2. Academic Validation
  3. DHCR7 promotes lymph node metastasis in cervical cancer through cholesterol reprogramming-mediated activation of the KANK4/PI3K/AKT axis and VEGF-C secretion

DHCR7 promotes lymph node metastasis in cervical cancer through cholesterol reprogramming-mediated activation of the KANK4/PI3K/AKT axis and VEGF-C secretion

  • Cancer Lett. 2024 Jan 9:216609. doi: 10.1016/j.canlet.2024.216609.
Xinyu Mei 1,  Jinfeng Xiong 2,  Jian Liu 1,  Anni Huang 3,  Da Zhu 4,  Yafei Huang 5,  Hui Wang 6
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China.
  • 2 Department of Gynecology and Obstetrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430022, China.
  • 3 Department of Medical, Guangxi Hospital, The First Affiliated Hospital, Sun Yat-sen University, Nanning, Guangxi, 530022, China.
  • 4 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China. Electronic address: doctorzhuda@tjh.tjmu.edu.cn.
  • 5 Department of Pathogen Biology, School of Basic Medicine, Tongji Medical College, And State Key Laboratory for Diagnosis and Treatment of Severe Zoonotic Infectious Diseases, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China. Electronic address: huangy2018@hust.edu.cn.
  • 6 Department of Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China; Department of Gynecologic Oncology, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China. Electronic address: wang71hui@zju.edu.cn.
PMID: 38211648 DOI: 10.1016/j.canlet.2024.216609
Abstract

Cervical Cancer (CC) patients with lymph node metastasis (LNM) have a poor prognosis. However, the molecular mechanism of LNM in CC is unclear, and there is no effective clinical treatment. Here, we found that 7-dehydrocholesterol reductase (DHCR7), an Enzyme that catalyzes the last step of Cholesterol synthesis, was upregulated in CC and closely related to LNM. Gain-of-function and loss-of-function experiments proved that DHCR7 promoted the invasion ability of CC cells and lymphangiogenesis in vitro and induced LNM in vivo. The LNM-promoting effect of DHCR7 was partly mediated by upregulating KN motif and ankyrin repeat domains 4 (KANK4) expression and subsequently activating the PI3K/Akt signaling pathway. Alternatively, DHCR7 promoted the secretion of vascular endothelial growth factor-C (VEGF-C), and thereby lymphangiogenesis. Interestingly, Cholesterol reprogramming was needed for the DHCR7-mediated promotion of activation of the KANK4/PI3K/Akt axis, VEGF-C secretion, and subsequent LNM. Importantly, treatment with the DHCR7 inhibitors AY9944 and tamoxifen (TAM) significantly inhibited LNM of CC, suggesting the clinical application potential of DHCR7 inhibitors in CC. Collectively, our results uncover a novel molecular mechanism of LNM in CC and identify DHCR7 as a new potential therapeutic target.

Keywords

Cervical cancer; Lymphangiogenesis; Tamoxifen; Tumor metabolism.

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