Wnt/β-catenin signaling pathway in uterine leiomyoma: role in tumor biology and targeting opportunities.
Wnt/β-catenin signaling pathway in uterine leiomyoma: role in tumor biology and targeting opportunities.
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DOI：
10.1007/s11010-021-04174-6
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发表时间：
2021-09
影响因子：
4.3
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中科院分区：
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子宫肌瘤是女性生殖系统最常见的肿瘤，起源于单个转化的子宫肌层平滑肌细胞。尽管存在巨大的医学、社会心理和经济影响，但对肌瘤病理生物学的确切潜在机制仍知之甚少。信号通路的改变被认为在肌瘤生物学中起着重要作用。WnT/β-连环蛋白通路似乎参与了肌瘤发生的多个方面。例如，Wnt5b在肌瘤中过表达，Wnt/β-连环蛋白通路似乎介导了MED12突变在肿瘤发生中的作用，MED12突变是肌瘤中最常见的突变。此外，Wnt/β-Catenin途径在雌激素/孕激素处理成熟的子宫肌层或子宫肌瘤细胞时起旁分泌作用，导致WNT11和WNT16表达增加，从而诱导肌瘤干细胞增殖和肿瘤生长。在动物模型中，β-连环蛋白的结构性激活导致子宫肌层增生和子宫肌瘤样病变。Wnt/β-catenin信号通路还与肌瘤的机械转导、细胞外基质调节及相关改变密切相关，Wnt/β-catenin信号通路与雌激素、孕激素、转化生长因子β、PI3K/Akt/mTor、RAS/RAF/MEK/ERK、胰岛素样生长因子、河马和Notch信号通路之间存在串扰。最后，有证据表明，使用β-连环蛋白抑制剂抑制典型的Wnt通路可以抑制肌瘤细胞的增殖。了解子宫肌瘤发生的分子机制是有效治疗的关键。本综述中讨论的特定的Wnt/β-Catenin途径分子构成了治疗靶向的引人注目的候选分子。
Uterine leiomyoma is the most common tumor of the female reproductive system and originates from a single transformed myometrial smooth muscle cell. Despite the immense medical, psychosocial, and financial impact, the exact underlying mechanisms of leiomyoma pathobiology are poorly understood. Alterations of signaling pathways are thought to be instrumental in leiomyoma biology. Wnt/β-catenin pathway appears to be involved in several aspects of the genesis of leiomyomas. For example, Wnt5b is overexpressed in leiomyoma, and the Wnt/β-catenin pathway appears to mediate the role of MED12 mutations, the most common mutations in leiomyoma, in tumorigenesis. Moreover, Wnt/β-catenin pathway plays a paracrine role where estrogen/progesterone treatment of mature myometrial or leiomyoma cells leads to increased expression of Wnt11 and Wnt16, which induces proliferation of leiomyoma stem cells and tumor growth. Constitutive activation of β-catenin leads to myometrial hyperplasia and leiomyoma-like lesions in animal models. Wnt/β-catenin signaling is also closely involved in mechanotransduction and extracellular matrix regulation and relevant alterations in leiomyoma, and crosstalk is noted between Wnt/β-catenin signaling and other pathways are known to regulate leiomyoma development and growth such as estrogen, progesterone, TGFβ, PI3K/Akt/mTOR, Ras/Raf/MEK/ERK, IGF, Hippo, and Notch signaling. Finally, evidence suggests that inhibition of the canonical Wnt pathway using β-catenin inhibitors inhibits leiomyoma cell proliferation. Understanding the molecular mechanisms of leiomyoma development is essential for effective treatment. The specific Wnt/β-catenin pathway molecules discussed in this review constitute compelling candidates for therapeutic targeting.