Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Ann Surg Oncol. 2013 Dec;20 Suppl 3:S369-78. doi: 10.1245/s10434-012-2491-3. Epub 2012 Jul 18.
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.
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.
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.
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.
胰腺癌是一种侵袭性恶性肿瘤，其死亡率在所有癌症中位居前列。最近有研究报道， collapsin 反应介质蛋白（CRMPs）与多种癌症的增殖、凋亡、分化和侵袭有关。然而，CRMP 在胰腺癌中的表达及其作用尚未得到研究。本研究旨在阐明 CRMPs 在胰腺癌中的临床意义。
采用实时 RT-PCR 检测 11 对胰腺癌及其相应非癌胰腺组织中 crmp 基因的表达。用 siRNA 敲低胰腺癌细胞系中 CRMP4 的表达，以确定 CRMP4 是否调节体外细胞增殖和侵袭。此外，采用免疫组化法检测 53 例胰腺癌原发肿瘤中 CRMP4 蛋白的水平，并与肿瘤的临床病理特征进行比较。
在所有的 CRMPs 中，只有 CRMP4 在胰腺癌组织中差异表达（p = 0.008）。用 siRNA 敲低 CRMP4 可降低细胞侵袭，但不影响增殖。在 53 例胰腺癌样本中，34 例（64.2%）免疫组化检测到 CRMP4 表达，CRMP4 表达与严重静脉侵犯（p = 0.044）、分期（p = 0.019）和肝转移（p = 0.021）相关。多因素分析表明，静脉侵犯和 CRMP4 过表达是生存的预后因素。
我们的研究结果表明，CRMP4 通过促进肝转移与不良预后显著相关，可作为胰腺癌的一个新的治疗靶点。
