On 2 March 2024, after Associate Professor HANG Yafei from the Basic Medical Sciences, Tongji Medical College, Huazhong University of Science and Technology, and Professor WANG Hui of Tongji Hospital have published papers, developed a human tumor xenograft model of cervical cancer with high tumorigenicity and evaluated conventional and novel treatment strategies in the Journal of Translational Medicine (https://zhuanlan.zhihu.com/p/660468348), they have the latest collaboration: the publication of a paper in Cancer Letters entitled "DHCR7 promotes lymph node metastasis in cervical cancer through cholesterol reprogramming-mediated activation of the KANK4/PI3K/AKT axis and VEGF-C secretion" in Cancer Letters, revealing that DHCR7 mediates the KANK4/PI3K/AKT axis and VEGF-C secretion through cholesterol reprogramming. PI3K/AKT axis and VEGF-C secretion through reprogramming of cholesterol metabolism, thereby contributing to the molecular mechanism of lymph node metastasis in cervical cancer. This study highlights the important role of cholesterol metabolism in the development of cervical cancer, providing new insights into the understanding of the metastatic mechanisms of cervical cancer and potentially providing new targets for cervical cancer treatment and prevention.

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.

Paper link: https://pubmed.ncbi.nlm.nih.gov/38211648/