Targeting of MAPK-associated molecules identifies SON as a prime target to attenuate the proliferation and tumorigenicity of pancreatic cancer cells.
Targeting of MAPK-associated molecules identifies SON as a prime target to attenuate the proliferation and tumorigenicity of pancreatic cancer cells.
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DOI：
10.1186/1476-4598-11-88
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发表时间：
2012-12-10
期刊：
影响因子：
37.3
通讯作者：
Shiratori K
中科院分区：
文献类型：
--
作者：
Furukawa T;Tanji E;Kuboki Y;Hatori T;Yamamoto M;Shimizu K;Shibata N;Shiratori K
胰腺癌的特征在于丝裂原活化蛋白激酶（MAPK）的组成性活化。MAPK的激活与胰腺癌细胞增殖和存活相关基因的上调有关。我们假设这些MAPK相关分子的敲低可以产生显著的抗癌表型。RNA干扰介导的敲低筛选先前确定的78个MAPK相关分子，以发现与胰腺癌细胞增殖特异性相关的分子。通过免疫组织化学检查胰腺癌组织中鉴定的分子的表达。通过使用异种移植模型测定具有稳定敲低分子的癌细胞的体内致瘤性。采用流式细胞术和活细胞成像来评估分子与细胞周期的关联。敲低筛选显示，敲低SON（编码SON的基因，其是参与RNA加工的大的富含丝氨酸/丝氨酸的蛋白质）基本上抑制胰腺癌细胞的体外增殖和存活以及体内致瘤性。SON在导管腺癌中的表达高于正常导管细胞和胰腺癌前病变组织。SON的敲除诱导培养的癌细胞G2/M期阻滞和凋亡。SON敲低对增殖的抑制作用在培养的正常导管上皮细胞中不太明显。SON在细胞周期的间期形成核斑点，在有丝分裂期弥散分布于细胞质中。活细胞成像显示SON在有丝分裂早期呈弥散分布，晚期聚集于胞浆内，有丝分裂后逐渐重新聚集成斑点状。这些结果表明SON在胰腺癌细胞的增殖、存活和致瘤性中发挥关键作用，表明SON是胰腺癌的新型治疗分子靶点。
Pancreatic cancer is characterized by constitutive activation of mitogen-activated protein kinase (MAPK). Activation of MAPK is associated with the upregulation of genes implicated in the proliferation and survival of pancreatic cancer cells. We hypothesized that knockdown of these MAPK-associated molecules could produce notable anticancer phenotypes. A RNA interference-mediated knockdown screening of 78 MAPK-associated molecules previously identified was performed to find molecules specifically associated with proliferation of pancreatic cancer cells in vitro. Expression of an identified molecule in pancreatic cancer tissues was examined by immunohistochemistry. In vivo tumorigenicity of cancer cells with stable knockdown of the molecule was assayed by using xenograft models. Flow cytometry and live cell imaging were employed to assess an association of the molecule with cell cycle. The knockdown screening revealed that knockdown of SON, the gene encoding SON, which is a large serine/arginine-rich protein involved in RNA processing, substantially suppressed pancreatic cancer cell proliferation and survival in vitro and tumorigenicity in vivo. SON expression was higher in ductal adenocarcinomas than in cells of normal ducts and precursor lesions in pancreatic cancer tissues. Knockdown of SON induced G2/M arrest and apoptosis in cultured cancer cells. The suppressive effect of SON knockdown on proliferation was less pronounced in cultured normal duct epithelial cells. SON formed nuclear speckles in the interphase of the cell cycle and dispersed in the cytoplasm during mitosis. Live cell imaging showed that SON diffusely dispersed in the early mitotic phase, accumulated in some foci in the cytoplasm in the late mitotic phase, and gradually reassembled into speckles after mitosis. These results indicate that SON plays a critical role in the proliferation, survival, and tumorigenicity of pancreatic cancer cells, suggesting that SON is a novel therapeutic molecular target for pancreatic cancer.
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