Cancer Res:川大长江学者结肠癌新成果刊登权威期刊
生物帮 · 2015/12/27
12月23日,四川大学973项目首席科学家黄灿华带领的课题组在Cancer Research研究成果表明,PDLIM1基因可通过稳定细胞间连接处的β-连环蛋白,抑制结直肠癌细胞的EMT和转移潜能。


12月23日,四川大学生物治疗国家重点实验室教授、博士生导师、国家杰出青年、长江学者特聘教授、973项目首席科学家黄灿华带领的课题组,在国际权威癌症研究杂志《Cancer Research》发表题为“PDLIM1 stabilizes the E-cadherin/β-catenin complex to prevent epithelial-mesenchymal transition and metastatic potential of colorectal cancer cells”的研究成果。这项研究表明,PDLIM1基因可通过稳定细胞间连接处的β-连环蛋白,抑制结直肠癌细胞的EMT和转移潜能,它在转移组织中的缺失,可能是恶性疾病一个潜在的预后标记。

转移是结直肠癌(CRC)患者死亡的主要原因,越来越多的证据支持上皮间质转化(EMT)的癌症发展的促进作用。E-cadherin /β-连环蛋白粘附复合体的解离,代表着EMT的关键一步,并促进肿瘤的侵袭和转移,但是,调节这种相互作用的上游信号通路,我们还了解甚少。延伸阅读:一个蛋白是结肠癌的“双刃剑”。

在这项研究中,研究人员表明,PDLIM1——PDZ和LIM蛋白家族的一个成员,在来自CRC患者的高转移性CRC细胞和肝转移中是上调的。研究人员发现,PDLIM1缺失可促进EMT标记基因的表达,并增加了多个CRC细胞系的侵袭和迁移特性。

此外,在中,PDLIM1基因敲除可增加原位移植CRC模型的结肠源性肝转移,并且促进了实验性肺转移模型的远端转移性定植。机制研究表明,PDLIM1可与E-cadherin /β-catenin复合物相互作用并使其稳定,从而抑制了β-catenin的转录活性,并阻止了EMT。因此,PDLIM1基因的过表达,可减弱CRC细胞的EMT。

此外,PDLIM1在CRC样品中的下调,与E-cadherin和膜β-连环蛋白水平下降有关,并与总生存期较短相关。

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  • PDLIM1 stabilizes the E-cadherin/β-catenin complex to prevent epithelial-mesenchymal transition and metastatic potential of colorectal cancer cells

    Metastasis is a major cause of death in patients with colorectal cancer (CRC), and increasing evidence supports the contribution of the epithelial-mesenchymal transition (EMT) to cancer progression. The dissociation of the E-cadherin/β-catenin adhesion complex represents a key step in EMT and promotes cancer invasion and metastasis, but the upstream signaling pathways regulating this interaction are poorly understood. Here, we show that PDLIM1, a member of the PDZ and LIM protein family, was downregulated in highly metastatic CRC cells and liver metastases from CRC patients. We found that loss of PDLIM1 promoted the expression of EMT markers and increased the invasive and migratory properties of multiple CRC cell lines. Furthermore, PDLIM1 knockdown increased colon-derived liver metastasis in an orthotopic CRC model and promoted distant metastatic colonization in an experimental lung metastasis model. Mechanistic investigations revealed that PDLIM1 interacted with and stabilized the E-cadherin/β-catenin complex, thereby inhibiting the transcriptional activity of β-catenin and preventing EMT. Accordingly, PDLIM1 overexpression attenuated EMT of CRC cells. Moreover, the downregulation of PDLIM1 in CRC samples correlated with reduced E-cadherin and membrane β-catenin levels, and was associated with shorter overall survival. In conclusion, our study demonstrates that PDLIM1 suppresses EMT and metastatic potential of CRC cells by stabilizing β-catenin at cell-cell junctions, and its loss in metastatic tissues may represent a potential prognostic marker of aggressive disease.

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