β-Catenin Attenuation Inhibits Tumor Growth and Promotes Differentiation in a BRAFV600E-Driven Thyroid Cancer Animal Model

Abstract

BRAFV600E mutation is the most frequent genetic alteration in papillary thyroid cancer (PTC). β-Catenin (Ctnnb1) is a key downstream component of canonical Wnt signaling pathway and is frequently overexpressed in PTC. BRAFV600E-driven tumors have been speculated to rely on Wnt/β-catenin signaling to sustain its growth, although many details remain to be elucidated. In this study, we investigated the role of β-catenin in BrafV600E-driven thyroid cancer in a transgenic mouse model. In BrafV600E mice with wild-type (WT) Ctnnb1 (BVE-Ctnnb1WT or BVE), overexpression of β-catenin was observed in thyroid tumors. In BrafV600E mice with Ctnnb1 knockout (BVE-Ctnnb1null), thyroid tumor growth was slowed with significant reduction in papillary architecture. This was associated with increased expression of genes involved in thyroid hormone synthesis, elevated 124iodine uptake, and serum T4. The survival of BVE-Ctnnb1null mice was increased by more than 50% during 14-month observation. Mechanistically, downregulation of MAPK, PI3K/Akt, and TGFβ pathways and loss of epithelial–mesenchymal transition (EMT) were demonstrated in the BVE-Ctnnb1null tumors. Treatment with dual β-catenin/KDM4A inhibitor PKF118–310 dramatically improved the sensitivity of BVE-Ctnnb1WT tumor cells to BRAFV600E inhibitor PLX4720, resulting in significant growth arrest and apoptosis in vitro, and tumor regression and differentiation in vivo. These findings indicate that β-catenin signaling plays an important role in thyroid cancer growth and resistance to BRAFV600E inhibitors. Simultaneously targeting both Wnt/β-catenin and MAPK signaling pathways may achieve better therapeutic outcome in BRAFV600E inhibitor-resistant and/or radioiodine-refractory thyroid cancer.

Targeting miR‐31 represses tumourigenesis and dedifferentiation of BRAFV600E‐associated thyroid carcinoma

“…Clinical investigation has shown that the cumulative RAI received by patients significantly and positively correlates with β‐catenin expression 44 . In BRAF V600E ‐induced PTC mouse model, Ctnnb1 deletion resulted in up‐regulated Nis so as to increased iodine uptake 3 . Since miR‐31 is indispensable for BRAF V600E ‐induced PTC due to its regulation on Wnt/β‐catenin pathway, we asked whether miR‐31 is involved in PTC dedifferentiation and RAI refractoriness.…”

“… 44 In BRAF V600E ‐induced PTC mouse model, Ctnnb1 deletion resulted in up‐regulated Nis so as to increased iodine uptake. 3 Since miR‐31 is indispensable for BRAF V600E ‐induced PTC due to its regulation on Wnt/β‐catenin pathway, we asked whether miR‐31 is involved in PTC dedifferentiation and RAI refractoriness. Indeed, GSEA analysis showed that low miR‐31 enriched for genes involved in thyroid hormone metabolic processes (Figure S7A ).…”

“…This oncogenic driver mutation can result in tumour progression of DTCs causing increased metastasis, cancer stemness, dedifferentiation with decreased expression of thyroid‐specific factors and resistance to radioactive iodine (RAI) therapy 2 . Moreover, recent reports show that dysregulated Wnt/β‐catenin pathway correlates with PTC dedifferentiation and that Ctnnb1 knockout (KO) impedes BRAF V600E ‐induced PTC formation and restores differentiation factors expression 3 . Therefore, to understand the molecular mechanisms and identify reliable downstream targets of BRAF V600E for PTC stratification, prognosis prediction and RAI uptake restoration is of great importance for managing advanced DTC.…”

“… 2 Moreover, recent reports show that dysregulated Wnt/β‐catenin pathway correlates with PTC dedifferentiation and that Ctnnb1 knockout (KO) impedes BRAF V600E ‐induced PTC formation and restores differentiation factors expression. 3 Therefore, to understand the molecular mechanisms and identify reliable downstream targets of BRAF V600E for PTC stratification, prognosis prediction and RAI uptake restoration is of great importance for managing advanced DTC.…”

In colon cancer cells, fascin1 functions as a mechanosensor that transforms adherens junction mechanotransduction

“…11,[14][15][16] Previous studies have also shown that inducing dedifferentiation or restoring Wnt signaling stimulates BRAF V600E -driven tumorigenesis. 11,13,18,23,68,69 Elevated Wnt signaling is also common to both the genetic mouse models of BRAF V600E -driven SCRC. 11 Consistent with that precursor intestinal lesions with BRAF V600E mutation progress to cytologic dysplasia only after they acquire Wnt pathway activity.…”