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SRY?related HMG box?2 role in anaplastic thyroid cancer aggressiveness is related to the fibronectin 1 and PI3K/AKT pathway.

ABSTRACT: Anaplastic thyroid cancer (ATC) is a rare thyroid tumor associated with high mortality rates; thus, the identification of novel molecular targets and the development of therapeutic strategies are urgently required. The present study aimed to investigate the role of SRY?related HMG box?2 (SOX2) in ATC cells and explore whether the underlying mechanism was associated with fibronectin 1 (FN1). The proliferative, migratory and invasive ability of ATC cell lines was investigated using Cell Counting Kit?8, colony formation, wound?healing and Transwell assays, respectively; SOX2 expression in FRO cells was knocked down using small interfering RNA and SOX2 overexpression in FRO cells was achieved using cDNA constructs; and reverse transcription?quantitative PCR and western blotting were used to identify the mechanism of action underlying the SOX?2 mediated increased in cell aggressive phenotypes. Increased protein expression levels of SOX2 protein were observed in ATC tissue, and FRO and 8505c ATC cell lines. SOX2 overexpression increased the cell viability, and proliferative, migratory and invasive abilities of FRO cell lines. SOX2 overexpression increased FN1, p65, phosphorylated PI3K and AKT expression levels, whereas the knockdown of SOX2 promoted the opposite effects. In conclusion, the present study suggested a possible model of SOX2?mediated gene regulation in ATC cells, in which the overexpression of SOX2 promoted FN1 expression via the PI3K/AKT signaling pathway to induce the aggressive phenotype of ATC. These findings may provide crucial molecular insights into ATC pathogenesis and may demonstrate potential to develop into novel therapeutic interventions for patients with ATC.

SUBMITTER: Wang P

PROVIDER: S-EPMC7002997 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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SRY‑related HMG box‑2 role in anaplastic thyroid cancer aggressiveness is related to the fibronectin 1 and PI3K/AKT pathway.

Wang Peng P Shang Jinbiao J Zhao Jianqiang J Wang Kejing K Guo Liang L Gu Jialei J Wang Wendong W

Molecular medicine reports 20200102 3

Anaplastic thyroid cancer (ATC) is a rare thyroid tumor associated with high mortality rates; thus, the identification of novel molecular targets and the development of therapeutic strategies are urgently required. The present study aimed to investigate the role of SRY‑related HMG box‑2 (SOX2) in ATC cells and explore whether the underlying mechanism was associated with fibronectin 1 (FN1). The proliferative, migratory and invasive ability of ATC cell lines was investigated using Cell Counting K ...[more]

PMID: 31922212

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Project description:BackgroundAnaplastic Thyroid Cancer (ATC) is an undifferentiated and aggressive tumor that often originates from well-Differentiated Thyroid Carcinoma (DTC) through a trans-differentiation process. Epithelial-to-Mesenchymal Transition (EMT) is recognized as one of the major players of this process. OVOL2 is a transcription factor (TF) that promotes epithelial differentiation and restrains EMT during embryonic development. OVOL2 loss in some types of cancers is linked to aggressiveness and poor prognosis. Here, we aim to clarify the unexplored role of OVOL2 in ATC.MethodsGene expression analysis in thyroid cancer patients and cell lines showed that OVOL2 is mainly associated with epithelial features and its expression is deeply impaired in ATC. To assess OVOL2 function, we established an OVOL2-overexpression model in ATC cell lines and evaluated its effects by analyzing gene expression, proliferation, invasion and migration abilities, cell cycle, specific protein localization through immunofluorescence staining. RNA-seq profiling showed that OVOL2 controls a complex network of genes converging on cell cycle and mitosis regulation and Chromatin Immunoprecipitation identified new OVOL2 target genes.ResultsCoherently with its reported function, OVOL2 re-expression restrained EMT and aggressiveness in ATC cells. Unexpectedly, we observed that it caused G2/M block, a consequent reduction in cell proliferation and an increase in cell death. This phenotype was associated to generalized abnormalities in the mitotic spindle structure and cytoskeletal organization. By RNA-seq experiments, we showed that many pathways related to cytoskeleton and migration, cell cycle and mitosis are profoundly affected by OVOL2 expression, in particular the RHO-GTPase pathway resulted as the most interesting. We demonstrated that RHO GTPase pathway is the central hub of OVOL2-mediated program in ATC and that OVOL2 transcriptionally inhibits RhoU and RhoJ. Silencing of RhoU recapitulated the OVOL2-driven phenotype pointing to this protein as a crucial target of OVOL2 in ATC.ConclusionsCollectively, these data describe the role of OVOL2 in ATC and uncover a novel function of this TF in inhibiting the RHO GTPase pathway interlacing its effects on EMT, cytoskeleton dynamics and mitosis.

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SRY?related HMG box?2 role in anaplastic thyroid cancer aggressiveness is related to the fibronectin 1 and PI3K/AKT pathway.

Publications

SRY‑related HMG box‑2 role in anaplastic thyroid cancer aggressiveness is related to the fibronectin 1 and PI3K/AKT pathway.

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