Abstract 摘要
Branched-chain amino acid transaminase 2 (BCAT2) encodes a crucial protein involved in the initial catalysis of branched-chain amino acid (BCAA) catabolism, with emerging evidence suggesting its association with tumor progression. This study explores BCAT2 in a pan-cancer multi-omics context and evaluates its prognostic significance. We utilized a multi-database approach, analyzing cBioPortal for genetic alterations, RNA-Seq data from TCGA and GTEx for expression patterns, and RSEM for transcript analysis. Protein expression and interaction networks were assessed using the Human Protein Atlas, UniProt, and STRING. Prognostic value was determined through Cox regression analysis of TCGA clinical survival data, while immune cell infiltration across various cancers was examined using TCGA data and the TIMER2 platform. Our results revealed that BCAT2 alterations are primarily amplifications and is upregulated in various tumors, correlating with poor survival rates in several tumor types, including GBMLGG, LGG, and UVM. Elevated BCAT2 protein levels were common in pan-cancer, interacting with a range of metabolic enzymes. Additionally, BCAT2 expression significantly influenced CD4+ T cells, CD8+ T cells, and Treg cells infiltration, with varied correlations across cancer types. These findings indicate BCAT2 as a potential biomarker for cancer diagnosis and therapy, potentially regulating key metabolic and immune factors to mediate tumor progression and the microenvironment.
支链氨基酸转氨酶 2（BCAT2）编码参与支链氨基酸（BCAA）代谢初始催化的关键蛋白，现有证据表明其与肿瘤进展有关。本研究从泛癌多组学角度探讨 BCAT2，并评估其预后意义。我们采用多数据库方法，通过 cBioPortal 分析基因变异，利用 TCGA 和 GTEx 的 RNA-Seq 数据研究表达模式，使用 RSEM 进行转录分析。通过人类蛋白质图谱、UniProt 和 STRING 评估蛋白质表达和相互作用网络。通过 TCGA 临床生存数据的 Cox 回归分析确定其预后价值，使用 TCGA 数据和 TIMER2 平台研究各种癌症中的免疫细胞浸润。研究结果表明，BCAT2 的变异主要为扩增，并在多种肿瘤中上调，与 GBMLGG、LGG 和 UVM 等多种肿瘤类型的不良生存率相关。泛癌中 BCAT2 蛋白水平升高，与多种代谢酶相互作用。 此外，BCAT2 表达显著影响了 CD4+ T 细胞、CD8+ T 细胞和 Treg 细胞的浸润，在不同类型的癌症中表现出不同的相关性。这些发现表明，BCAT2 可能是一个潜在的癌症诊断和治疗生物标志物，可能通过调节关键的代谢和免疫因素来促进肿瘤进展和微环境的改变。
Subject terms: Tumour biomarkers, Tumour immunology, Cancer genetics, Cancer genomics, Cancer, Computational biology and bioinformatics
主题词：肿瘤生物标志物，肿瘤免疫学，癌症遗传学，癌症基因组学，癌症，计算生物学和生物信息学
Introduction 简介
Cancer remains a foremost cause of death and a substantial public health challenge worldwide, directly impacting both healthcare systems and the global economy1. Despite advancements in primary treatment strategies such as surgery, radiotherapy, and chemotherapy2, patients frequently face poor prognoses and survival, hindered by complications such as drug resistance and side effects3. This underscores the urgent need for novel biomarkers as therapeutic and diagnostic targets. Pan-cancer analysis, transcending traditional organ-specific approaches, offers a comprehensive perspective by integrating genomics data across various cancer types. This approach is crucial for identifying biomarker genes. By discovering and validating these biomarkers, pan-cancer analysis holds the potential to revolutionize cancer prognosis, treatment, and the understanding of cancer biology4.
