Wnt inhibitory factor 1 suppresses cancer stemness and induces cellular senescence

Abstract

Hyperactivation of the Wingless-type (Wnt)/β-catenin pathway promotes tumor initiation, tumor growth and metastasis in various tissues. Although there is evidence for the involvement of Wnt/β-catenin pathway activation in salivary gland tumors, the precise mechanisms are unknown. Here we report for the first time that downregulation of the Wnt inhibitory factor 1 (WIF1) is a widespread event in salivary gland carcinoma ex-pleomorphic adenoma (CaExPA). We also show that WIF1 downregulation occurs in the CaExPA precursor lesion pleomorphic adenoma (PA) and indicates a higher risk of progression from benign to malignant tumor. Our results demonstrate that diverse mechanisms including WIF1 promoter hypermethylation and loss of heterozygosity contribute to WIF1 downregulation in human salivary gland tumors. In accordance with a crucial role in suppressing salivary gland tumor progression, WIF1 re-expression in salivary gland tumor cells inhibited cell proliferation, induced more differentiated phenotype and promoted cellular senescence, possibly through upregulation of tumor-suppressor genes, such as p53 and p21. Most importantly, WIF1 significantly diminished the number of salivary gland cancer stem cells and the anchorage-independent cell growth. Consistent with this observation, WIF1 caused a reduction in the expression of pluripotency and stemness markers (OCT4 and c-MYC), as well as adult stem cell self-renewal and multi-lineage differentiation markers, such as WNT3A, TCF4, c-KIT and MYB. Furthermore, WIF1 significantly increased the expression of microRNAs pri-let-7a and pri-miR-200c, negative regulators of stemness and cancer progression. In addition, we show that WIF1 functions as a positive regulator of miR-200c, leading to downregulation of BMI1, ZEB1 and ZEB2, with a consequent increase in downstream targets such as E-cadherin. Our study emphasizes the prognostic and therapeutic potential of WIF1 in human salivary gland CaExPA. Moreover, our findings demonstrate a novel mechanism by which WIF1 regulates cancer stemness and senescence, which might have major implications in the field of cancer biology.

miR‐200c suppresses stemness and increases cellular sensitivity to trastuzumab in HER2+ breast cancer

“…miR‐200c can activate the Notch signalling pathway by targeting the ligand of Notch (Jagged‐1) . Additionally, miR‐200c is associated with the increased expression of ZEB‐1, which is the direct target gene of miR‐200c, and important genes in stemness‐related Wnt pathways . Bmi1 is a key member of the Hedgehog pathway.…”

Salivary gland stem cells: A review of development, regeneration and cancer

“…WNT/β-catenin signalling may play a role in regulating these cells as activity correlates with expression of CD44 in SG cancers and treatment of CICs with a WNT/β-catenin active small molecule inhibitor, LF3, blocked their self-renewal capacity (Fang et al , 2016). Indeed, WNT inhibition supresses CIC stemness and induces cellular senescence in SG squamous cell carcinoma (SCC) (Ramachandran et al , 2014), whereas activation of the WNT/β-catenin pathway, via a β-catenin gain of function approach, induces a rapidly growing, aggressive phenotype (Wend et al , 2013). While these studies did not specifically investigate the association between WNT/β-catenin and CD24/CD44 expression in SG CICs, this result suggests that dysregulated WNT/β-catenin signalling may be, at least in part, responsible for the expansion of SG CICs and tumor progression.…”

WNT signaling in glioblastoma and therapeutic opportunities

“…65 Several studies have shown that inhibition of WNT signaling via modulation of β-catenin, LEF and TCF impeded the clonogenic growth of various cancer cells. [66][67][68][69][70] In addition, WNT inhibitory factor 1 (WIF1) induced cellular senescence, thereby impeding stemness and tumor growth. 67 As two recent papers have provided excellent reviews of WNT signaling and CSCs, 71,72 this review focuses on studies conducted in GBM.…”