Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan.
School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City 242, Taiwan.
Int J Mol Sci. 2023 May 22;24(10):9103. doi: 10.3390/ijms24109103.
Methionine adenosyl transferases (MATs) catalyze the synthesis of the biological methyl donor adenosylmethionine (SAM). Dysregulation of MATs has been associated with carcinogenesis in humans. We previously found that downregulation of the gene enriches the protein-associated translation process and worsens liver hepatocellular carcinoma (LIHC) prognosis. We also discovered that subcellular localization of the MAT2A protein has independently prognostic relevance in breast cancer patients. The present study aimed to examined the clinical relevance of MAT2A translocation in human LIHC. Essential methionine cycle gene expressions in TCGA LIHC datasets were analyzed using Gene Expression Profiling Interactive Analysis 2 (GEPIA2). The protein expression pattern of MAT2A was determined in the tissue array of our own LIHC cohort (n = 261) using immuno-histochemistry, and the prognostic relevance of MAT2A protein's subcellular localization expression was examined using Kaplan-Meier survival curves. LIHC patients with higher mRNA expression had a worse survival rate ( = 0.0083). MAT2A protein immunoreactivity was observed in both cytoplasm and nucleus fractions in the tissue array. Tumor tissues had elevated MAT2A protein expression in both cytoplasm and nucleus compared to their adjacent normal tissues. A higher cytoplasmic to nuclear MAT2A protein expression ratio (C/N) was found in female LIHC patients compared to that of male patients ( = 0.047). Kaplan-Meier survival curves showed that a lower MAT2A C/N correlated with poor overall survival in female LIHC patients (10-year survival rate: 29.2% vs. 68.8%, C/N ≤ 1.0 vs. C/N > 1.0, log-rank = 0.004). Moreover, we found that specificity protein 1 (SP1) may have a potential interaction with nuclear MAT2A protein, using protein-protein interaction; this we found using the GeneMANIA algorithm. We explored the possible protective effects of the estrogen axis in LIHC using the Human Protein Atlas (HPA), and found evidence supporting a possible protective effect of estrogen-related protein ESSRG in LIHC. The localization of SP1 and MAT2 appeared to be inversely associated with ESRRG expression in LIHC. The present study demonstrated the translocation of MAT2A and its prognostic relevance in female LIHC patients. Our findings suggest the potential of estrogen in SP1 regulation and localization of MAT2A, as therapeutic modalities against in female LIHC patients.
蛋氨酸腺苷转移酶（MATs）催化生物甲基供体腺苷甲硫氨酸（SAM）的合成。MATs 的失调与人类的致癌作用有关。我们之前发现，下调基因富集了与蛋白质相关的翻译过程，从而恶化了肝癌（LIHC）的预后。我们还发现，MAT2A 蛋白的亚细胞定位在乳腺癌患者中有独立的预后相关性。本研究旨在研究 MAT2A 易位在人类 LIHC 中的临床相关性。使用基因表达谱交互式分析 2（GEPIA2）分析 TCGA LIHC 数据集的必需蛋氨酸循环基因表达。使用免疫组织化学法在我们自己的 LIHC 队列（n=261）的组织阵列中确定 MAT2A 的蛋白表达模式，并使用 Kaplan-Meier 生存曲线检查 MAT2A 蛋白亚细胞定位表达的预后相关性。具有较高 mRNA 表达的 LIHC 患者的生存率较差（=0.0083）。在组织阵列中，MAT2A 蛋白免疫反应性在细胞质和核部分均可见。与相邻正常组织相比，肿瘤组织中细胞质和核中的 MAT2A 蛋白表达均升高。与男性患者相比，女性 LIHC 患者的细胞质到核 MAT2A 蛋白表达比值（C/N）更高（=0.047）。Kaplan-Meier 生存曲线显示，较低的 MAT2A C/N 与女性 LIHC 患者的总体生存率较差相关（10 年生存率：29.2%对 68.8%，C/N≤1.0 对 C/N>1.0，对数秩=0.004）。此外，我们使用蛋白质-蛋白质相互作用的 GeneMANIA 算法发现，特异性蛋白 1（SP1）可能与核 MAT2A 蛋白有潜在的相互作用。我们使用人类蛋白质图谱（HPA）探索了雌激素轴在 LIHC 中的可能保护作用，发现雌激素相关蛋白 ESSRG 在 LIHC 中可能具有保护作用的证据。SP1 和 MAT2 的定位似乎与 LIHC 中 ESRRG 表达呈负相关。本研究证明了 MAT2A 的易位及其在女性 LIHC 患者中的预后相关性。我们的研究结果表明，雌激素在 SP1 调节和 MAT2A 定位中的潜在作用，可能成为女性 LIHC 患者的治疗方法。
