SREBP-2 promotes cancer progression through the mevalonate-Akt pathway in non-small cell lung cancer

  • Sci Rep. 2025 Jul 2;15(1):23103. doi: 10.1038/s41598-025-07437-0.
Wenjie You  #  1  2  3  4  5 ,  Lili Su  #  4  5 ,  Shuping Weng  #  6 ,  Jing Li  7 ,  Xingguang Wang  4  5 ,  Bin Liang  4  5 ,  Daowei Li  4  5 ,  Lijun Li  8 ,  Haiquan Chen  9  10  11
Affiliations
  • 1. Departments of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Dong-An Road 270#, Shanghai, 200032, China.
  • 2. Institute of Thoracic Oncology, Fudan University, Shanghai, 200032, China.
  • 3. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 4. Department of Respiratory and Critical Care Medicine, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 5. Shandong Key Laboratory of Infectious Respiratory Disease, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China.
  • 6. Institute of Immunotherapy, Fujian Medical University, Xue-Yuan Road 1#, University Town, Fuzhou, 350122, Fujian, China.
  • 7. Department of Respiratory and Critical Care Medicine, Shandong Public Health Clinical Center, Jinan, 250013, Shandong, China.
  • 8. Institute of Immunotherapy, Fujian Medical University, Xue-Yuan Road 1#, University Town, Fuzhou, 350122, Fujian, China. [email protected].
  • 9. Departments of Thoracic Surgery and State Key Laboratory of Genetic Engineering, Fudan University Shanghai Cancer Center, Dong-An Road 270#, Shanghai, 200032, China. [email protected].
  • 10. Institute of Thoracic Oncology, Fudan University, Shanghai, 200032, China. [email protected].
  • 11. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. [email protected].
  • # Contributed equally.
PMID: 40595126 DOI: 10.1038/s41598-025-07437-0
Abstract

Sterol regulatory element-binding protein-2 (SREBP-2) is a transcriptional factor, which mainly regulates cholesterogenesis-associated genes. The metabolism of Cholesterol was found to be abnormal in non-small cell lung Cancer (NSCLC). However, the clinical relevance of SREBP-2 in NSCLC has yet to be elucidated. Herein, the prognostic significance of SREBP-2 in NSCLC patients, and the functional roles of SREBP-2 in NSCLC proliferation, migration and invasion was examined. Then, therapeutic potential of targeting SREBP-2 in NSCLC was evaluated using mouse xenograft tumor models. We found that SREBP-2 was significantly increased in NSCLC, as compared with pericarcinous lung tissues. High expression of SREBP-2 was associated with poor clinical characteristics, and predicted a shorter overall survival (OS) in NSCLC patients. COX multivariate regression revealed that high SREBP-2 expression served as an independent predictor for poor OS. Biofunctional analysis showed that gene silencing of SREBP-2 abrogated the proliferation, migration and invasion of NSCLC cells, while enforced SREBP-2 promoted NSCLC cell proliferation, migration and invasion. Mechanistically, SREBP-2 was found to promote cell proliferation, migration and invasion via the mevalonate-Akt pathway in NSCLC cells. Further in vivo treatment experiments showed that SREBP inhibitor decreased NSCLC tumor growth in mouse xenograft models in vivo. In combination, this study dissected the clinical significance and oncogenic role of SREBP-2 in NSCLC progression, providing evidence that have both prognostic and therapeutic implications.

Keywords
Akt signaling pathway; Cholesterol metabolism; Non-small cell lung cancer; Prognostic indicator; Sterol regulatory element-binding protein-2.
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