Mesenchymal-like stemness is characterized by epithelial-mesenchymal transition (EMT). Breast cancer (BC) cell mesenchymal-like stemness is responsible for distal lung metastasis. Interrogation of databases showed that Fzd7 was closely associated with a panel of mesenchymal-related genes and a panel of stemness-related genes. Fzd7 knockdown in mesenchymal-like MDA-MB-231 and Hs578T cells reduced expression of Vimentin, Slug and Zeb1, induced an epithelial-like morphology, inhibited cell motility, impaired mammosphere formation and decreased Lgr5+ subpopulation. In contrast, Fzd7 overexpression in MCF7 cells resulted in opposite changes. Fzd7 knockdown delayed xenograft tumor formation, suppressed tumor growth, and impaired lung metastasis. Mechanistically, Fzd7 combined with Wnt5a/b and modulated expression of phosphorylated Stat3 (p-STAT3), Smad3 and Yes-associated protein 1 (Yap1). Moreover, Fzd7-Wnt5b modulated expression of collagen, type VI, alpha 1 (Col6a1). Both Wnt5b knockdown and Col6a1 knockdown disrupted BC cell mesenchymal phenotype and stemness. Taken together, Fzd7 contributes to BC cell EMT and stemness, inducing tumorigenesis and metastasis, mainly through a non-canonical Wnt5b pathway. Col6a1 is implicated in Fzd7-Wnt5b signaling, and mediates Fzd7-Wnt5b -induced mesenchymal-like stemness.

中文翻译：

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非规范 Fzd7 信号传导有助于涉及 Col6a1 的乳腺癌间充质样干细胞。

间充质样干细胞的特征是上皮间质转化 (EMT)。乳腺癌 (BC) 细胞间充质样干细胞负责远端肺转移。对数据库的询问表明 Fzd7 与一组间充质相关基因和一组干性相关基因密切相关。间充质样 MDA-MB-231 和 Hs578T 细胞中的 Fzd7 敲低降低了波形蛋白、Slug 和 Zeb1 的表达，诱导了上皮样形态，抑制了细胞运动，损害了乳腺球形成并减少了 Lgr5+ 亚群。相比之下，MCF7 细胞中的 Fzd7 过表达导致相反的变化。Fzd7 敲低延迟了异种移植肿瘤的形成，抑制了肿瘤生长，并损害了肺转移。从机制上讲，Fzd7 与 Wnt5a/b 结合并调节磷酸化 Stat3（p-STAT3）的表达，Smad3 和 Yes 相关蛋白 1 (Yap1)。此外，Fzd7-Wnt5b 调节胶原蛋白 VI 型 alpha 1 (Col6a1) 的表达。Wnt5b 敲低和 Col6a1 敲低都破坏了 BC 细胞间充质表型和干细胞。总之，Fzd7 有助于 BC 细胞 EMT 和干性，主要通过非经典 Wnt5b 途径诱导肿瘤发生和转移。Col6a1 与 Fzd7-Wnt5b 信号传导有关，并介导 Fzd7-Wnt5b 诱导的间充质样干细胞。