Kallikrein 7 enhances pancreatic cancer cell invasion by shedding E-cadherin
Kallikrein 7 enhances pancreatic cancer cell invasion by shedding E-cadherin
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DOI：
10.1002/cncr.22606
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发表时间：
2007-05-01
期刊：
影响因子：
6.2
通讯作者：
Haun, Randy S.
中科院分区：
文献类型：
--
作者：
Johnson, Sarah K.;Rarnani, Vishnu C.;Haun, Randy S.
背景胰腺癌（PaC）以局部浸润和早期转移为特征。丝氨酸蛋白酶由于其降解细胞外基质（ECM）蛋白和激活其他蛋白酶的能力而与许多癌症的侵袭和转移相关;因此，研究了PaC中表达的丝氨酸蛋白酶。使用聚合酶链反应（PCR）为基础的屏幕和激肽释放酶7的差异表达的丝氨酸蛋白酶的表达谱产生的正常和恶性胰腺组织进行了检查，通过逆转录酶PCR（RT-PCR）和免疫组化分析。在体外使用重组E-cadherin和BxPC-3细胞检测人激肽释放酶7（hK 7）切割上皮细胞粘附分子E-cadherin的能力，并检查hK 7蛋白水解活性对胰腺细胞侵袭和聚集的影响。表达谱分析显示，激肽释放酶7（KLK 7）在胰腺癌中过表达，并通过RT-PCR分析证实其差异表达。在所有检查的肿瘤的肿瘤细胞中观察到hK 7，在70%的检查的肿瘤中具有中等至强的染色（16/23）。相反，只有15%的非恶性组织标本（2/13）显示中度hK 7染色，而其余标本产生弱，如果有的话，免疫反应性。体外实验表明，hK 7能切割E-cadherin，可溶性E-cadherin片段能显著增强Panc-1细胞通过ECM蛋白的侵袭能力，并相应减少Panc-1细胞的聚集。这些结果表明，hK 7的异常表达在PaC中起着重要的作用，并提供了新的洞察hK 7蛋白酶活性升高的影响，在这个，也许其他腺癌。
BACKGROUND. Pancreatic cancer (PaC) is characterized by local invasion and early metastasis. Serine proteases have been associated with invasion and metastasis of many cancers due to their ability to degrade extracellular matrix (ECM) proteins and to activate other proteases; thus, the serine proteases expressed in PaC were investigated.METHODS. An expression profile of serine proteases was generated from both normal and malignant pancreatic tissues using a polymerase chain reaction (PCR)-based screen and differential expression of kallikrein 7 was examined by reverse-transcriptase PCR (RT-PCR) and immunohistochemical analyses. The ability of human kallikrein 7 (hK7) to cleave the epithelial cell adhesion molecule E-cadherin was tested in vitro using both recombinant E-cadherin and BxPC-3 cells and the effects of hK7 proteolytic activity on pancreatic cell invasion and aggregation were examined.RESULTS. Expression profiling revealed that kallikrein 7 (KLK7) was overexpressed in pancreatic adenocarcinomas and its differential expression was confirmed by RT-PCR analysis. hK7 was observed in neoplastic cells of all tumors examined with moderate-to-intense staining in 70% of tumors examined (16/23). In contrast, only 15% of nonmalignant tissue specimens (2/13) displayed moderate hK7 staining, whereas the remaining specimens yielded weak, if any, immunoreactivity. Using in vitro assays, hK7 was shown to cleave E-cadherin and the soluble E-cadherin fragment produced significantly enhanced Panc-1 cell invasion through ECM proteins with a corresponding reduction in Panc-1 cell aggregation.CONCLUSIONS. These results suggest that aberrant expression of hK7 plays an important role in PaC and provides novel insight into the effects of elevated hK7 proteinase activity in this, and perhaps other, adenocarcinomas.