Key Takeaways & Executive Findings
- •• SEC61G expression is significantly correlated with glycolytic activity in LUAD, as evidenced by increased FDG uptake on PET/CT scans. • SEC61G promotes an immunosuppressive tumor microenvironment by negatively correlating with immune cell infiltration and modulating immune checkpoint genes. • Knockdown of SEC61G inhibits LUAD cell migration and downregulates key regulators of EMT and glycolysis, including HIF-1α and LDHA. • SEC61G emerges as a potential prognostic biomarker and therapeutic target for LUAD, with implications for predicting immunotherapeutic responses.
Abstract
Lung adenocarcinoma (LUAD) remains a predominant cause of cancer-related mortality globally, underscoring the urgency for targeted therapeutic strategies. The specific role and impact of the SEC61 translocon gamma subunit (SEC61G) in LUAD progression and metastasis remain largely unexplored. In this study, we use a multifaceted approach, combining bioinformatics analysis with experimental validation, to elucidate the pivotal role of SEC61G and its associated molecular mechanisms in LUAD. Our integrated analyses reveal a significant positive correlation between SEC61G expression and the glycolytic activity of LUAD, as evidenced by increased fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET)/CT scans. Further investigations show the potential influence of SEC61G on metabolic reprogramming, which contributes to the immunosuppressive tumor microenvironment (TME). Remarkably, we identify a negative association between SEC61G expression levels and the infiltration of critical immune cell populations within the TME, along with correlations with immune checkpoint gene expression and tumor heterogeneity scores in LUAD. Functional studies demonstrate that SEC61G knockdown markedly inhibits the migration of A549 and H2030 LUAD cells. This inhibitory effect is accompanied by a significant down-regulation of key regulators of tumor progression, including hypoxia-inducible factor-1 alpha (HIF-1α), lactate dehydrogenase A, and genes involved in the epithelial-mesenchymal transition pathway. In conclusion, our comprehensive analyses position SEC61G as a potential prognostic biomarker intricately linked to glycolytic metabolism, the EMT pathway, and the establishment of an immune-suppressive phenotype in LUAD. These findings underscore the potential of SEC61G as a therapeutic target and predictive marker for immunotherapeutic responses in LUAD patients.
1. Introduction
Despite advances in diagnosis and treatment, recent research highlights lung adenocarcinoma (LUAD) as a leading cause of cancer-related deaths, especially in patients without driver gene mutations [1,2]. As a result, understanding the molecular mechanisms and discovering new LUAD biomarkers are crucial.
SEC61 translocon subunit gamma (SEC61G) is a core subunit within the SEC61 complex located in the endoplasmic reticulum (ER) membrane and plays essential roles in ER protein translocation and cytoplasmic calcium (Ca2+) homeostasis, especially in hypoxic microenvironments [3‒5]. In several cancers, including breast cancer, head and neck squamous cell carcinoma, glioblastoma, and kidney cancer, SEC61G is overexpressed and acts as a cancer promoter [6‒9]. Previous studies have also implicated SEC61G as an oncogene in lung cancer that contributes to ER stress, cell proliferation, apoptosis resistance, and EGFR activation [10‒13]. SEC61G is involved in ER protein translocation, and its overexpression can disrupt ER homeostasis, leading to ER stress and promoting adaptation to the stressful tumor microenvironment, aiding in tumor cell survival and chemoresistance [10,13]. However, the potential associations between SEC61G expression and glucose metabolism, as well as epigenetic mechanisms in LUAD warrant further exploration.
SEC61G has been found to be associated with immune infiltration and the immune microenvironment in LUAD. It may modulate the immune response within the tumor by influencing the infiltration of immune cells such as T cells and macrophages [11]. A high level of SEC61G expression may affect the composition and function of immune cells within the tumor, potentially impacting the anti-tumor immune response. Interestingly, SEC61G is reportedly linked to metabolic reprogramming, such as glucose metabolism and glycolysis, in breast cancer cells [6]. This metabolic shift can provide cancer cells with a growth advantage and may impact the tumor microenvironment by altering nutrient availability and acidity.
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Changshuai Zhou, Huanhuan Cui, Yuechao Yang, Lei Chen, Mingtao Feng, Yang Gao, Deheng Li, Liangdong Li, Xin Chen, Xiaoqiu Li, Yiqun Cao (2026). SEC61 translocon gamma subunit is correlated with glycolytic activity, epithelial mesenchymal transition and the immune suppressive phenotype of lung adenocarcinoma. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2024109
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Frequently Asked Questions
What is the role of SEC61G in lung adenocarcinoma?
SEC61G is overexpressed in LUAD and correlates with glycolytic activity, promotes epithelial-mesenchymal transition, and contributes to an immunosuppressive tumor microenvironment, making it a potential prognostic biomarker and therapeutic target.
How does SEC61G affect the tumor immune microenvironment?
High SEC61G expression is negatively associated with infiltration of critical immune cells and correlates with immune checkpoint gene expression, thereby contributing to an immunosuppressive phenotype in LUAD.
What methods were used in this study?
The study combined bioinformatics analysis of multiple datasets with experimental validation, including immunohistochemistry, enrichment analysis, and functional assays such as SEC61G knockdown in A549 and H2030 LUAD cells.
What are the clinical implications of SEC61G?
SEC61G could serve as a prognostic biomarker and a predictive marker for immunotherapeutic responses, as well as a potential therapeutic target for LUAD patients.
How does SEC61G relate to glycolysis in LUAD?
SEC61G expression positively correlates with glycolytic activity, as evidenced by increased FDG uptake on PET/CT scans, and its knockdown downregulates key glycolytic regulators like HIF-1α and LDHA.
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