癌症仍然是全球主要的死亡原因之一，对公共卫生构成了重大挑战，直接影响到医疗保健系统和全球经济 1 。尽管在主要治疗策略如手术、放疗和化疗方面取得了进展 2 ，患者仍经常面临不良预后和生存率低的问题，这主要是由于药物耐药性和副作用等并发症的阻碍 3 。这凸显了迫切需要新的生物标志物作为治疗和诊断目标的必要性。泛癌分析超越了传统的器官特异性方法，通过整合各种癌症类型的基因组数据提供了一个全面的视角。这种方法对于识别生物标志物基因至关重要。通过发现和验证这些生物标志物，泛癌分析有可能彻底改变癌症的预后、治疗和对癌症生物学的理解 4 。
Given these challenges, our study focuses on the metabolic pathways involving branched-chain amino acids (BCAAs), specifically examining the role of branched-chain amino acid transaminase 2 (BCAT2) within a pan-cancer framework. We hypothesize that BCAT2 could serve as a critical biomarker, offering new insights into cancer prognosis and therapeutic strategies.
面对这些挑战，我们的研究集中在支链氨基酸（BCAAs）代谢途径上，特别是探讨支链氨基酸转氨酶 2（BCAT2）在泛癌框架中的作用。我们假设 BCAT2 可能作为一个关键的生物标志物，为癌症预后和治疗策略提供新的见解。
Branched-chain amino acids (BCAAs)—leucine, valine, and isoleucine—are essential hydrophobic amino acids predominantly metabolized in muscle tissues5. Under normal circumstances, BCAAs participate in protein synthesis and molecular signal regulations by mediating the production of coenzyme A (CoA) and glutamate6. Recently, anomalous BCAAs metabolism was found in multiple tumors accompanied by disturbed nitrogen and carbon sources, leading tumor cells to obtain BCAAs from other circulation or peripheral tissues7,8. Emerging evidence highlights a significant correlation between dysregulated BCAA metabolism and increased cancer risk across various cancer types9.
支链氨基酸（BCAAs）——亮氨酸、缬氨酸和异亮氨酸——是必需的疏水性氨基酸，主要在肌肉组织中代谢 5 。在正常情况下，BCAAs 参与蛋白质合成和分子信号调节，通过生成辅酶 A（CoA）和谷氨酸 6 。最近的研究发现，在多种肿瘤中，BCAAs 的代谢异常伴随着氮源和碳源的紊乱，导致肿瘤细胞从其他循环或周围组织获取 BCAAs 7,8 。新兴的证据表明，BCAAs 代谢失调与多种癌症类型中癌症风险增加之间存在显著的相关性 9 。
Branched-chain amino acid transaminase (BCAT) plays a crucial role in the transamination of BCAAs, which is a reversible process to form branched-chain
支链氨基酸转氨酶（BCAT）在支链氨基酸（BCAA）的转氨基作用中发挥着关键作用，这是一个可逆过程，形成支链-酮酸（BCKA）。经过支链酮酸脱氢酶复合体（BCKDH）进行的氧化脱羧后，BCKA 转化为具有调节能量产生功能的最终代谢物，触发三羧酸循环（TCA）。BCAT2 是 BCAT 家族的一员，编码一种广泛表达的酶，催化 BCAA 代谢。近期研究表明，BCAT2 在肿瘤发展中的参与，包括其由原癌基因 c-myc 调节以及通过 BCAA 氧化分解促进癌症进展。然而，BCAT2 在癌症中的作用和机制的全面理解仍然缺乏。
To elucidate the function and mechanism of BCAT2 in pan-cancer progression and to identify its potential as a valuable biomarker for cancer diagnosis and prognosis, this study is structured as follows. We first conducted a pan-cancer bioinformatics analysis of BCAT2, encompassing gene expression and genetic alterations, along with protein-level changes. Subsequently, we performed a pan-cancer survival analysis and investigated the association of BCAT2 with immune cell infiltration, integrating molecular findings with clinical implications.
