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Purpose <p>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.</p> Methods <p>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<sub>2</sub>)-mediated KCNQ3 regulation was examined using chromatin immunoprecipitation–qPCR (ChIP–qPCR). The therapeutic potential of the KCNQ channel inhibitor, XE991, was also investigated.</p> Results <p>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<sub>2</sub> enhanced KCNQ3 transcription by binding estrogen receptor alpha (ESR1) to the KCNQ3 promoter. Notably, XE991 inhibited PTC cell proliferation and migration.</p> Conclusion <p>Our research uncovers a novel KCNQ3-driven oncogenic axis in PTC, establishing KCNQ3 as a promising therapeutic target. Our findings also establish E<sub>2</sub> as a KCNQ3 regulator in PTC, elucidating a mechanism underlying the female gender bias of the disease. Additionally, XE991 shows potential in PTC treatment.</p>

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Increased KCNQ3 expression in papillary thyroid cancer promotes proliferation and migration

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月17日

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  • Qiuli Li,
  • Muyuan Liu,
  • Xuhong Song,
  • Lingzhu Xie,
  • Dongchen Liu,
  • Ting Su,
  • Yangzhan Xu,
  • Gengquan Li,
  • Bin Liang,
  • Dongyang Huang

摘要

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 (E2)-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 E2 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 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.