Pancreatic cancer cells enhance the ability of collagen internalization during epithelial-mesenchymal transition.
Pancreatic cancer cells enhance the ability of collagen internalization during epithelial-mesenchymal transition.
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DOI：
10.1371/journal.pone.0040434
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Tanaka M
中科院分区：
文献类型：
--
作者：
Ikenaga N;Ohuchida K;Mizumoto K;Akagawa S;Fujiwara K;Eguchi D;Kozono S;Ohtsuka T;Takahata S;Tanaka M
细胞外基质（ECM）重塑主要由成纤维细胞通过细胞内和细胞外途径介导。虽然众所周知，来源于癌细胞的蛋白酶对ECM的细胞外降解促进了细胞侵袭，但癌细胞对ECM组分的细胞内降解尚未阐明。本研究的目的是表征胶原内化，这是在胰腺癌细胞的细胞内降解途径的第一步，在上皮间质转化（EMT）。我们使用俄勒冈州绿色488-明胶分析了两种胰腺癌细胞系SUIT-2和KP-2以及胰腺星状细胞（PSC）中胶原内化的功能。PSC具有较强的胶原摄取能力，胰腺癌细胞也内化胶原，但效率较低。重组人转化生长因子β1诱导的EMT能促进SUIT-2和KP-2细胞胶原内化能力（P<0.05）。EMT标记物检测显示胰腺癌细胞系中胶原摄取受体Endo 180表达增高（P<0.01）。定量RT-PCR和western blot分析表明，EMT诱导SUIT-2和KP-2细胞中Endo 180的表达也增加。RNA干扰抑制Endo 180表达可明显降低SUIT-2和KP-2细胞的胶原摄取能力（P<0.01）和侵袭能力（P<0.05）。胰腺癌细胞能够胶原内化，这是由EMT增强。这种ECM清除系统可能是胰腺癌细胞侵袭的一种新机制，也是一种潜在的治疗靶点。
Extracellular matrix (ECM) remodeling is predominantly mediated by fibroblasts using intracellular and extracellular pathways. Although it is well known that extracellular degradation of the ECM by proteases derived from cancer cells facilitates cellular invasion, the intracellular degradation of ECM components by cancer cells has not been clarified. The aim of this study was to characterize collagen internalization, which is the initial step of the intracellular degradation pathway in pancreatic cancer cells, in light of epithelial–mesenchymal transition (EMT). We analyzed the function of collagen internalization in two pancreatic cancer cell lines, SUIT-2 and KP-2, and pancreatic stellate cells (PSCs) using Oregon Green 488-gelatin. PSCs had a strong ability for collagen uptake, and the pancreatic cancer cells also internalized collagen although less efficiently. The collagen internalization abilities of SUIT-2 and KP-2 cells were promoted by EMT induced by human recombinant transforming growth factor β1 (P<0.05). Expression of Endo180, a collagen uptake receptor, was high in mesenchymal pancreatic cancer cell lines, as determined by EMT marker expression (P<0.01). Quantitative RT-PCR and western blot analyses showed that Endo180 expression was also increased by EMT induction in SUIT-2 and KP-2 cells. Endo180 knockdown by RNA interference attenuated the collagen uptake (P<0.01) and invasive abilities (P<0.05) of SUIT-2 and KP-2 cells. Pancreatic cancer cells are capable of collagen internalization, which is enhanced by EMT. This ECM clearance system may be a novel mechanism for cellular invasion and a potential therapeutic target in pancreatic cancer.
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11.5
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