SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia
SCRIB expression is deregulated in human prostate cancer, and its deficiency in mice promotes prostate neoplasia
复制标题
DOI：
10.1172/jci58509
复制
发表时间：
2011-11-01
影响因子：
15.9
通讯作者：
Humbert, Patrick O.
中科院分区：
文献类型：
--
作者：
Pearson, Helen B.;Perez-Mancera, Pedro A.;Humbert, Patrick O.
细胞极性的丧失是上皮癌的标志，提高了极性调节剂在抑制肿瘤发生中发挥作用的可能性。Scribble复合物是至少三种相互作用的蛋白质复合物之一，其在建立和维持上皮极性中具有关键作用。在人类结直肠癌、乳腺癌和子宫内膜癌中，Scribble复合体成员SCRIB的表达经常被错误定位和失调。在这里，我们报告Scrib对于小鼠前列腺的稳态是不可或缺的。Scrib杂合性引发前列腺增生，而靶向双等位基因Scrib缺失使小鼠易患前列腺上皮内瘤形成。从机制上讲，Scrib显示出负调节MAPK级联以抑制肿瘤发生。进一步的分析显示，小鼠中Scrib的前列腺特异性丢失与致癌Kras突变的表达相结合，促进了前列腺癌的进展，这重演了人类疾病。我们观察到SCRIB失调与人类前列腺癌的生存率低密切相关，这突出了小鼠研究的临床意义。这些数据表明，极性网络可以为治疗干预提供新的途径。
Loss of cellular polarity is a hallmark of epithelial cancers, raising the possibility that regulators of polarity have a role in suppressing tumorigenesis. The Scribble complex is one of at least three interacting protein complexes that have a critical role in establishing and maintaining epithelial polarity. In human colorectal, breast, and endometrial cancers, expression of the Scribble complex member SCRIB is often mislocalized and deregulated. Here, we report that Scrib is indispensable for prostate homeostasis in mice. Scrib heterozygosity initiated prostate hyperplasia, while targeted biallelic Scrib loss predisposed mice to prostate intraepithelial neoplasia. Mechanistically, Scrib was shown to negatively regulate the MAPK cascade to suppress tumorigenesis. Further analysis revealed that prostate-specific loss of Scrib in mice combined with expression of an oncogenic Kras mutation promoted the progression of prostate cancer that recapitulated the human disease. The clinical significance of the work in mice was highlighted by our observation that SCRIB deregulation strongly correlated with poor survival in human prostate cancer. These data suggest that the polarity network could provide a new avenue for therapeutic intervention.