RNA干扰抑制胰腺癌细胞系fascin基因表达的研究
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摘要
胰腺癌是预后最差、死亡率最高的恶性肿瘤之一。胰腺癌极强的侵袭和转移能力与其预后差直接相关。研究胰腺癌这种高度恶性生长扩散方式的机制,从而找到治疗胰腺癌的新方法,是目前医学研究的迫切任务之一。
Fascin是进化上高度保守的细胞骨架蛋白,参与细胞膜表面丝状伪足和微刺的形成,在细胞迁移、细胞黏附以及细胞间信息交流等过程中发挥重要作用。文献报道fascin在人类的多种上皮性肿瘤中有不同程度的上调表达。胰腺癌基因差异表达和蛋白质组研究发现,fascin是胰腺癌与正常胰腺组织表达差异最大的基因之一。通过干预fascin表达探讨fascin对胰腺癌细胞生物学行为的影响,目前尚未见研究报道。
本研究运用RNA干扰技术,成功找到了fascin的有效干扰位点,构建干扰载体,并建立了稳定干扰克隆细胞系。
对稳定干扰克隆细胞的生物学行为研究发现:fascin表达的抑制在体外和体内都可以显著地减慢细胞的增殖速度,在体外实验能使细胞停滞在G1期,而对凋亡没有明显影响;能使胰腺癌细胞的细胞突起和表面微绒毛明显减少,细胞内线粒体显著减少并形成漩涡状排列的板层结构;可以促进细胞的聚集黏附,降低细胞的锚着非依赖性生长能力;fascin表达的抑制可以显著地降低胰腺癌细胞的运动和迁移能力,干扰细胞划痕迁移速度明显减慢,迁移至Transwell Chambers下室的数量明显减少,穿过基质胶侵袭至Invasion Chambers下室的细胞数量明显减少;fascin表达抑制对胰腺癌细胞的E-cadherin、β-catenin、β-actin、vimentin表达没有明显影响,可引起胰腺癌细胞的蛋白水解酶MMP-2表达的下降,而对MMP-9和cathepsin D的表达没有明显影响。
本研究结果表明,fascin可以影响胰腺癌细胞的形态、增殖、黏附、锚着非依赖性生长、运动和侵袭,其影响都有利于癌的侵袭和转移。因此,针对fascin表达的干预可能会使胰腺癌肿瘤细胞的侵袭和转移能力下降,有望成为胰腺癌治疗的一个新靶点,从而为胰腺癌的治疗提供了一条新的途径。
Pancreatic ductal adenocarcinoma is one of the most lethal malignancies in human. Pancreatic cancer cell has an extremely strong ability of invasion and metastasis, which is directly correlated with its poor prognosis. It is urgent for both the clinicians and the scientists who devote themselves to pancreatic cancer to find a breakthrough of curable therapy.
Fascin is an evolutionary highly conserved cytoskeletal protein that is expressed in activated migrating cells and in cells with numerous membranous protrusions. Fascin is located in the core actin bundles of spikes and filopodia at the leading edge of migrating cells, and has been implicated in cell motility in several cell types playing an important role in cell migration, adhesion, and cell-cell interaction. There are several reports on fascin expression in human epithelial neoplasms. Fascin is the one of the most differentially expressed genes in pancreatic cancers compared with normal pancreas tissues using global gene expression profiling and proteomics technology. However, the role of fascin in pancreatic cancer has not clearly delineated.
In our study, a human pancreatic cancer cell line, PANC-1, was transfected with the plasmid pSilencer2.1-U6 neo containing target sequence for fascin-1 gene, along with the scramble sequence as control. We found the effective target sequence for fascin-1 gene using RNA interference. Stable G418-resistant clones were obtained, and the expanded cells were then used for subsequent studies. The roles of fascin in cell behaviors such as morphology, proliferation, migration, invasion, etc. were detected, and the significance of fascin as a potential gene therapy target was evaluated.