为了阐明 BCAT2 在泛癌进展中的功能和机制，并确定其作为癌症诊断和预后有价值的生物标志物的潜力，本研究结构如下。我们首先进行了泛癌生物信息学分析，涵盖基因表达和遗传改变，以及蛋白质水平的变化。随后，我们进行了泛癌生存分析，并探讨了 BCAT2 与免疫细胞浸润的相关性，将分子发现与临床意义相结合。
Results 结果
The genetic alteration of BCAT2
BCAT2 的遗传改变
Understanding that genetic alterations and epigenetic modifications can trigger abnormal gene expression, we began our analysis with BCAT2 alterations across different cancer types using the cBioPortal platform. Our findings revealed a notably high frequency of BCAT2 alterations in adrenocortical carcinoma (4.47%), primarily characterized by gene amplification. This was followed by patients with endometrial cancer exhibiting various alterations including amplification, deep deletion, multiple alterations, and mutations (Fig. 1A).
了解遗传改变和表观遗传修饰可以触发异常基因表达，我们使用 cBioPortal 平台分析了不同癌症类型中 BCAT2 的改变。我们的发现显示，BCAT2 在肾上腺皮质癌中的改变频率特别高（4.47%），主要表现为基因扩增。随后是患有子宫内膜癌的患者，这些患者表现出各种改变，包括扩增、深度缺失、多重改变和突变（图 1 A）。
Fig. 1. 图 1.
The genetic alteration of BCAT2 in pan-cancer. (A) cBioPortal tool was used to evaluate the genetic alteration of BCAT2. (B) Lollipop diagram presented the alteration sites of BCAT2. (C) RSEM quantized the transcript of BCAT2.
泛癌种中 BCAT2 的基因改变。（A）使用 cBioPortal 工具评估 BCAT2 的基因改变。（B）棒棒糖图展示了 BCAT2 的改变位点。（C）RSEM 量化了 BCAT2 的转录本。
To delve deeper into the nature of these alterations, the lollipop diagram (Fig. 1B) of mutations indicated that there existed 59 missenses, 5 splices, 2 truncating sties and 2 fusion sites in the gene structure of BCAT2, with the highest mutation frequency occurred at the missense site E153K. Complementing these findings, we employed RSEM14 for quantitative transcript analysis, revealing that the highest transcript expression of BCAT2 occurred in the amplification group on average (Fig. 1C).
为了更深入地了解这些改变的本质，棒图（图 B）显示，在 BCAT2 基因结构中存在 59 个错义突变、5 个剪接突变、2 个截断突变位点和 2 个融合位点，其中错义突变位点 E153K 的突变频率最高。这些发现得到了补充，我们使用 RSEM（相对序列表达量分析）进行定量转录分析，结果显示 BCAT2 在扩增组中的平均转录表达量最高（图 C）。
The expression analysis of BCAT2 in pan-cancer
泛癌种中 BCAT2 的表达分析
Building on our genetic analysis, we next explored BCAT2 gene expression across various cancer types using the TCGA pan-cancer database. Our results revealed that after multiple testing adjustment, BCAT2 was upregulated in 12 tumor types compared to normal tissues, including BLCA, BRCA, CESC, CHOL, GBM, HNSC, KICH, KIRP, LIHC, PRAD, STAD, and UCEC. Notably, higher BCAT2 expression was observed in HPV-positive HNSC compared to HPV-negative HNSC, and in metastatic SKCM relative to primary SKCM tumors. Conversely, BCAT2 expression was downregulated in COAD, PCPG, and THCA tumors (Fig. 2A).
在进行遗传分析的基础上，我们接着使用 TCGA 泛癌数据库探索了 BCAT2 基因在各种癌症类型中的表达情况。结果显示，在多重检验校正后，与正常组织相比，BCAT2 在 12 种肿瘤类型中上调，包括 BLCA、BRCA、CESC、CHOL、GBM、HNSC、KICH、KIRP、LIHC、PRAD、STAD 和 UCEC。值得注意的是，在 HPV 阳性 HNSC 中观察到 BCAT2 表达高于 HPV 阴性 HNSC，而在转移性 SKCM 中 BCAT2 表达高于原发性 SKCM 肿瘤。相反，BCAT2 在 COAD、PCPG 和 THCA 肿瘤中下调（图 2 A）。
Fig. 2. 图 2.
