Molecular determinants of retinoic acid sensitivity in pancreatic cancer.
Molecular determinants of retinoic acid sensitivity in pancreatic cancer.
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DOI：
10.1158/1078-0432.ccr-11-2165
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发表时间：
2012-01-01
期刊：
影响因子：
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通讯作者：
Maitra A
中科院分区：
文献类型：
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作者：
Gupta S;Pramanik D;Mukherjee R;Campbell NR;Elumalai S;de Wilde RF;Hong SM;Goggins MG;De Jesus-Acosta A;Laheru D;Maitra A
确定胰腺癌对维甲酸敏感性的预测性分子“特征”。使用14个脂肪酸结合蛋白5（FABP 5）和细胞视黄酸结合蛋白2（CRABP 2）表达不同的患者来源的低传代胰腺导管腺癌（PDAC）细胞系来评估对全反式视黄酸（ATRA）的反应。使用细胞增殖、凋亡和迁移/侵袭测定来测量体外反应。在无胸腺裸鼠的皮下异种移植物中监测肿瘤生长4周。观察到对ATRA的反应依赖于FABP 5与CRABP 2的差异表达。因此，升高的FABP 5表达与最小的细胞毒性和肿瘤生长抑制以及迁移和侵袭的矛盾增加相关。相反，在FABP 5缺乏的情况下，CRABP 2表达与ATRA显著的肿瘤生长抑制相关，即使在吉西他滨耐药肿瘤中也是如此。FABP 5 highCRABP 2 null细胞的ATRA抗性表型可以通过CRABP 2的异位表达来规避。或者，内源性CRABP 2的再表达可以通过暴露于地西他滨和阿司他汀A而在FABP 5 highCRABP 2无效PDAC系中实现，从而减轻CRABP 2基因启动子的表观遗传沉默。在存档的人类组织微阵列中FABP 5的免疫组织化学染色鉴定了FABP 5表达阴性的病例子集（13/63，~20%），并且可能是ATRA治疗的候选者。广泛使用的药物ATRA值得在PDAC中进行“第二次观察”，但需要靶向活检证实FABP 5阴性肿瘤的患者亚群，或与染色质修饰剂组合以重新表达内源性CRABP 2。
To identify a predictive molecular ‘signature’ for sensitivity to retinoic acid in pancreatic cancer. Fourteen patient-derived, low-passage pancreatic ductal adenocarcinoma (PDAC) lines with varied expression of fatty acid binding protein 5 (FABP5) and cellular retinoic acid binding protein 2 (CRABP2) were used to evaluate the response to all-trans retinoic acid (ATRA). Cell proliferation, apoptosis, and migration/invasion assays were used to measure the in vitro response. Tumor growth was monitored in subcutaneous xenografts in athymic nude mice for 4 weeks. Response to ATRA was observed to be dependent upon differential expression of FABP5 versus CRABP2. Thus, elevated FABP5 expression was associated with minimal cytotoxicity and tumor growth inhibition, and a paradoxical increase in migration and invasion. Conversely, CRABP2 expression in the absence of FABP5 was associated with significant tumor growth inhibition with ATRA, even in gemcitabine-resistant tumors. The ATRA-resistant phenotype of FABP5highCRABP2null cells could be circumvented by ectopic expression of CRABP2. Alternatively, re-expression of endogenous CRABP2 could be enabled in FABP5highCRABP2null PDAC lines by exposure to decitabine and trichostatin A, thereby relieving epigenetic silencing of the CRABP2 gene promoter. Immunohistochemical staining for FABP5 in archival human tissue microarrays identifies a subset of cases (13/63, ~20%) which are negative for FABP5 expression and might be candidates for ATRA therapy. The widely used agent ATRA deserves a “second look” in PDAC, but needs to be targeted to patient subsets with biopsy-proven FABP5-negative tumors, or be combined with a chromatin modifying agent in order to re-express endogenous CRABP2.