FOXE1 supports the tumor promotion of Gli2 on papillary thyroid carcinoma by the Wnt/β‐catenin pathway

Abstract

Papillary thyroid carcinoma (PTC) is a common malignancy in thyroid tissue. However, the molecular mechanism of PTC tumor progression remains unknown. The hedgehog (Hh) pathway is thought to play a key role during PTC development. Here we investigate the effects of glioma‐associated oncogene protein‐2 (Gli2), an important transcription factor of the Hh‐signaling pathway, on PTC. Gli2 and forkhead box E1 (FOXE1) protein levels were upregulated in tissues of PTC patients and PTC cell lines. Using the PTC cell line TPC‐1, we show that Gli2 small interfering RNA (siRNA) reduces cell proliferation, migration, and invasion; whereas overexpression of FOXE1 produces the opposite effects. Moreover, Gli2 siRNA inhibited the expression of genes implicated in the Wnt/β‐catenin pathway and that FOXE1 overexpression produces the opposite effects. Thus, it was indicated that Gli2 promoted the proliferation, migration, and invasion of TPC‐1 cells by activating Wnt/β‐catenin and FOXE1 is involved in this process. Xenograft models of PTC were also constructed, the results showed that Gli2 siRNA reduced the rate of tumor growth, FOXE1 levels, and the expression of the Wnt/β‐catenin pathway but FOXE1 overexpression reversed that effects. In conclusion, this study demonstrates that Gli2 promotes the growth of PTC tumors and TPC‐1 cell proliferation, migration, and invasion by activating the Wnt/β‐catenin pathway via FOXE1.

FOXE1 regulates migration and invasion in thyroid cancer cells and targets ZEB1

“…Our analysis of FOXE1 expression in a panel of thyroid cancer cell lines shows that FOXE1 levels inversely correlate with differentiation degree according to histological sub-type origin of cell lines, which is consistent with data on the expression patterns of FOXE1 in PTC and normal tissues by TCGA and fits with data of FOXE1 expression in a genome array of human tumors that include all histological variants (Giordano et al 2006). It should be mentioned that other recent studies have reported overexpression of FOXE1 in PTC samples as well as in K1 and TPC1 cell lines (Ding et al 2019, Ma et al 2019, which contrasts with our data. We do not have an Endocrine-Related Cancer explanation for this apparent discrepancy other than the use of different antibodies in the studies; however, our results showing lower levels of FOXE1 in PTC cells than in control cells are in agreement with data from TCGA on more than 500 samples of patients with PTC.…”

LMCD1 antisense RNA 1 (LMCD1-AS1) potentiates thyroid cancer cell growth and stemness via a positive feedback loop of LMCD1-AS1/miR-1287-5p/GLI2

“…As a core protein in Hedgehog (Hh) signaling during tumorigenesis, GLI2 has been shown to be pro-tumorigenic in pancreatic cancer (25), bladder cancer (26), and ovarian cancer (27) amongst others. Additionally, GLI2 was tumor-promoting via FOXE1 in papillary thyroid carcinoma through the Wnt/β-catenin pathway (28). In this study, we found that oncogenic GLI2 was a transcription activator of LMCD1-AS1, supporting its role in THCA regulation.…”

Tspan8-Tumor Extracellular Vesicle-Induced Endothelial Cell and Fibroblast Remodeling Relies on the Target Cell-Selective Response

“…This tempted us speculating on upregulation of Tf that was confirmed for 44 mRNA versus only 3 mRNA in AS-TEX treated EC. Strongly upregulated ARID3a mRNA promotes IFNα expression [104], BCL11a 1 binds to selective histone subunits, particularly RBP4 [105], FOXE1 together with ETV1 1 promotes telomerase reverse transcription promoter activation [106] and also affects via GLI2 1 Wnt/β-catenin pathway activation [107]. HES7 is best known for its dominant role in somitogenesis with synergistic signaling including TBX6 1 and Notch [108].…”