BCAT2 expression profile in pan-cancer. (A) The expression of BCAT2 in normal and tumor tissues from TCGA database. (B) BCAT2 expression in paired normal and tumor tissues from TCGA database. (C) Pan-cancer expression of BCAT2 between tumor tissues from TCGA database and normal tissues from GTEx database. *q-value < 0.05; **q-value < 0.01; ***q-value < 0.001.
BCAT2 在泛癌中的表达谱。(A) TCGA 数据库中正常组织和肿瘤组织的 BCAT2 表达。(B) TCGA 数据库中配对的正常组织和肿瘤组织的 BCAT2 表达。(C) TCGA 数据库中肿瘤组织与 GTEx 数据库中正常组织的 BCAT2 泛癌表达。*q 值<0.05；**q 值<0.01；***q 值<0.001。
To strengthen these findings, we examined BCAT2 expression in paired tumor and normal tissues. This analysis indicated elevated BCAT2 levels in BRCA, CHOL, HNSC, KIRP, LIHC, PRAD, and STAD tumors, whereas lower levels were observed in LUAD, READ, and THCA tumors (Fig. 2B).
为了进一步验证这些发现，我们检测了肿瘤组织和正常组织中 BCAT2 的表达水平。分析结果显示，在 BRCA、CHOL、HNSC、KIRP、LIHC、PRAD 和 STAD 肿瘤中 BCAT2 水平升高，而在 LUAD、READ 和 THCA 肿瘤中 BCAT2 水平较低（图 2 B）。
Further validation was achieved by integrating data from both the TCGA and GTEx databases, comparing BCAT2 expression in normal and tumor tissues. This comprehensive comparison showed increased BCAT2 expression in 10 tumor types: BRCA, CHOL, DLBC, GBM, HNSC, KICH, KIRP, LIHC, PRAD, and THYM. In contrast, decreased expression was noted in ACC, ESCA, KIRC, LAML, LGG, LUAD, LUSC, OV, PAAD, PCPG, READ, SKCM, STAD, TGCT, THCA, and UCS compared to their respective normal tissues (Fig. 2C).
进一步通过整合 TCGA 和 GTEx 数据库的数据，比较 BCAT2 在正常组织和肿瘤组织中的表达情况，进行了全面验证。结果显示，BCAT2 在 10 种肿瘤类型中表达上调：BRCA、CHOL、DLBC、GBM、HNSC、KICH、KIRP、LIHC、PRAD 和 THYM。相比之下，在 ACC、ESCA、KIRC、LAML、LGG、LUAD、LUSC、OV、PAAD、PCPG、READ、SKCM、STAD、TGCT、THCA 和 UCS 中，BCAT2 的表达下调（图 2 C）。
Combining these analysis, we concluded that BCAT2 is consistently upregulated in BRCA, CHOL, HNSC, KIRP, LIHC, and PRAD tumors, while it is downregulated in THCA tumors. These expression difference between tumor and normal samples further underscored the potential role of BCAT2 as tumor progression biomarker. The upregulation of BCAT2 in multiple cancer types aligns with previous findings on its role in metabolic reprogramming15, where cancer cells rely on BCAA metabolism to support their growth and survival. BCAT2 promotes BCAA uptake and sustains BCAA catabolism, providing essential nutrients and energy for tumor progression. This suggests that these tumors may depend heavily on BCAA metabolism for their advancement16. However, the mechanism underlying BCAT2 downregulation in THCA tumors has not been well characterized, and its potential role in thyroid cancer progression remains to be verified, indicating a need for further investigation.
