Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, China.
J Cell Physiol. 2014 Dec;229(12):1908-17. doi: 10.1002/jcp.24566.
Colon cancer remains one of the lethal malignancies in the world. Aberrant activation of canonical Wnt/β-catenin signaling pathway has been observed in colon cancer. In contrast, the non-canonical Wnt signaling functions remain obscure. Wnt5a is a representative non-canonical Wnt ligand which has gained extensive attention nowadays. Wnt5a has been shown to play an important role in EMT in prostate cancer and melanoma, but its role in colon cancer is still ambiguous. Here we have evaluated Wnt5a expression in a large cohort of 217 colon cancers by immunohistochemistry and analyzed its correlation with clinicopathologic characteristics. We found that expression of Wnt5a was diminished significantly in majority of primary colon cancers and negatively related with EMT biomarkers. To further enlighten the mechanism which Wnt5a regulates EMT in vitro, we established ectopic Wnt5a expression models. Protein analysis demonstrated that Wnt5a inhibited EMT and antagonized canonical Wnt signaling in colon cancer cells. Overexpression of Wnt5a impaired cell motility and invasion and inhibited cell proliferation by manipulating Bax. Moreover, Wnt5a suppressed the tumor growth in nude mice and impaired tumorigenicity in vivo. Wnt5a also induced intracellular calcium and activated non-canonical Wnt/Ca(2+) signaling in colon cancer. In summary, although Wnt5a was down-regulated in majority of colon cancers, enhanced Wnt5a expression predict preferable outcome in colon cancer patients. Our findings indicate that Wnt5a might act as tumor suppressor by inhibiting cell proliferation and attenuating EMT in colon cancer cells. Wnt5a could be used as a novel prognostic marker and/or therapeutic target for colon cancer in the future.
结肠癌仍然是世界上致命的恶性肿瘤之一。在结肠癌中观察到经典 Wnt/β-连环蛋白信号通路的异常激活。相比之下，非经典 Wnt 信号功能仍然不清楚。Wnt5a 是一种有代表性的非经典 Wnt 配体，目前受到广泛关注。已经表明，Wnt5a 在前列腺癌和黑色素瘤中的 EMT 中发挥重要作用，但它在结肠癌中的作用仍然不明确。在这里，我们通过免疫组织化学评估了 217 例结肠癌中的 Wnt5a 表达，并分析了其与临床病理特征的相关性。我们发现，大多数原发性结肠癌中 Wnt5a 的表达明显减少，并且与 EMT 生物标志物呈负相关。为了进一步阐明 Wnt5a 在体外调节 EMT 的机制，我们建立了异位 Wnt5a 表达模型。蛋白质分析表明，Wnt5a 抑制 EMT 并拮抗结肠癌细胞中的经典 Wnt 信号。Wnt5a 的过表达通过操纵 Bax 损害细胞迁移和侵袭，并抑制细胞增殖。此外，Wnt5a 在裸鼠中抑制肿瘤生长并在体内损害肿瘤发生。Wnt5a 还诱导结肠癌细胞内的钙内流并激活非经典 Wnt/Ca(2+)信号。总之，尽管大多数结肠癌中 Wnt5a 下调，但增强的 Wnt5a 表达预示着结肠癌患者的预后较好。我们的研究结果表明，Wnt5a 可能通过抑制细胞增殖和减弱 EMT 来发挥肿瘤抑制作用。Wnt5a 将来可能成为结肠癌的一种新的预后标志物和/或治疗靶点。
