Transmembrane protein 97 exhibits oncogenic properties via enhancing LRP6-mediated Wnt signaling in breast cancer.
Transmembrane protein 97 exhibits oncogenic properties via enhancing LRP6-mediated Wnt signaling in breast cancer.
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跨膜蛋白 97 通过增强乳腺癌中 LRP6 介导的 Wnt 信号传导表现出致癌特性
DOI：
10.1038/s41419-021-04211-8
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发表时间：
2021-10-06
影响因子：
9
通讯作者：
Lu D
中科院分区：
文献类型：
--
作者：
Zhu H;Su Z;Ning J;Zhou L;Tan L;Sayed S;Song J;Wang Z;Li H;Sun Q;Liu S;Sha O;Leng F;Chen X;Lu D
跨膜蛋白97（TMEM 97）的上调与多种人类癌症（包括乳腺癌）的进展和不良结局相关。最近的研究表明TMEM 97可能参与Wnt/β-catenin通路的激活。然而，TMEM 97对Wnt/β-连环蛋白信号传导作用的分子机制完全不清楚。在目前的研究中，TMEM 97被鉴定为LRP 6相互作用蛋白。TMEM 97可与LRP 6胞内结构域相互作用，并以CK 1 δ/ε依赖的方式增强LRP 6介导的Wnt信号转导。TMEM 97与LRP 6的结合促进了CK 1 δ/ε向LRP 6复合物的募集，导致LRP 6在Ser 1490处磷酸化和β-catenin的稳定。在乳腺癌细胞中，TMEM 97的敲除通过调节LRP 6磷酸化减弱了Wnt/β-catenin信号级联，导致Wnt靶基因AXIN 2、LEF 1和生存素的表达降低。TMEM 97缺陷还抑制乳腺癌细胞中的细胞活力、增殖、集落形成、迁移、侵袭和干性性质。重要的是，TMEM 97敲除通过下调乳腺癌异种移植模型中的Wnt/β-连环蛋白信号传导途径来抑制肿瘤生长。综上所述，我们的结果表明，TMEM 97是典型Wnt信号传导的正调节剂。TMEM 97介导的Wnt信号通路与乳腺癌的发生有关，靶向抑制Wnt信号通路可能成为乳腺癌治疗的一种新策略。
Upregulation of transmembrane protein 97 (TMEM97) has been associated with progression and poor outcome in multiple human cancers, including breast cancer. Recent studies suggest that TMEM97 may be involved in the activation of the Wnt/β-catenin pathway. However, the molecular mechanism of TMEM97 action on Wnt/β-catenin signaling is completely unclear. In the current study, TMEM97 was identified as an LRP6-interacting protein. TMEM97 could interact with LRP6 intracellular domain and enhance LRP6-mediated Wnt signaling in a CK1δ/ε-dependent manner. The binding of TMEM97 to LRP6 facilitated the recruitment of CK1δ/ε to LRP6 complex, resulting in LRP6 phosphorylation at Ser 1490 and the stabilization of β-catenin. In breast cancer cells, knockout of TMEM97 attenuated the Wnt/β-catenin signaling cascade via regulating LRP6 phosphorylation, leading to a decrease in the expression of Wnt target genes AXIN2, LEF1, and survivin. TMEM97 deficiency also suppressed cell viability, proliferation, colony formation, migration, invasion, and stemness properties in breast cancer cells. Importantly, TMEM97 knockout suppressed tumor growth through downregulating the Wnt/β-catenin signaling pathway in a breast cancer xenograft model. Taken together, our results revealed that TMEM97 is a positive modulator of canonical Wnt signaling. TMEM97-mediated Wnt signaling is implicated in the tumorigenesis of breast cancer, and its targeted inhibition may be a promising therapeutic strategy for breast cancer.
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