ARNTL2: a key player in promoting tumor aggressiveness in papillary thyroid cancer.

Background: The increasing occurrence of thyroid cancer (TC), particularly papillary thyroid cancer (PTC), highlights our need for better diagnostic indicators and new therapeutic targets. Aryl hydrocarbon receptor nuclear translocator-like 2 (ARNTL2) plays a crucial function in multiple tumor types. Accordingly, we investigated the oncogenic function and molecular pathways associated with ARNTL2 in PTC.

Methods: Our study utilized the The Cancer Genome Atlas (TCGA) database to examine ARNTL2 expression, which was subsequently confirmed in PTC tissues and cell lines employing quantitative real-time polymerase chain reaction (qRT-PCR) and western blot (WB) analysis. Herein, we evaluated PTC cell proliferation, cell cycle progression, apoptosis, migration, and invasion through Cell Counting Kit-8 (CCK-8), flow cytometry, wound-healing assay, and Transwell assay. Eventually, we determined the mechanism behind ARNTL2 in PTC via WB.

Results: In PTC, a significant ARNTL2 upregulation was observed, which exhibited a positive correlation with enhanced tumor aggressiveness. Additionally, knocking down ARNTL2 facilitated apoptosis, besides impeding cell cycle progression, cell proliferation, migration, and invasion, alongside epithelial-mesenchymal transition (EMT) in PTC. However, the outcomes were reversed when ARNTL2 was overexpressed. Enhanced expression of ARNTL2 led to an elevation in phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) phosphorylation within PTC cells, while the administration of alpelisib effectively mitigated the effects induced by upregulated ARNTL2 on EMT, PTC cell proliferation, apoptosis, and invasion.

Conclusions: Elevated ARNTL2 levels enhance PTC proliferation, migration, invasion, and EMT while inhibiting apoptosis through the cell cycle signaling, elucidating its potential as a diagnostic PTC biomarker.