ACAT-1-Regulated Cholesteryl Ester Accumulation Modulates Gemcitabine Resistance in Biliary Tract Cancer
ACAT-1-Regulated Cholesteryl Ester Accumulation Modulates Gemcitabine Resistance in Biliary Tract Cancer
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DOI：
10.1245/s10434-021-11152-1
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发表时间：
2022-01-07
影响因子：
3.7
通讯作者：
Eguchi, Hidetoshi
中科院分区：
文献类型：
--
作者：
Ueno, Goro;Iwagami, Yoshifumi;Eguchi, Hidetoshi
背景胆道癌（BTC）的化疗选择很少，包括吉西他滨，因此探索吉西他滨耐药的机制是重要的。我们专注于脂质代谢，因为胆道上皮细胞在胆固醇和胆汁酸代谢中是必不可少的，并且信使RNA（mRNA）微阵列分析显示高酰基辅酶A：胆固醇酰基转移酶1（ACAT-1）在BTC吉西他滨耐药（GR）细胞系中表达。我们假设ACAT-1调节的胆固醇酯（CE）异常积累可以调节BTC. Methods GR。在人BTC细胞系中测量CE积累，并分析CE水平、ACAT-1表达和吉西他滨敏感性之间的关系。我们在BTC细胞系中进行了小干扰RNA（siRNA）介导的ACAT-1敲低和生化抑制，并评估了吉西他滨敏感性的改变。为探讨ACAT-1在GR中的临床意义，采用免疫组化方法检测了BTC患者手术切除标本中ACAT-1的表达。在四种人BTC细胞系中，CE水平与ACAT-1表达和GR相关。在两个独立的GR细胞克隆中，siRNA介导的ACAT-1敲低以及ACAT-1抑制剂处理显著增加了吉西他滨的敏感性; ACAT-1敲低：分别为5.63倍和8.02倍; ACAT-1抑制剂：分别为8.75倍和9.13倍。切除的BTC标本中的ACAT-1表达显示，在术后吉西他滨治疗下，ACAT-1低强度组的无病生存期（中位数2.3年）显著优于ACAT-1高强度组（中位数1.1年）（*p < 0.05）。我们的研究结果表明，CE和ACAT-1可能是一个新的治疗BTC GR的靶点。
Background. Biliary tract cancer (BTC) has few choices of chemotherapy, including gemcitabine, therefore exploring the mechanisms of gemcitabine resistance is important. We focused on lipid metabolism because biliary tract epithelial cells are essential in cholesterol and bile acid metabolism and the messenger RNA (mRNA) microarray analysis showed high acyl coenzyme A: cholesterol acyltransferase 1 (ACAT-1) expression in BTC gemcitabine-resistant (GR) cell lines. We hypothesized that aberrant accumulation of cholesteryl ester (CE) regulated by ACAT-1 could modulate GR in BTC.Methods. CE accumulations were measured in human BTC cell lines, and the relationships between CE levels, ACAT-1 expressions, and gemcitabine sensitivity were analyzed. We performed a small-interfering RNA (siRNA)-mediated knockdown and biochemical inhibition of ACAT-1 in BTC cell lines and alterations of gemcitabine sensitivity were evaluated. To evaluate the clinical significance of ACAT-1 in regard to GR, immunohistochemistry was performed and ACAT-1 expressions were analyzed in resected BTC specimens.Results. CE levels were correlated with ACAT-1 expressions and GR in four human BTC cell lines. siRNA-mediated knockdown of ACAT-1 in two independent GR cell clones as well as ACAT-1 inhibitor treatment significantly increased gemcitabine sensitivity; knockdown of ACAT-1: 5.63- and 8.02-fold; ACAT-1 inhibitor: 8.75- and 9.13-fold, respectively. ACAT-1 expression in resected BTC specimens revealed that the disease-free survival of the ACAT-1 low-intensity group (median 2.3 years) had a significantly better outcome than that of the ACAT-1 high-intensity group (median 1.1 years) under gemcitabine treatment after surgery (*p < 0.05).Conclusions. Our findings suggest that CE and ACAT-1 might be a novel therapeutic target for GR in BTC.