Wnt非经典信号与疾病关系

尽管从分子生物学和生物化学的角度对Wnt 经典信号进行了广泛的研究，但非典型的Wnt/Ca2+信号却很少受到关注。近年研究发现Wnt/Ca2+途径可以通过和经典的Wnt/β-catenin 信号通路相互作用在多种疾病中发挥作用。Wnt/β-catenin 信号通路在许多癌症中均出现上调，而Wnt/Ca2+信号通路则表现出下调，而在这种情况表明，癌症的预后可能与Wnt/Ca2+信号通路的下调有关。但是也有报道显示，Wnt5a 信号在神经母细胞瘤和培养的转移性神经母细胞中被显著下调，但是β-catenin 却在那些细胞中高表达，由此可见，Wnt /β-catenin 与Wnt 钙信号通路之间的相互关系十分复杂，这其中的机制尚未阐明。

Wnt/Ca2+信号通路在抑制癌细胞增殖方面也有积极作用。如Wnt5a 在甲状腺癌细胞系中通过激活Ca2+/CaMKII 途径降低了癌细胞的运动能力和侵袭性，CaMKII 可以独立地参与β-catenin 的磷酸化，这样使蛋白质更易于降解。通过将结肠癌细胞系培养在加外源Ca2+的培养液中发现，这种条件有利于降解结肠癌细胞系中的β-连环蛋白，他们发现，肠上皮细胞中的细胞外Ca2+激活了钙敏感受体（CaSR），进而导致Wnt5a 的转录和翻译。首先Wnt5a表现出自分泌信号，Wnt5a 同时激活了Wnt5a / Ror2 信号通路，随后在泛素连接酶的作用下导致β-catenin 降解。这些研究将为探索钙在治疗β-catenin异常表达的癌症中的作用机制提供新的思路。

Wnt 途径中平面细胞极性途径与传染性疾病和神经性疾病的联系也不容忽视。比如专性细胞内查菲埃里克菌（E. chaffeensis）具有利用非经典Wnt 途径引发人类单核细胞发生营养性大肠杆菌病（HME）的能力。这种细菌会上调Wnt 途径的几个关键组分，其中包括配体Wnt6 和Wnt10a 及信号通路中的关键基因Fzd5、Fzd59、LRP6 和TCF7，最终影响Wnt 信号的激活。Wnt/β-catenin信号通路在结核分枝杆菌感染方面也发挥了重要作用。有趣的是，近几年有研究发现分枝杆菌感染介导了非经典的Wnt 成分（Wnt5a 和Wnt6）的表达。比如Wnt5a-Fzd5 在TB 病灶的髓样细胞中被激活，以便从T 细胞中产生IFNγ，引发细胞介导的炎性免疫反应。另外，Wnt6 在结核性肉芽肿中特异的表达于巨噬细胞中，并且这种特性与Arginase1 的表达相关，与此同时与促炎因子TNFα 产生呈负相关关系。尽管两项研究都是在慢性结核感染的小鼠模型中进行的，但是特定的Wnt 配体的细胞类型可能也影响免疫细胞的极化和免疫效果。迄今为止，Wnt5a 是癌症中研究最多的Wnt/PCP 配体。但是，其他特异性较差的Wnt，例如Wnt-2、Wnt-7 和Wnt-11 在肿瘤发生发展方面也有促进作用。但是有些方面他们作用又有相互协同和竞争的地方，如Wnt5a 和受体（例如PTK7）在激活Wnt 非经典和经典信号通路上的双重作用。因此，需要做更多的工作来进一步剖析Wnt/PCP 调控的分子基础及Wnt 信号的作用机制。

近年来，人们对Wnt 信号通路的机制和功能的理解取得了巨大进步。特别是Wnt/β-catenin 稳定性调节和肿瘤发生之间的关系以及Wnt/PCP 失控导致肿瘤发生方面的机制研究取得了重要进展。但是，目前仍有许多问题悬而未决。比如Frizzleds 的具体功能，以及它在Wnt 信号通路过程中的确切作用机制；β-catenin 在信号激活中的转录调控；Wnt/Ca2+途径对感染性疾病的调控过程；Wnt/Ca2+通路与Wnt 经典信号通路的协同与拮抗作用。随着研究的不断深入，相信在不久的将来，对于Wnt 信号通路与细胞生命活动过程的关系会更加明确，这将为揭示疾病发生发展机制及靶向药物研制提供新的思路。

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