Genetic Alterations in Papillary Thyroid Carcinoma With Hashimoto’s Thyroiditis： ANK3, an Indolent Maintainer of Papillary Thyroid Carcinoma

Abstract

Hashimoto’s thyroiditis (TH) is a risk factor for the occurrence of papillary thyroid carcinoma (PTC), which is considered to be the most common type of thyroid cancer. In recent years, the prevalence of PTC with TH has been increasing, but little is known about the genetic alteration in PTC with TH. This study analyzed the mutation spectrum and mutation signature of somatic single nucleotide variants (SNV) for 10 non-tumor and tumor pair tissues of PTC with TH using whole-exome sequencing. The ANK3 protein expression was evaluated by immunohistochemistry in PTC with TH and PTC samples. Moreover, the functional role of ANK3 in PTC cells was determined by CCK-8 proliferation assay, colony formation assays, cell cycle analysis, cell invasion and migration and in vivo study through overexpression assay. Our results showed three distinct mutational signatures and the C>T/G>A substitution was the most common type of SNV. Gene-set enrichment analysis showed that most of the significantly mutated genes were enriched in the regulation of actin cytoskeleton signaling. Moreover, NCOR2, BPTF, ANK3, and PCSK5 were identified as the significantly mutated genes in PTC with TH, most of which have not been previously characterized. Unexpectedly, it was found that ANK3 was overexpressed in cytoplasm close to the membrane of PTC cells with TH and in almost all PTC cases, suggesting its role as a diagnostic marker of PTC. Ectopic expression of ANK3 suppressed invasion and migration, increased apoptosis of B-CPAP and TPC-1 cells. Moreover, our findings revealed that enhanced ANK3 expression inhibits growth of PTC cells both in vitro and in vivo. Ectopic expression of ANK3 significantly enhanced E-cadherin protein expression and inhibited PTC progression, at least in part, by suppression of epithelial-mesenchymal transition (EMT). Our study shows that ANK3 exerts an anti-oncogenic role in the development of PTC and might be an indolent maintainer of PTC.

A comprehensive analysis of the prognostic and immunological role of ANK3 in pan-cancer

“…According to the literature, alterations in ANK3 and type I collagen may increase the risk of developing ureteral primary malignant melanoma ( 25 ). The ectopic expression of ANK3 significantly increased E-calcineurin expression and restricted the progression of papillary thyroid carcinoma (PTC), which suggests that ANK3 has an anti-cancer action in PTC development, and serves as the inert maintainer of PTC ( 26 ). However, Previous studies suggest the function and mechanism of ANK3 in tumor tissues are currently unknown, and need to be investigated further in future research.…”

Bioinformatic analyses reveal the prognostic significance and potential role of ankyrin 3 (ANK3) in kidney renal clear cell carcinoma

“…It has been shown that ANK3 regulates cell cycle and inhibits cell invasion in prostate cancer cells [14]. Overexpression of ANK3 promotes cell apoptosis and suppresses epithelial-mesenchymal transition in papillary thyroid carcinoma cells [16]. These findings indicate the prognostic value and tumor suppressive function of ANK3 in cancers.…”

“…ANK3 is the most abundant ankyrin in kidney [6] and plays a crucial role in membrane assembly, epithelial cell polarization, and regulation of ion channels [7][8][9]. In cancers, genetic and expression alterations of ANK3 have been reported in several studies [10][11][12][13][14][15][16]. Decreased ANK3 expression was associated with poor survival outcome in prostate cancer [14] and androgen receptor-positive breast cancer [15].…”

Acidic Growth Conditions Promote Epithelial-to-Mesenchymal Transition to Select More Aggressive PDAC Cell Phenotypes In Vitro

“…Among top downregulated genes, amphiregulin (AREG) is involved in EMT and growth in different types of cancer, including PDAC [80], while Adhesion G Protein-Coupled Receptor F1 (ADGRF1) has an important role in inducing quiescence and chemoresistance in breast cancer [81]. Other downregulated genes include Traf2-and Nck-interacting kinase (TNIK), involved in colorectal carcinogenesis via modulation of Wnt signaling pathway [82], and Ankyrin-3 (ANK3), whose knock-down was reported to decrease the growth of prostate cancer cells while promoting their invasion both in vitro and in vivo [83], and to inhibit invasive abilities of thyroid cancer cells and their tumorigenesis when ectopically expressed [84].…”