Segara Davendra, Biankin Andrew V, Kench James G, Langusch Catherine C, Dawson Amanda C, Skalicky David A, Gotley David C, Coleman Maxwell J, Sutherland Robert L, Henshall Susan M
Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Clin Cancer Res. 2005 May 1;11(9):3587-96. doi: 10.1158/1078-0432.CCR-04-1813.
Despite significant progress in understanding the molecular pathology of pancreatic cancer and its precursor lesion: pancreatic intraepithelial neoplasia (PanIN), there remain no molecules with proven clinical utility as prognostic or therapeutic markers. Here, we used oligonucleotide microarrays to interrogate mRNA expression of pancreatic cancer tissue and normal pancreas to identify novel molecular pathways dysregulated in the development and progression of pancreatic cancer.
RNA was hybridized to Affymetrix Genechip HG-U133 oligonucleotide microarrays. A relational database integrating data from publicly available resources was created to identify candidate genes potentially relevant to pancreatic cancer. The protein expression of one candidate, homeobox B2 (HOXB2), in PanIN and pancreatic cancer was assessed using immunohistochemistry.
We identified aberrant expression of several components of the retinoic acid (RA) signaling pathway (RARalpha, MUC4, Id-1, MMP9, uPAR, HB-EGF, HOXB6, and HOXB2), many of which are known to be aberrantly expressed in pancreatic cancer and PanIN. HOXB2, a downstream target of RA, was up-regulated 6.7-fold in pancreatic cancer compared with normal pancreas. Immunohistochemistry revealed ectopic expression of HOXB2 in 15% of early PanIN lesions and 48 of 128 (38%) pancreatic cancer specimens. Expression of HOXB2 was associated with nonresectable tumors and was an independent predictor of poor survival in resected tumors.
We identified aberrant expression of RA signaling components in pancreatic cancer, including HOXB2, which was expressed in a proportion of PanIN lesions. Ectopic expression of HOXB2 was associated with a poor prognosis for all patients with pancreatic cancer and was an independent predictor of survival in patients who underwent resection.
尽管在了解胰腺癌及其前驱病变——胰腺上皮内瘤变（PanIN）的分子病理学方面取得了重大进展，但仍没有经证实具有临床实用价值的分子可作为预后或治疗标志物。在此，我们使用寡核苷酸微阵列来研究胰腺癌组织和正常胰腺的mRNA表达，以识别在胰腺癌发生和发展过程中失调的新分子途径。
将RNA与Affymetrix Genechip HG-U133寡核苷酸微阵列进行杂交。创建了一个整合来自公开可用资源数据的关系数据库，以识别可能与胰腺癌相关的候选基因。使用免疫组织化学评估一种候选基因——同源框B2（HOXB2）在PanIN和胰腺癌中的蛋白表达。
我们发现维甲酸（RA）信号通路的几个成分（RARα、MUC4、Id-1、MMP9、uPAR、HB-EGF、HOXB6和HOXB2）表达异常，其中许多已知在胰腺癌和PanIN中表达异常。HOXB2是RA的下游靶点，与正常胰腺相比，在胰腺癌中上调了6.7倍。免疫组织化学显示，HOXB2在15%的早期PanIN病变和128个胰腺癌标本中的48个（38%）中异位表达。HOXB2的表达与不可切除肿瘤相关，并且是切除肿瘤患者生存不良的独立预测因子。
我们发现胰腺癌中RA信号成分表达异常，包括HOXB2，其在一部分PanIN病变中表达。HOXB2的异位表达与所有胰腺癌患者的不良预后相关，并且是接受切除术患者生存的独立预测因子。
