The Role of GNMT and MMP12 Expression in Determining TACE Efficacy: Validation at Transcription and Protein Levels

Abstract

Tianhao Cong,1 Chao Yang,1 Qi Cao,2 Jinrui Ren,1 Yingen Luo,1 Pei Yuan,2 Bo Zheng,2 Yu Liu,1 Hongcai Yang,1 Wendi Kang,1 Aixin Ou,1 Xiao Li1 1Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of ChinaCorrespondence: Xiao Li, Department of Interventional Therapy, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, People’s Republic of China, Tel [phone], Fax [phone], Email [email protected]: Transarterial chemoembolization (TACE) represents a significant therapeutic modality for hepatocellular carcinoma (HCC). We aimed to develop a gene signature to accurately predict patient TACE response and explore the underlying mechanisms.Methods: Three independent datasets were utilized, including GSE104580, GSE14520 and external validation from the Cancer Hospital Chinese Academy of Medical Sciences. GSE104580 was randomly partitioned into a training set and a validation set, whereas GSE14520 was categorized into a resection group and a TACE group. Logistic regression was used to develop a TACE effectiveness model. Immunohistochemistry is utilized to confirm the protein expression trends of the signature genes. Immune infiltration and functional enrichment analyses were conducted to investigate the potential underlying mechanisms.Results: A 2-gene signature consisting of glycine N-methyltransferase (GNMT) and matrix metalloproteinase-12 (MMP12) was constructed, and based on this, all the patients were assigned TACE effectiveness scores and categorized into high effectiveness (HE) and low effectiveness (LE) groups. The HE group exhibited a better prognosis than the LE group in the various cohorts (p < 0.05). In the external validation set, immunohistochemistry confirmed the expression of the signature genes exhibiting an upregulated trend of GNMT in the HE group and MMP12 in the LE group, the LE group also exhibited a poorer prognosis [for overall survival (OS), HE group: 881 days vs LE group: 273 days (p < 0.05), and for progression-free survival (PFS), HE group: 458 days vs LE group: 136 days (p < 0.05)]. Multivariate analysis in all the datasets identified LE status as an independent risk factor for OS, disease-free survival (DFS) and PFS. The infiltration level of M0 macrophages and activated mast cells in the LE group was significantly higher than in the HE group. The hypoxia signaling pathway and glycolysis pathway were significantly enriched in the LE group.Conclusion: The loss of GNMT and the overexpression of MMP12 may be critical factors influencing TACE efficacy.Keywords: hepatocellular carcinoma, transarterial chemoembolization, immune infiltration, mast cell, glucose metabolism, hypoxic microenvironment

Keywords

• hepatocellular carcinoma
• transarterial chemoembolization
• immune infiltration
• mast cell
• glucose metabolism
• hypoxic microenvironment