Abstract
PURPOSE: Papillary thyroid cancer (PTC), the most prevalent thyroid malignancy, is witnessing a global surge in incidence. The potassium voltage-gated channel subfamily Q member 3 (KCNQ3) is aberrantly overexpressed in PTC, yet its mechanistic contribution to oncogenesis remains unclear. Thus, we aimed to elucidate the oncogenic mechanism of KCNQ3 in PTC. METHODS: We integrated gene expression profiling interactive analysis (GEPIA), immunohistochemistry, and western blotting to assess KCNQ3 expression during PTC tumorigenesis and progression, and validated in vitro and in vivo using BALB/c nude mice. The functional roles of KCNQ3 were evaluated using wound-healing, transwell, and colony formation assays. Protein interactions were elucidated through co-immunoprecipitation, mass spectrometry (MS), and immunofluorescence, while estradiol (E(2))-mediated KCNQ3 regulation was examined using chromatin immunoprecipitation-qPCR (ChIP-qPCR). The therapeutic potential of the KCNQ channel inhibitor, XE991, was also investigated. RESULTS: KCNQ3 was upregulated in PTC and drove tumor cell proliferation and migration. Mechanistically, KCNQ3 interacted with GRB2-associated regulator of MAPK1 subtype 1(GAREM1), growth factor receptor-bound protein 2(GRB2), and SOS Ras/Rac guanine nucleotide exchange factor 1 (SOS1), activating the RAS/RAF/MAPK signaling cascade to promote oncogenesis. ChIP-qPCR revealed that E(2) enhanced KCNQ3 transcription by binding estrogen receptor alpha (ESR1) to the KCNQ3 promoter. Notably, XE991 inhibited PTC cell proliferation and migration. CONCLUSION: Our research uncovers a novel KCNQ3-driven oncogenic axis in PTC, establishing KCNQ3 as a promising therapeutic target. Our findings also establish E(2) as a KCNQ3 regulator in PTC, elucidating a mechanism underlying the female gender bias of the disease. Additionally, XE991 shows potential in PTC treatment.