second leading cause of cancer-related deaths in the Western world. It has a nearly 50% metastasis rate and only a subset of patients respond to current treatment strategy. UVRAG, a key autophagy effector and a guardian of chromosomal stability, is truncated by a frameshift (FS) mutation in CRC with microsatellite instability (MSI). However, the pathological and clinical significance of this UVRAG truncation remains less understood. Our recent study discovered that this FS mutation yields a much shortened form of the UVRAG protein, which counteracts most of the tumor-suppressor functions of wild-type (WT) UVRAG in autophagy, centrosome stability, and DNA repair in a dominant-negative fashion. Whereas this truncated mutation of UVRAG promotes tumorigenesis, epithelial-to-mesenchymal transition, and metastasis, it appears to sensitize CRC tumors to adjuvant chemotherapy, making it a potential molecular marker to individualize therapeutic approach in CRC.
在西方世界，结直肠癌（CRC）是癌症相关死亡的第二大主要原因。其转移率近50%，只有一部分患者对当前的治疗策略有反应。UVRAG是自噬的关键效应因子和染色体稳定性的守护者，在微卫星不稳定（MSI）的CRC中因移码（FS）突变而被截断。然而，这种UVRAG截断的病理和临床意义仍不太清楚。我们最近的研究发现，这种FS突变产生了一种大大缩短的UVRAG蛋白形式，它以显性负性方式抵消了野生型（WT）UVRAG在自噬、中心体稳定性和DNA修复中的大部分肿瘤抑制功能。虽然UVRAG的这种截断突变促进肿瘤发生、上皮-间质转化和转移，但它似乎使CRC肿瘤对辅助化疗敏感，使其成为CRC个体化治疗方法的潜在分子标志物。
