Increased KCNQ3 expression in papillary thyroid cancer promotes proliferation and migration

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.

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 (E₂)-mediated KCNQ3 regulation was examined using chromatin immunoprecipitation-qPCR (ChIP-qPCR). The therapeutic potential of the KCNQ channel inhibitor, XE991, was also investigated.

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 E₂ enhanced KCNQ3 transcription by binding estrogen receptor alpha (ESR1) to the KCNQ3 promoter. Notably, XE991 inhibited PTC cell proliferation and migration.

Our research uncovers a novel KCNQ3-driven oncogenic axis in PTC, establishing KCNQ3 as a promising therapeutic target. Our findings also establish E₂ as a KCNQ3 regulator in PTC, elucidating a mechanism underlying the female gender bias of the disease. Additionally, XE991 shows potential in PTC treatment.