Increased KCNQ3 expression in papillary thyroid cancer promotes proliferation and migration

  • Cancer Cell Int. 2025 Nov 17;25(1):406. doi: 10.1186/s12935-025-04049-6.
Qiuli Li  1  2 ,  Muyuan Liu  3 ,  Xuhong Song  2 ,  Lingzhu Xie  2 ,  Dongchen Liu  1  2  4 ,  Ting Su  2 ,  Yangzhan Xu  2 ,  Gengquan Li  2 ,  Bin Liang  5 ,  Dongyang Huang  6  7
Affiliations
  • 1. Department of Central Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, China.
  • 2. Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High- Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, No. 22, Xinling Road, Shantou, 515041, China.
  • 3. Department of Head and Neck, Cancer Hospital of Shantou University Medical College, Shantou, China.
  • 4. Department of Radiotherapy, Cancer Hospital of Shantou University Medical College, No. 7 Raoping Road, Shantou, 515041, Guangdong, China.
  • 5. Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High- Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, No. 22, Xinling Road, Shantou, 515041, China. [email protected].
  • 6. Department of Central Laboratory, Cancer Hospital of Shantou University Medical College, Shantou, China. [email protected].
  • 7. Department of Cell Biology and Genetics, Key Laboratory of Molecular Biology in High- Cancer Incidence Coastal Chaoshan Area of Guangdong Higher Education Institutes, Shantou University Medical College, No. 22, Xinling Road, Shantou, 515041, China. [email protected].
PMID: 41250218 DOI: 10.1186/s12935-025-04049-6
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 (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.

Keywords
ESR1; KCNQ3; Papillary thyroid cancer; RAS/RAF/MAPK signaling pathway; XE991.
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