Collapsin Response Mediator Protein 4 Expression is Associated with Liver Metastasis and Poor Survival in Pancreatic Cancer
Collapsin Response Mediator Protein 4 Expression is Associated with Liver Metastasis and Poor Survival in Pancreatic Cancer
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DOI：
10.1245/s10434-012-2491-3
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发表时间：
2013-12-01
影响因子：
3.7
通讯作者：
Endo, Itaru
中科院分区：
文献类型：
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作者：
Hiroshima, Yukihiko;Nakamura, Fumio;Endo, Itaru
背景胰腺癌是一种侵袭性的恶性肿瘤，是所有癌症中死亡率最高的一种。近年来，研究发现，细胞增殖反应介导蛋白（CRMPs）与多种肿瘤的增殖、凋亡、分化和侵袭有关。然而，CRMP表达及其在胰腺癌中的作用尚未研究。本研究旨在探讨CRMPs在胰腺癌中的临床意义。采用实时荧光定量RT-PCR方法检测11对胰腺癌组织及相应癌旁胰腺组织中crmp基因的表达。在胰腺癌细胞系中检查使用siRNA敲低CRMP 4表达以确定CRMP 4是否在体外调节细胞增殖和侵袭。应用免疫组织化学方法检测53例胰腺癌原发灶中CRMP 4蛋白的表达，并与胰腺癌的临床病理特征进行比较。在所有CRMP中，仅CRMP 4在胰腺癌组织中差异表达（p = 0.008）。使用siRNA敲低CRMP 4降低细胞侵袭，但不影响增殖。在53例胰腺癌样本中，34例（64.2%）的CRMP 4表达被化学检测到，CRMP 4表达与严重静脉浸润（p = 0.044）、分期（p = 0.019）和肝转移（p = 0.021）相关。多因素分析提示静脉侵犯和CRMP 4过表达是影响生存的预后因素。我们的研究结果表明，CRMP 4通过促进肝转移与不良预后显著相关，可以作为胰腺癌的新的治疗靶点。
Background. Pancreatic cancer is an aggressive malignancy with one of the worst mortality rates of all cancers. Recently, collapsin response mediator proteins (CRMPs) were reported to be associated with proliferation, apoptosis, differentiation, and invasion in several cancers. However, CRMP expression and their role in pancreatic cancer have not been investigated. This study aimed to clarify the clinical significance of CRMPs in pancreatic cancer.Methods. Expression of crmp genes in 11 pairs of pancreatic cancer and corresponding noncancerous pancreas tissues were examined by real-time RT-PCR. Knockdown of CRMP4 expression using siRNA was examined in pancreatic cancer cell lines to determine whether CRMP4 regulates cell proliferation and invasion in vitro. Furthermore, CRMP4 protein levels in primary tumors of pancreatic cancer (n = 53) were examined by immunohistochemistry and compared with the clinicopathological features of the tumors.Results. Of all the CRMPs, only CRMP4 was differentially expressed in pancreatic cancer tissues (p = 0.008). CRMP4 knockdown using siRNA reduced cellular invasion, but did not affect proliferation. The expression of CRMP4 was detected immunohistochemically in 34 (64.2 %) of the 53 pancreatic cancer samples, and CRMP4 expression was correlated with severe venous invasion (p = 0.044), stage (p = 0.019), and liver metastasis (p = 0.021). Multivariate analyses suggested that venous invasion and CRMP4 overexpression were prognostic factors for survival.Conclusions. Our results suggested that CRMP4 is significantly associated with poor prognosis by promoting liver metastasis and can serve as a novel therapeutic target for pancreatic cancer.