Long noncoding RNA HOXC-AS3 remodels lipid metabolism and promotes the proliferation of transformed macrophages in the glioma stem cell microenvironment by regulating the hnRNPA1/CaM axis

Yujing Sheng; Baomin Chen; Liang Liu; Suwen Li; Shilu Huang; Shan Cheng; Zhe Li; Yifang Ping; Zhigang Gong; Jun Dong

doi:10.1016/j.heliyon.2023.e19034

Long noncoding RNA HOXC-AS3 remodels lipid metabolism and promotes the proliferation of transformed macrophages in the glioma stem cell microenvironment by regulating the hnRNPA1/CaM axis

Heliyon. 2023 Aug 9;9(8):e19034. doi: 10.1016/j.heliyon.2023.e19034. eCollection 2023 Aug.

Authors

Yujing Sheng¹, Baomin Chen¹, Liang Liu², Suwen Li¹, Shilu Huang¹, Shan Cheng¹, Zhe Li³, Yifang Ping⁴, Zhigang Gong⁵, Jun Dong¹

Affiliations

¹ Department of Neurosurgery, Second Affiliated Hospital of Soochow University, Suzhou, China.
² Department of Neurosurgery, Affiliated Nanjing Brain Hospital, Nanjing Medical University, Nanjing, Jiangsu, China.
³ State Key Laboratory of Analytical Chemistry for Life Science, Nanjing University, Nanjing, China.
⁴ Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
⁵ Department of Neurosurgery, Suzhou TCM Hospital Affiliated of Nanjing University of Chinese Medicine, Suzhou, China.

Abstract

Metabolism remodelling of macrophages in the glioblastoma microenvironment contributes to immunotherapeutic resistance. However, glioma stem cell (GSC)-initiated lipid metabolism remodelling of transformed macrophages (tMΦs) and its effect on the glioblastoma microenvironment have not been fully elucidated. Total cholesterol (TC) levels and lipid metabolism enzyme expression in macrophages in the GSC microenvironment were evaluated and found that the TC levels of tMΦs were increased, and the expression of the lipid metabolism enzymes calmodulin (CaM), apolipoprotein E (ApoE), and liver X receptor (LXR) was upregulated. Knockdown of HOXC-AS3 led to a decrease in the proliferation, colony formation, invasiveness, and tumorigenicity of tMΦs. Downregulation of CaM resulted in a decline in TC levels. HOXC-AS3 overexpression led to increases in both CaM expression levels and TC levels in tMΦs. RNA pull down and mass spectrometry experiments were conducted and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) was screened as the HOXC-AS3 binding proteins related to lipid metabolism. RIP and RNA pull down assays verified that HOXC-AS3 can form a complex with hnRNPA1. Knockdown of hnRNPA1 downregulated CaM expression; however, downregulation of HOXC-AS3 did not affect hnRNPA1 expression.TMΦs underwent lipid metabolism remodelling induced by GSC via the HOXC-AS3/hnRNPA1/CaM pathway, which enhanced the protumor activities of tMΦs, and may serve as a potential metabolic intervening target to improve glioblastoma immunotherapy.

Keywords: Glioma stem cells; HOXC-AS3; Lipid metabolism remodelling; Transformed macrophages; Tumour microenvironment.