Wnt7a activates canonical Wnt signaling, promotes bladder cancer cell invasion, and is suppressed by miR-370-3p

Abstract

Once urinary bladder cancer (UBC) develops into muscle-invasive bladder cancer, its mortality rate increases dramatically. However, the molecular mechanisms of UBC invasion and metastasis remain largely unknown. Herein, using 5637 UBC cells, we generated two sublines with low (5637 NMI) and high (5637 HMI) invasive capabilities. Mass spectrum analyses revealed that the Wnt family protein Wnt7a is more highly expressed in 5637 HMI cells than in 5637 NMI cells. We also found that increased Wnt7a expression is associated with UBC metastasis and predicted worse clinical outcome in UBC patients. Wnt7a depletion in 5637 HMI and T24 cells reduced UBC cell invasion and decreased levels of active β-catenin and its downstream target genes involved in the epithelial-to-mesenchymal transition (EMT) and extracellular matrix (ECM) degradation. Consistently, treating 5637 NMI and J82 cells with recombinant Wnt7a induced cell invasion, EMT, and expression of ECM degradation-associated genes. Moreover, TOP/FOPflash luciferase assays indicated that Wnt7a activated canonical β-catenin signaling in UBC cells, and increased Wnt7a expression was associated with nuclear β-catenin in UBC samples. Wnt7a ablation suppressed matrix metalloproteinase 10 (MMP10) expression, and Wnt7a overexpression increased promoter activity through two TCF/LEF promoter sites, confirming that Wnt7a-mediated MMP10 activation is mediated by the canonical Wnt/β-catenin pathway. Of note, the microRNA miR-370-3p directly repressed Wnt7a expression and thereby suppressed UBC cell invasion, which was partially restored by Wnt7a overexpression. Our results have identified an miR-370-3p/Wnt7a axis that controls UBC invasion through canonical Wnt/β-catenin signaling, which may offer prognostic and therapeutic opportunities.

Extracellular Matrix in Secondary Palate Development

“…The effects on the ECM of some of the identified genes associated with cleft palate are well known for the Fgf family [ FGF8 and associated receptors in craniocynostic syndromes (101200 and 123500) and hypogonadotropic hypogonadism syndromes (612702, 147950, and 615,465)] or for the transforming growth factor superfamily causing Orofacial cleft 11 ( BMP4 , 600625), Klippel–Feil syndrome ( GDF6 , 118100), and Loeys–Dietz syndromes ( TGFB3 , 615582; TGFBR1 , 609192; TGFBR2 , 610168) and do not warrant further discussion. Other genes like EDNRA (mandibulofacial dysostosis 616367) are involved in the degradation of the ECM by regulating the expression of MMPs (Ruest et al, ); ECM degradation is also promoted by Wnt7a activity (Huang et al, ), a factor also linked to cleft palate (228930). Factors that sense changes in ECM stiffness likely play a role in palate development, since mutations in the Gordon syndrome gene PIEZO2 (114300) are associated with palatal defects (Coste et al, ).…”

<p>miR-370-3p Alleviates Ulcerative Colitis-Related Colorectal Cancer in Mice Through Inhibiting the Inflammatory Response and Epithelial-Mesenchymal Transition</p>

“…For instance, miR-370-3p acted as a tumor inhibitor in ovarian cancer, 9 cholangiocarcinoma, 10 glioma, 11 thyroid cancer 12 and bladder cancer. 13 On the contrary, some studies showed that up-regulated expression of miR-370-3p promoted the progression of prostate cancer, 14 gastric cancer 15 and Wilms tumor. 16 It has been reported that miR-370-3p is significantly down-regulated in the biopsy tissues of colon mucosa of UC patients 17 as well as in CRC tissues and cells.…”

circRNA_001275 upregulates Wnt7a expression by competitively sponging miR‑370‑3p to promote cisplatin resistance in esophageal cancer

“…miR-370-3p is located at the ∆-like homolog 1/D103 region of chromosome 14. Several reports have shown that miR-370-3p may promote the progression of bladder cancer (19) and glioma (20), and affect temozolomide sensitivity in glioblastoma (21). Furthermore, the Wnt signaling pathway plays an important role in embryogenesis and cancer development by regulating the expression of genes involved in cell proliferation, differentiation and survival (22).…”