Our experiments showed that the interference of fascin expression could slow down the cell proliferation in vitro and in vivo. The proliferating cells in cell cycle might stop at G1 stage but showed scarce apoptotic cell. Fascin suppression could inhibit the formation of cell protrusion and cell microvilli as well as cause a decrease mitochondria number. Moreover, whirled laminal structure was observed in transmission EM. We revealed that fascin silencing might promote the cell adhension and reduce the anchorage-independent growth of the tumor cells in soft agar. Furthermore, interference of fascin expression could decrease the ability of cell migration and invasion. The correlative proteins detection found that fascin suppression had no effect on E-cadherin,β-catenin,β-actin or vimentin expression. The production of MMP-2 could be inhibited by fascin interfering, which showed no definite relation with MMP-9 or cathepsin D.
The results of our study indicate that fascin plays an intriguing role in tumor cell morphology, proliferation, adhesion, anchorage-independent growth, migration and invasion, all of these can facilitate tumor's invasion and metastasis. Consistent with these results, fascin may be a promising target for inhibiting the invasion and metastasis of pancreatic cancer.
Fascin是进化上高度保守的细胞骨架蛋白,参与细胞膜表面丝状伪足和微刺的形成,在细胞迁移、细胞黏附以及细胞间信息交流等过程中发挥重要作用。文献报道fascin在人类的多种上皮性肿瘤中有不同程度的上调表达。胰腺癌基因差异表达和蛋白质组研究发现,fascin是胰腺癌与正常胰腺组织表达差异最大的基因之一。通过干预fascin表达探讨fascin对胰腺癌细胞生物学行为的影响,目前尚未见研究报道。
本研究运用RNA干扰技术,成功找到了fascin的有效干扰位点,构建干扰载体,并建立了稳定干扰克隆细胞系。
对稳定干扰克隆细胞的生物学行为研究发现:fascin表达的抑制在体外和体内都可以显著地减慢细胞的增殖速度,在体外实验能使细胞停滞在G1期,而对凋亡没有明显影响;能使胰腺癌细胞的细胞突起和表面微绒毛明显减少,细胞内线粒体显著减少并形成漩涡状排列的板层结构;可以促进细胞的聚集黏附,降低细胞的锚着非依赖性生长能力;fascin表达的抑制可以显著地降低胰腺癌细胞的运动和迁移能力,干扰细胞划痕迁移速度明显减慢,迁移至Transwell Chambers下室的数量明显减少,穿过基质胶侵袭至Invasion Chambers下室的细胞数量明显减少;fascin表达抑制对胰腺癌细胞的E-cadherin、β-catenin、β-actin、vimentin表达没有明显影响,可引起胰腺癌细胞的蛋白水解酶MMP-2表达的下降,而对MMP-9和cathepsin D的表达没有明显影响。
本研究结果表明,fascin可以影响胰腺癌细胞的形态、增殖、黏附、锚着非依赖性生长、运动和侵袭,其影响都有利于癌的侵袭和转移。因此,针对fascin表达的干预可能会使胰腺癌肿瘤细胞的侵袭和转移能力下降,有望成为胰腺癌治疗的一个新靶点,从而为胰腺癌的治疗提供了一条新的途径。
Pancreatic ductal adenocarcinoma is one of the most lethal malignancies in human. Pancreatic cancer cell has an extremely strong ability of invasion and metastasis, which is directly correlated with its poor prognosis. It is urgent for both the clinicians and the scientists who devote themselves to pancreatic cancer to find a breakthrough of curable therapy.
Fascin is an evolutionary highly conserved cytoskeletal protein that is expressed in activated migrating cells and in cells with numerous membranous protrusions. Fascin is located in the core actin bundles of spikes and filopodia at the leading edge of migrating cells, and has been implicated in cell motility in several cell types playing an important role in cell migration, adhesion, and cell-cell interaction. There are several reports on fascin expression in human epithelial neoplasms. Fascin is the one of the most differentially expressed genes in pancreatic cancers compared with normal pancreas tissues using global gene expression profiling and proteomics technology. However, the role of fascin in pancreatic cancer has not clearly delineated.
