Loss of BAP1 expression is associated with genetic mutation and can predict outcomes in gallbladder cancer
Loss of BAP1 expression is associated with genetic mutation and can predict outcomes in gallbladder cancer
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DOI：
10.1371/journal.pone.0206643
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发表时间：
2018-11-05
期刊：
影响因子：
3.7
通讯作者：
Unno, Michiaki
中科院分区：
文献类型：
--
作者：
Hirosawa, Takashi;Ishida, Masaharu;Unno, Michiaki
背景BRCA-1 相关蛋白 (BAP1) 是一种调节基因表达的去泛素化酶。最近，在一系列肿瘤类型中报道了 BAP1 突变及其与癌症生存的关系，包括葡萄膜黑色素瘤、间皮瘤、肾癌和胆道癌。然而，BAP1突变和下调的频率因肿瘤类型而异，并且对于BAP1沉默在癌细胞中的功能知之甚少。胆囊癌（GBC）是一种预后不良的胆道癌。很少有突变研究调查 BAP1 在 GBC 中的作用，也没有进行关于癌症生存的体外功能研究或临床研究。 方法通过小干扰 RNA 介导的 BAP1 沉默来研究 GBC 细胞的增殖、迁移、侵袭和药物敏感性。我们进行了基因组、表观基因组和免疫组织化学分析，以检测 47 名接受手术切除的 GBC 患者的体细胞 BAP1 改变。结果 BAP1 缺失导致迁移和侵袭增加，但不增加增殖，并且还导致对蛋白酶体抑制剂硼替佐米的敏感性降低。 22 例 GBC 病例 (46.8%) 出现 BAP1 表达抑制，并且中位生存时间有明显缩短的趋势，为 13.3 个月 (95% CI，17.6-62.6) (p = 0.0034)。桑格测序显示，在这 22 例 GBC 病例中，有 11 例（50%）BAP1 表达低，检测到 BAP1 功能丧失突变；而在 25 例 GBC 病例中，有 2 例（8%）在 BAP1 高表达病例中检测到。 47 例中有 6 例观察到部分甲基化变化，但甲基化与 BAP1 表达或预后没有显着关系。结论我们的研究结果表明，基因突变参与 BAP1 下调，导致 GBC 中癌细胞的侵袭性增强和预后不良。
BackgroundBRCA-1 associated protein (BAP1) is a de-ubiquitinating enzyme that regulates gene expression. Recently, the BAP1 mutation and its involvement in cancer survival have been reported in a range of tumor types, including uveal melanoma, mesothelioma, renal cancers, and biliary tract cancers. However, the frequency of BAP1 mutation and down-regulation varies among tumor types, and little is known about the function of BAP1 silencing in cancer cells. Gallbladder carcinoma (GBC) is a type of biliary tract cancer with a poor prognosis. Few mutational studies have investigated the role of BAP1 in GBC, and no functional study in vitro-, or clinical studies about cancer survival have been done.MethodsGBC cells were studied by following the small interfering RNA mediated silencing of BAP1 with regard to proliferation, migration, invasion, and drug sensitivity. We carried out genomic, epigenomic and immunohistochemical analyses to detect somatic BAP1 alterations in 47 GBC patients undergoing surgical resection.ResultsBAP1 depletion resulted in increased migration and invasion, but not proliferation, and also resulted in decreased sensitivity to bortezomib, a proteasome inhibitor. Suppressed expression of BAP1 occurred in 22 GBC cases (46.8%) and showed a strong trend toward a worse median survival time of 13.3 months (95% CI, 17.6-62.6) (p = 0.0034). Sanger sequencing revealed a loss-of-function mutation of BAP1 in 11 out of these 22 GBC cases (50%) with low BAP1 expression, whereas 2 out of 25 GBC cases (8%) were detected in cases with high BAP1 expression. Partial changes in methylation were observed in 6 out of 47 cases, but methylation did not show a strong relationship to BAP1 expression or to the prognosis.ConclusionOur findings showed that genetic mutations are involved in BAP1 down-regulation, leading to promotion of the invasive character of cancer cells and poor prognosis in GBC.