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.

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.

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.

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.