Shen Xin, Shi Hai, Liu Lei, Chong Shujing, Han Junwei, Gu Yuping
Yan'an Medical College of Yan'an University, Yan'an City, Shaanxi Province, China.
Department of Gastrointestinal Surgery, Xi'an Daxing Hospital Affiliated to Yan'an University, No. 4999, Shanglin Road, Xi'an Economic and Technological Development Zone, Xi'an, 710082, Shaanxi Province, China.
Appl Biochem Biotechnol. 2025 Jul 3. doi: 10.1007/s12010-025-05319-9.
Gastric cancer (GC) stands as one of the most common malignancies globally, characterized by significant incidence rates. Phosphofructokinase muscle isoform (PFKM), a critical rate-limiting enzyme in glycolysis, has its expression modulated by lactate production in tumor cells. The objective of this study is to elucidate the underlying molecular mechanisms by which PFKM contributes to the pathogenesis of GC. The viability, migration, and invasion of GC cells were analyzed by CCK-8 and transwell assays. Each condition was repeated three times. The regulation of H3K18la on transcription activity of CNTNl was evaluated by·dua-luciferase reporter assay. Animal experiment was performed using nude mice with six mice in each group, and tumor growth was evaluated. Statistical analysis was performed using GraphPad Prism software with t-test, one-way or two-way ANOVA. We found that PFKM was over-expressed in GC. Downregulated PFKM restrained the viability, migration, invasion, glucose uptake, and lactate production of GC cells. Mechanically, PFKM interacted with CNTN1 and facilitated the enrichment of H3K18la at the CNTN1 promoter region. Overexpression of CNTN1 reversed the inhibitory effects of PFKM knockdown on GC progression. Our research showed that increasing PFKM levels accelerated GC development by regulating CNTN1 expression through mechanisms involving histone lactylation, which could potentially contribute to novel approaches in diagnosing and treating GC.
胃癌（GC）是全球最常见的恶性肿瘤之一，发病率很高。磷酸果糖激酶肌肉同工型（PFKM）是糖酵解中的一种关键限速酶，其表达受肿瘤细胞中乳酸生成的调节。本研究的目的是阐明PFKM促进GC发病机制的潜在分子机制。通过CCK-8和Transwell实验分析GC细胞的活力、迁移和侵袭能力。每个条件重复三次。通过双荧光素酶报告基因实验评估H3K18la对CNTNl转录活性的调控。使用裸鼠进行动物实验，每组六只小鼠，并评估肿瘤生长情况。使用GraphPad Prism软件进行统计学分析，采用t检验、单向或双向方差分析。我们发现PFKM在GC中高表达。下调PFKM可抑制GC细胞的活力、迁移、侵袭、葡萄糖摄取和乳酸生成。机制上，PFKM与CNTN1相互作用，并促进H3K18la在CNTN1启动子区域的富集。CNTN1的过表达逆转了PFKM敲低对GC进展的抑制作用。我们的研究表明，通过涉及组蛋白乳酸化的机制调节CNTN1表达，提高PFKM水平会加速GC的发展，这可能有助于GC诊断和治疗的新方法。
