Ciliogenesis in pancreatic neuroendocrine tumors: insight into the role of WDR60.

Primary cilia have emerged as key regulators in cancer biology, influencing tumor progression and therapeutic response through diverse signaling pathways. In this study, we identify WDR60, a component of the dynein-2 complex essential for retrograde intraflagellar transport, as a novel modulator of pancreatic neuroendocrine tumor (Pa-NET) behavior. Transcriptomic analysis of the GEO dataset GSE73338 revealed that WDR60 is significantly upregulated in both primary and metastatic Pa-NETs compared to normal pancreatic islets. Moreover, WDR60 expression is higher in G2 compared to G1 Pa-NETs. Functional analyses in QGP-1 cells following WDR60 silencing demonstrated broad transcriptional reprogramming with enrichment of pathways related to cell adhesion and extracellular matrix (ECM) remodeling. Notably, WDR60 knockdown reduced cell migration and enhanced adhesion without affecting cell viability or proliferation. Among the key upregulated genes were PIK3AP1, RAP1B, and RFLNA, suggesting that WDR60 is involved in regulating PI3K/AKT signaling and cytoskeletal dynamics. To explore potential therapeutic implications, we examined the effects of Ciliobrevin A (HPI-04), an inhibitor of Hedgehog signaling and ciliogenesis. HPI-04 significantly reduced WDR60 expression, impaired cell migration, and increased adhesion. RT-qPCR confirmed overlapping gene expression changes between HPI-04 treatment and WDR60 silencing, although some differences, such as CD164 regulation, suggest WDR60-independent mechanisms. Collectively, these findings identify WDR60 as a critical regulator of cell motility and adhesion in Pa-NETs via ciliary signaling and cytoskeletal remodeling. They also support the therapeutic potential of targeting cilia-associated pathways, including WDR60 and Hedgehog signaling, in the treatment of Pa-NETs.