Class III β-tubulin, a marker of resistance to paclitaxel, is overexpressed in pancreatic ductal adenocarcinoma and intraepithelial neoplasia
Class III β-tubulin, a marker of resistance to paclitaxel, is overexpressed in pancreatic ductal adenocarcinoma and intraepithelial neoplasia
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DOI：
10.1111/j.1365-2559.2007.02792.x
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发表时间：
2007-10-01
期刊：
影响因子：
6.4
通讯作者：
Ouellette, M. M.
中科院分区：
文献类型：
--
作者：
Lee, K. M.;Cao, D.;Ouellette, M. M.
目的：III类β-微管蛋白（TUBB 3）降低微管稳定性并赋予对微管稳定紫杉烷类（包括紫杉醇和多西他赛）的抗性。胰腺导管腺癌对紫杉烷类药物的反应性有限，但其潜在机制尚不清楚。本研究的目的是检测胰腺癌细胞系、浸润性胰腺癌和胰腺上皮内瘤变（PanIN）中TUBB 3的表达。方法和结果：采用逆转录-聚合酶链反应（RT-PCR）和蛋白质印迹法（Western blot）检测胰腺癌细胞系中TUBB 3的表达。采用免疫组织化学法评估胰腺癌标本中的TUBB 3，包括75例浸润性腺癌和41例PanIN前体病变。TUBB 3在胰腺的非肿瘤性导管中检测不到。相反，绝大多数（78-93%）胰腺导管腺癌表现为弥漫性或局灶性TUBB 3表达。TUBB 3在PanIN病变中逐渐增加，从3/16的PanIN-1（19%），5/17的PanIN-2（29%）到5/8的PanIN-3病变（63%）。结论：TUBB 3在大多数胰腺导管腺癌中表达，可能是这些肿瘤对微管稳定剂的次优反应的原因。TUBB 3在PanIN病变中的上调表明微管功能障碍是这种疾病的早期特征。TUBB 3免疫组化可能有助于识别缺乏TUBB 3表达的胰腺癌患者，这些患者可能从紫杉烷治疗中获益。
Aims: Class III beta-tubulin (TUBB3) reduces microtubule stability and confers resistance to microtubule-stabilizing taxanes, including paclitaxel and docetaxel. Pancreatic ductal adenocarcinomas show limited responsiveness to taxanes, but little is known of the underlying mechanisms. The aim of this study was to examine TUBB3 expression in pancreatic cancer cell lines, invasive pancreatic adenocarcinoma and pancreatic intraepithelial neoplasia (PanIN).Methods and results: Reverse transcriptase-polymerase chain reaction and Western blot were used to study TUBB3 expression in pancreatic cancer cell lines. Immunohistochemistry was employed to assess TUBB3 in pancreatic cancer specimens, including 75 invasive adenocarcinomas and 41 PanIN precursor lesions. TUBB3 was undetectable in non-neoplastic ducts of the pancreas. In contrast, the vast majority (78-93%) of pancreatic ductal adenocarcinomas demonstrated either diffuse or focal TUBB3 expression. TUBB3 was found to increase progressively in PanIN lesions from 3/16 of PanIN-1 (19%), 5/17 of PanIN-2 (29%) to 5/8 of PanIN-3 lesions (63%).Conclusions: TUBB3 is expressed in most pancreatic ductal adenocarcinomas, possibly accounting for the suboptimal response of these tumours to microtubule-stabilizing agents. Up-regulation of TUBB3 in PanIN lesions suggests that microtubule dysfunction is an early feature of this disease. TUBB3 immunohistochemistry could potentially help identify pancreatic cancer patients lacking TUBB3 expression who might benefit from taxane therapy.