Gallbladder cancer (GBC) is an aggressive malignancy of biliary tract with poor prognosis. Although several studies have shown the frequency of relevant genetic alterations, there are few genetic models or translational studies that really benefit for GBC treatment in the era of precision medicine. By targeted sequencing and immunohistochemistry staining, we identified that phosphate and tension homology deleted on chromosome ten (PTEN) was frequently altered in GBC specimens, and loss of PTEN expression was independently correlated with poor survival outcomes. Further drug screening assays revealed proteasome inhibitor bortezomib as a promising agent for GBC treatment, and knockdown of PTEN increased bortezomib efficacy both in vivo and in vitro. Therapeutic evaluation of patient derived xenografts (PDXs) strongly supported the utilization of bortezomib in PTEN deficient GBC. Mechanically, functional PTEN inhibited ARE-dependent transcriptional activity, the same machinery regulating the transcription of proteasome subunits, thus PTEN suppressed proteasome activity and bortezomib sensitivity. Through siRNA screening, we identified the ARE-related transcriptional suppressor BACH1 involved in PTEN-mediated proteasome inhibition and regulated by PTEN-AKT1 axis. In summary, our study indicates that proteasome activity represents a prime therapeutic target in PTEN-deficient GBC tumors, which is worthy of further clinical validation.

胆囊癌（GBC）是一种侵袭性胆道恶性肿瘤，预后不良。尽管多项研究显示了相关基因改变的频率，但在精准医学时代，真正有利于 GBC 治疗的基因模型或转化研究很少。通过靶向测序和免疫组织化学染色，我们发现在 GBC 标本中，第十号染色体 (PTEN) 上缺失的磷酸盐和张力同源性经常发生改变，并且 PTEN 表达的丧失与较差的生存结果独立相关。进一步的药物筛选试验表明蛋白酶体抑制剂硼替佐米是治疗 GBC 的一种有前途的药物，并且敲除 PTEN 增加了硼替佐米在体内和体外的疗效。患者来源的异种移植物 (PDX) 的治疗评估强烈支持硼替佐米在 PTEN 缺陷型 GBC 中的应用。从机制上讲，功能性 PTEN 抑制 ARE 依赖性转录活性，与调节蛋白酶体亚基转录的机制相同，因此 PTEN 抑制蛋白酶体活性和硼替佐米敏感性。通过 siRNA 筛选，我们确定了参与 PTEN 介导的蛋白酶体抑制并受 PTEN-AKT1 轴调节的 ARE 相关转录抑制因子 BACH1。总之，我们的研究表明蛋白酶体活性是 PTEN 缺陷型 GBC 肿瘤的主要治疗靶点，值得进一步临床验证。调节蛋白酶体亚基转录的相同机制，因此 PTEN 抑制蛋白酶体活性和硼替佐米敏感性。通过 siRNA 筛选，我们确定了参与 PTEN 介导的蛋白酶体抑制并受 PTEN-AKT1 轴调节的 ARE 相关转录抑制因子 BACH1。总之，我们的研究表明蛋白酶体活性是 PTEN 缺陷型 GBC 肿瘤的主要治疗靶点，值得进一步临床验证。调节蛋白酶体亚基转录的相同机制，因此 PTEN 抑制蛋白酶体活性和硼替佐米敏感性。通过 siRNA 筛选，我们确定了参与 PTEN 介导的蛋白酶体抑制并受 PTEN-AKT1 轴调节的 ARE 相关转录抑制因子 BACH1。总之，我们的研究表明蛋白酶体活性是 PTEN 缺陷型 GBC 肿瘤的主要治疗靶点，值得进一步临床验证。