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Link to original content: https://pubmed.ncbi.nlm.nih.gov/33999334
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Review
. 2021 Sep;476(9):3513-3536.
doi: 10.1007/s11010-021-04174-6. Epub 2021 May 17.

Wnt/β-catenin signaling pathway in uterine leiomyoma: role in tumor biology and targeting opportunities

Malak El Sabeh #  1 , Subbroto Kumar Saha #  1 , Sadia Afrin  1 , Md Soriful Islam  1 , Mostafa A Borahay  2
Affiliations
Review

Wnt/β-catenin signaling pathway in uterine leiomyoma: role in tumor biology and targeting opportunities

Malak El Sabeh et al. Mol Cell Biochem. 2021 Sep.

Abstract

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 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.

Keywords: Leiomyoma; Pathobiology; Signaling pathway; Uterine fibroid; Wnt/β-catenin pathway.

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Conflict of interest statement

Conflicts of interest/competing interests: The authors declare no conflict of interest.

Figures

Figure 1.
Figure 1.. Schematic diagram of canonical and noncanonical Wnt signaling pathways.
In the absence of Wnt ligand, β-catenin binds to the destruction complex formed by APC, axin, CK1 and GSK3β, resulting in the phosphorylation of β-catenin, its ubiquitination and proteosomal degradation, thus inhibiting its entry to the nucleus. In the presence of Wnt ligand, its receptor gets activated, resulting in the phosphorylation of GSK3β. This inhibits the formation of the degradation complex, freeing the β-catenin to accumulate in the cytoplasm and translocate to the nucleus, where it associates with the TCF/LEF complex, altering gene transcription related to proliferation, differentiation and survival. Wnt can also alter other cellular processes, including cell adhesion, tissue polarity and tumorigenesis, through the non-canonical pathways shown here. The two most studied non-canonical pathways are the planar cell polarity (PCP) and Wnt/Ca2+ pathways. PCP pathway is activated with Wnt binding to FZD and co-receptors such as Ryk, ROR2, or NRH which recruits Dvl. This activates Rho family GTPases and or c-Jun-N-terminal kinase (JNK). In the Wnt/Ca2+ pathway, the binding of Wnt receptor to FZD results in a temporary increase in the concentration of Ca2+ through the activation of phospholipase C (PLC) which results in the formation of inositol 1,4,5-triphosphate (IP3). IP3 increase results in the release of Ca2+ and the activation of calcium-calmodulin-dependent protein kinase II (CaMKII). Ca2+ and PLC pathway activate several regulatory proteins, including NFxB, CREB, and NFAT. Abbreviation: Wnt- Wingless-Type MMTV Integration Site Family; FZD- frizzled; LRP- low-density lipoprotein receptor-related protein; Dvl- disheveled; GSK3- glycogen synthase kinase 3; CK1- casein kinase 1; TCF/LEF- T-cell factor/lymphoid enhancer factor; RYK- Receptor Like Tyrosine Kinase; ROR- receptor tyrosine kinase-like orphan receptor; RAC- Rho family of GTPases; JNK- c-Jun N-terminal kinases; AP1- Activator protein 1; ATF2- Activating Transcription Factor 2; ROCK- Rho-associated protein kinase; RhoA- Ras homolog family member A; CaMKII- Calcium/calmodulin-dependent protein kinase type II alpha chain; PLC- Phospholipase C; PIP2- Phosphatidylinositol 4,5-bisphosphate; IP3- inositol 1,4,5-trisphosphate; NFAT- nuclear factor of activated T-cells; NF-κB- nuclear factor-κB, DAG- diacylglycerol; PKC- Protein kinase C; CDC42- Cell division control protein 42.
Figure 2.
Figure 2.. Role of Wnt signaling in mechanotransduction and extracellular matrix (ECM) alterations in uterine fibrosis.
Mechanical strain alters E-cadherin and integrinαvβ3, resulting in the release of β-catenin, and the activation of transcription of genes related to proliferation and ECM formation. Abbreviation: FAK- Focal adhesion kinase; ECM- extracellular matrix; TGFβ3- Transforming growth factor beta-3.
Figure 3.
Figure 3.. Schematic representation of the crosstalk between Wnt and other major signaling pathways in uterine fibrosis.
Several signaling pathways have been implicated in Wnt/β-catenin signaling. Estrogen and progesterone induce Wnt expression in mature myometrial cells, which exerts a pro-proliferative effect on stem cells. Wnt, progesterone, and IGF were shown to activate Akt which has phosphorylated β-catenin at Ser552, activating it and allowing it to induce the expression of its target genes. Akt activation also increases expression of downstream signaling targets of Wnt/β-catenin pathway including c-MYC and cyclin D1. Progesterone and IGF were shown to induce the expression of ERK, and Ras, an upstream activator of ERK, was shown to be degraded by the degradation complex in a similar manner to β-catenin. Hippo pathway exerts its effect through YAP/TAZ, which is activated with Wnt. Notch pathway is both activated and inhibited by Wnt/β-catenin pathway, as Wnt induces the expression of its inhibitor, NUMB, while β-catenin allows for the expression of its downstream signaling targets. Abbreviation: Wnt- Wingless-Type MMTV Integration Site Family; FZD- frizzled; LRP- low-density lipoprotein receptor-related protein; Dvl- disheveled; GSK3- glycogen synthase kinase 3; CK1- casein kinase 1; TCF/LEF- T-cell factor/lymphoid enhancer factor; Ras- ERK- extracellular signal-regulated kinases; ERα- estrogen receptor α; IGF- Insulin-like growth factor; NICD-notch intracellular domain; PI3K- phosphatidylinositol 3-kinase; AKT- protein kinase B; mTOR-mammalian target of rapamycin.
Figure 4.
Figure 4.. The structure of the small molecule inhibitors.
The structures of SM08502 and CWP232291 are not publicly available.
Figure 5.
Figure 5.. Schematic diagram of the site of action of the Wnt signaling pathway inhibitors that are in current or were in past clinical trials.
Abbreviation: Wnt- Wingless-Type MMTV Integration Site Family; FZD- frizzled; LRP- low-density lipoprotein receptor-related protein; Dvl- disheveled; GSK3- glycogen synthase kinase 3; CK1- casein kinase 1; TCF/LEF- T-cell factor/lymphoid enhancer factor; PORCN-Porcupine O-acyltransferase.
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