Endoplasmic Reticulum Membrane Protein Complex Regulates Cancer Stem Cells and is Associated with Sorafenib Resistance in Hepatocellular Carcinoma

Abstract

Yuan-Jie Liu,1,* Jing-Xiao Li,1,* Jie-Pin Li,1 Yi-Dou Hu,2 Zhi-Bin Ma,3 Wei Huang,1 Shen-Lin Liu,1 Xi Zou1 1Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, Jiangsu, 210029, People’s Republic of China; 2Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Zhangjiagang, Jiangsu, 215600, People’s Republic of China; 3Nanjing YOUMENG Biology Science and Technology Co. Ltd, Nanjing, Jiangsu, 210029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xi Zou; Shen-lin Liu, Email [email protected]; [email protected]: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, underscoring the need for novel therapeutic targets. This study aimed to elucidate the role of endoplasmic reticulum membrane protein complex subunit 1 (EMC1) in HCC progression and its therapeutic potential.Methods: Publicly available sequencing data and biopsy specimens were analyzed to assess EMC’s clinical value and functions in HCC. In vitro experiments validated EMC functions, and multiplex immunofluorescence analysis examined EMC-associated sorafenib resistance mechanisms. EMC1 expression was knocked down in HCC cell lines, followed by cell viability, wound healing, and transwell migration assays. Tumor growth and response to sorafenib treatment were evaluated in mouse models. Metabolomic analysis assessed changes in the TCA cycle.Results: EMC genes were aberrantly expressed in HCC, and high EMC1 expression correlated with poorer survival rates. EMC1 disruption enhanced HCC cells’ sensitivity to sorafenib, reducing cell viability, increasing apoptosis, and decreasing tumor size and weight. EMC1 maintained cancer cell stemness and promoted M2 macrophage infiltration. Metabolomic analysis revealed significant changes in the TCA cycle, indicating EMC1’s role in HCC metabolic reprogramming. Importantly, EMC1 is highly associated with sorafenib resistance, potentially linked to CTNNB1 mutation or activation.Conclusion: EMC1 plays a critical role in regulating the sorafenib resistance in HCC. Targeting EMC1 may improve HCC treatment efficacy.Keywords: endoplasmic reticulum membrane complex subunit 1, catenin beta 1, tumor stemness, M2 macrophage, sorafenib resistance

Keywords

• endoplasmic reticulum membrane complex subunit 1
• catenin beta 1
• tumor stemness
• m2 macrophage
• sorafenib resistance.