抑癌基因 BAP1 通过调控 Hippo 通路抑制胰腺导管腺癌的发生。
The Tumor Suppressor BAP1 Regulates the Hippo Pathway in Pancreatic Ductal Adenocarcinoma.
机构信息
Department of Discovery Oncology, Genentech, Inc., South San Francisco, California.
Department of Bioinformatics, Genentech, Inc., South San Francisco, California.
出版信息
Cancer Res. 2020 Apr 15;80(8):1656-1668. doi: 10.1158/0008-5472.CAN-19-1704. Epub 2020 Jan 27.
Abstract
The deubiquitinating enzyme BAP1 is mutated in a hereditary cancer syndrome with a high risk for mesothelioma and melanocytic tumors. Here, we show that pancreatic intraepithelial neoplasia driven by oncogenic mutant KrasG12D progressed to pancreatic adenocarcinoma in the absence of BAP1. The Hippo pathway was deregulated in BAP1-deficient pancreatic tumors, with the tumor suppressor LATS exhibiting enhanced ubiquitin-dependent proteasomal degradation. Therefore, BAP1 may limit tumor progression by stabilizing LATS and thereby promoting activity of the Hippo tumor suppressor pathway. SIGNIFICANCE: BAP1 is mutated in a broad spectrum of tumors. Pancreatic Bap1 deficiency causes acinar atrophy but combines with oncogenic Ras to produce pancreatic tumors. BAP1-deficient tumors exhibit deregulation of the Hippo pathway..
摘要
去泛素化酶 BAP1 发生突变会导致一种遗传性癌症综合征，这种综合征会增加患间皮瘤和黑色素瘤的风险。在这里，我们发现，在没有 BAP1 的情况下，由致癌突变型 KrasG12D 驱动的胰腺上皮内瘤变会进展为胰腺腺癌。在 BAP1 缺陷的胰腺肿瘤中，Hippo 通路被失调，肿瘤抑制因子 LATS 表现出增强的泛素依赖性蛋白酶体降解。因此，BAP1 可能通过稳定 LATS 来限制肿瘤的进展，从而促进 Hippo 肿瘤抑制途径的活性。意义：BAP1 在广泛的肿瘤中发生突变。胰腺 Bap1 缺失会导致腺泡萎缩，但与致癌性 Ras 结合会产生胰腺肿瘤。BAP1 缺陷型肿瘤表现出 Hippo 通路的失调。
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