Papillary thyroid cancers (PTCs) account for more than 80% of all thyroid cancers (TCs). PTC generally has an indolent nature, and although the incidence of PTC continues to rise, worldwide mortality has changed only minimally (Cabanillas et al., 2016). PTC metastases occur most frequently in cervical lymph nodes, and standard treatment is effective in most patients, though PTCs can develop into more aggressive malignancies (Cabanillas et al., 2016). PTC is characterized by a predominantly papillary histological architecture, and aggressive variants of PTCs generally result in a more aggressive clinical evolution, including metastasis and a higher risk of recurrence (Coca-Pelaz et al., 2020).

BRAF plays a key role in activating the mitogen-activated protein kinase pathway. The BRAFV600E mutation can result in up to a 500-fold increase in BRAF kinase activity and induces thyroid follicular cell transformation (Wan et al., 2004). Specific expression of BRAFV600E in thyroid follicular cells initiates invasive PTC, which may ultimately transition into poorly differentiated cancer (Knauf et al., 2005). The BRAFV600E mutation seems to be associated with aggressive variants and behavior in PTC, though this notion has often been disputed (Zurnadzhy et al., 2021). There are a plethora of studies addressing the pivotal role of the BRAFV600E mutation in driving cancer aggressiveness. Indeed, the BRAFV600E mutation accounts for 60% of all mutations in thyroid cancers (Fagin and Wells, 2016), and although the presence of this mutation is associated with poor outcome in only 2–3% of PTC cases, caution is warranted.

Primary cilia (PCs) emerge from the membrane surface of thyroid follicular cells, extend to the follicular lumen, and sense the colloid environment. In humans, PCs are conserved structures in the adult thyroid gland, and all thyroid follicular cells display one cilium, or occasionally two cilia (Utrilla et al., 2015). These findings suggest that PCs play a vital role in detecting extracellular cues. Variations in the distribution and emergence of PCs have been observed in PTC, with the number of thyrocytes exhibiting cilia being decreased (Nesland et al., 1987), though variations in PCs in PTC cells have not been observed across all studies (Nesland et al., 1987, Lee, Yi, Chang et al., 2019). PC loss has been found to cause irregular dilation of thyroid follicles and induce papillary histological architecture (Lee et al., 2019), and defective ciliogenesis in thyroid tumors is significantly associated with the BRAFV600E mutation. In addition, expression of the intraflagellar transport 88 (IFT88) gene needed for ciliary assembly is decreased in BRAFV600E-driven thyroid cancer (Lee, Yi, Won et al., 2018). Accordingly, PCs may play a tumor-suppressor role and/or serve as a therapeutic target (Peixoto et al., 2020).

Taken together, findings to date suggest that PCs may be involved in the tumorigenesis of PTC. Understanding the clinical characteristics of PCs can assist in predicting the aggressiveness of PTC. In this study, we investigated the role of PCs in BRAFV600E-driven PTC and revealed the association of PCs with the BRAFV600E mutation maintaining aggressiveness.