2. Academic Validation
  3. LncRNA CRCMSL interferes in phospholipid unsaturation to suppress colorectal cancer progression via reducing membrane fluidity

LncRNA CRCMSL interferes in phospholipid unsaturation to suppress colorectal cancer progression via reducing membrane fluidity

  • J Adv Res. 2025 Feb 5:S2090-1232(25)00075-X. doi: 10.1016/j.jare.2025.02.003.
Muhong Jiang 1,  Lijun Xu 2,  Wandie Lin 3,  Weiwei Liu 4,  Yujie Zhang 5,  Hui Wang 6,  Liang Zhao 7
Affiliations

Affiliations

  • 1 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Department of Pathology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China. Electronic address: 944613313@qq.com.
  • 2 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Department of Pathology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China. Electronic address: 774014457@qq.com.
  • 3 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China. Electronic address: wendy.lwd@foxmail.com.
  • 4 Department of Pathology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China. Electronic address: 714511642@qq.com.
  • 5 Department of Pathology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China. Electronic address: 754462281@qq.com.
  • 6 Department of Medical Oncology, Affiliated Tumour Hospital of Guangzhou Medical University, Guangzhou, China. Electronic address: wanghui_0226@126.com.
  • 7 Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Department of Pathology & Guangdong Province Key Laboratory of Molecular Tumor Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China; Department of Pathology, Shunde Hospital, Southern Medical University (The First People's Hospital of Shunde), Foshan, China. Electronic address: liangsmu@foxmail.com.
PMID: 39921055 DOI: 10.1016/j.jare.2025.02.003
Abstract

Introduction: Reprogrammed metabolism is an important basis of colorectal Cancer (CRC) progression; however, its mechanisms remain unclear. This study illustrated a novel mechanism for long noncoding RNA (lncRNA) CRCMSL in CRC, which was identified as a CRC suppressor in our previous study.

Objective: To investigate whether CRCMSL suppresses colorectal Cancer by interfering in lipid metabolism.

Methods: Potential functions of CRCMSL were predicted by GSEA, which led to lipidomics. Ferroptosis process in CRC were evaluated by protein markers, probe-reported lipid peroxidation signals and transmission electron microscopy. Order and fluidity of phospholipid bilayers were detected by Laurdan generalized polarization (GP) assays and fluorescence recovery after photobleaching (FRAP) assays, respectively. RNA pull-down and RIP assays were performed to explore the target of CRCMSL. qPCR, western blot and Enzyme activity detections were used to explore the effects of CRCMSL on the target. Orthotopic and subcutaneous xenografts in nude mice were used to validate efficacy of CRC in vivo.

Results: CRCMSL-knockdown upregulated lipid synthesis and remodeled fatty acyl chains in Phospholipids, inspiring studies on Ferroptosis and phospholipid bilayers. CRCMSL-mediated biological processes and behaviors were restored by stearoyl-CoA desaturase (SCD), a key Enzyme for the synthesis of monounsaturated fatty acids (MUFAs), suggesting that CRCMSL promotes Ferroptosis and reduces membrane fluidity by interfering in phospholipid unsaturation. The target of CRCMSL in fatty acid metabolism is Acetyl-CoA Carboxylase 1 (ACC1), a key Enzyme for de novo fatty acid synthesis. CRCMSL promoted ACC1 phosphorylation to restrict its activity. Firsocostat, an ACC oral inhibitor ND630, is a potential drug for CRC treatment in combination with CRCMSL.

Conclusion: Our study illustrated a novel mechanism of CRCMSL-ACC1 axis-associated fatty acid metabolism in CRC progression, providing laboratory evidence for the development of targeted therapies for patients with advanced CRC.

Keywords

Acetyl-CoA Carboxylase 1; CRCMSL; Colorectal cancer; Lipid metabolism; Membrane fluidity; Metastasis.

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