In our study, a human pancreatic cancer cell line, PANC-1, was transfected with the plasmid pSilencer2.1-U6 neo containing target sequence for fascin-1 gene, along with the scramble sequence as control. We found the effective target sequence for fascin-1 gene using RNA interference. Stable G418-resistant clones were obtained, and the expanded cells were then used for subsequent studies. The roles of fascin in cell behaviors such as morphology, proliferation, migration, invasion, etc. were detected, and the significance of fascin as a potential gene therapy target was evaluated.
Our experiments showed that the interference of fascin expression could slow down the cell proliferation in vitro and in vivo. The proliferating cells in cell cycle might stop at G1 stage but showed scarce apoptotic cell. Fascin suppression could inhibit the formation of cell protrusion and cell microvilli as well as cause a decrease mitochondria number. Moreover, whirled laminal structure was observed in transmission EM. We revealed that fascin silencing might promote the cell adhension and reduce the anchorage-independent growth of the tumor cells in soft agar. Furthermore, interference of fascin expression could decrease the ability of cell migration and invasion. The correlative proteins detection found that fascin suppression had no effect on E-cadherin,β-catenin,β-actin or vimentin expression. The production of MMP-2 could be inhibited by fascin interfering, which showed no definite relation with MMP-9 or cathepsin D.
The results of our study indicate that fascin plays an intriguing role in tumor cell morphology, proliferation, adhesion, anchorage-independent growth, migration and invasion, all of these can facilitate tumor's invasion and metastasis. Consistent with these results, fascin may be a promising target for inhibiting the invasion and metastasis of pancreatic cancer.
引文
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13. Svitkina TM, Bulanova EA, Chaga OY, et al. Mechanism of filopodia initiation by reorganization of a dendritic network. J Cell Biol. 2003 Feb 3;160(3):409-21.
14. Ono S, Yamakita Y, Yamashiro S, et al. Identification of an actin binding region and a protein kinase C phosphorylation site on human fascin. J Biol Chem. 1997 Jan 24;272(4):2527-33.
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21. Ishikawa R, Yamashiro S, Kohama K, et al. Regulation of actin binding and actin bundling activities of fascin by caldesmon coupled with tropomyosin. J Biol Chem. 1998 Oct 9;273(41):26991-7.
22. Yamashiro-Matsumura S, Matsumura F. Intracellular localization of the 55-kD actin-bundling protein in cultured cells: spatial relationships with actin, alpha-actinin, tropomyosin, and fimbrin. J Cell Biol. 1986 Aug; 103(2):631-40.
23. Helfman DM, Levy ET, Berthier C, et al. Caldesmon inhibits nonmuscle cell contractility and interferes with the formation of focal adhesions. Mol Biol Cell. 1999 Oct;10(10):3097-112.
24. Lin JJ, Lin JL, Davis-Nanthakumar EJ, et al. Monoclonal antibodies against caldesmon, a Ca++/calmodulin- and actin-binding protein of smooth muscle and nonmuscle cells. Hybridoma. 1988 Jun;7(3):273-88.
25. Ishikawa R, Hayashi K, Shirao T, et al. Drebrin, a development-associated brain protein from rat embryo, causes the dissociation of tropomyosin from actin filaments. J Biol Chem. 1994 Nov 25;269(47):29928-33.
26. Peitsch WK, Grund C, Kuhn C, et al. Drebrin is a widespread actin-associating protein enriched at junctional plaques, defining a specific microfilament anchorage system in polar epithelial cells. Eur J Cell Biol. 1999 Nov;78(11):767-78.
27. Edwards RA, Bryan J. Fascins, a family of actin bundling proteins. Cell Motil Cytoskeleton. 1995;32(1):1-9.
28. Anilkumar N, Parsons M, Monk R, et al. Interaction of fascin and protein kinase Calpha: a novel intersection in cell adhesion and motility. EMBO J. 2003 Oct 15;22(20):5390-402.
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