结合这些分析，我们得出结论，BCAT2 在 BRCA、CHOL、HNSC、KIRP、LIHC 和 PRAD 肿瘤中持续高表达，而在 THCA 肿瘤中则低表达。肿瘤样本与正常样本之间的表达差异进一步强调了 BCAT2 可能作为肿瘤进展生物标志物的作用。BCAT2 在多种癌症类型中的高表达与之前关于其在代谢重编程中作用的发现相一致，癌细胞依赖于支链氨基酸（BCAA）代谢来支持其生长和生存。BCAT2 促进 BCAA 的摄取并维持 BCAA 的代谢，为肿瘤进展提供必要的营养和能量。这表明这些肿瘤可能严重依赖 BCAA 代谢来促进其发展。然而，THCA 肿瘤中 BCAT2 下调的机制尚未得到充分研究，其在甲状腺癌进展中的潜在作用仍需验证，这表明需要进一步研究。
The protein abundance of BCAT2
BCAT2 蛋白的丰度
Having investigated the genetic alterations and gene expression of BCAT2, we next proceeded to analyze its protein abundance across various tissues. The distribution of BCAT2 protein abundance was initially examined (Fig. 3A). Notably, high BCAT2 expression was observed in a broad range of tissues, with particularly elevated levels in the adrenal gland, bladder, nerve, ovary, and prostate, whereas blood exhibited lower expression.
在研究了 BCAT2 的基因突变和基因表达后，我们接下来分析了其在各种组织中的蛋白质丰度。首先检查了 BCAT2 蛋白质丰度的分布情况（图 3 A）。值得注意的是，BCAT2 在多种组织中表达较高，特别是在肾上腺、膀胱、神经、卵巢和前列腺中水平特别高，而血液中的表达较低。
Fig. 3. 图 3.
The protein expression level of BCAT2 in pan-cancer. (A) The protein level of BCAT2 in normal tissues from GTEx database. (B,C) The protein expression of BCAT2 in tumor and normal tissues from HPA database. (D) BCAT2 location in the substructure of cells obtained from from UniProt database. (E) Interaction relationship of BCAT2 protein.
BCAT2 在泛癌种中的蛋白质表达水平。（A）来自 GTEx 数据库的正常组织中 BCAT2 的蛋白质水平。（B、C）来自 HPA 数据库的肿瘤和正常组织中 BCAT2 的蛋白质表达。（D）来自 UniProt 数据库的细胞亚结构中 BCAT2 的位置。（E）BCAT2 蛋白质的相互作用关系。
Further analysis using the Human Protein Atlas (HPA) database revealed that BCAT2 expression was highest in colorectal cancer, prostate cancer, breast cancer, endometrial cancer, and ovarian cancer (Fig. 3B). This widespread expression pattern was also consistent across various tissues, with the exception of bone marrow, caudate, cerebellum, hippocampus, skeletal muscle, smooth muscle, and adipose tissues, where BCAT2 was not expressed (Fig. 3C), suggesting that its function is more relevant in specific tissue environments and less critical in others, particularly those with lower proliferative activity.
进一步使用人类蛋白质图谱（HPA）数据库分析发现，BCAT2 表达在结直肠癌、前列腺癌、乳腺癌、子宫内膜癌和卵巢癌中最高（图 B）。这种广泛的表达模式在各种组织中也是一致的，除了骨髓、壳核、小脑、海马、骨骼肌、平滑肌和脂肪组织外，BCAT2 在这些组织中未表达（图 C），这表明其功能在特定组织环境中更为相关，而在其他组织中则不那么关键，尤其是那些增殖活性较低的组织。
Exploring the subcellular localization of BCAT2 through the UniProt database, we found its presence in both the mitochondrion and nucleoplasm (Fig. 3D). This subcellular localization suggests roles in both energy metabolism and nuclear processes. The presence of BCAT2 in the mitochondria suggests its role in enhancing the utilization of BCAA, which directly supports mitochondrial respiration by providing crucial metabolites for energy production16. In the nucleoplasm, BCAT2 participates in regulatory processes that influence gene expression or nuclear signaling pathways, potentially linking metabolic status to nuclear functions involved in tumor cell proliferation and survival17,18.
通过 UniProt 数据库探索 BCAT2 的亚细胞定位，我们发现它存在于线粒体和核质中（图 D）。这种亚细胞定位表明 BCAT2 在能量代谢和核过程方面都发挥着作用。BCAT2 存在于线粒体中，表明它在增强支链氨基酸（BCAA）的利用方面的作用，这直接支持了线粒体呼吸，为其提供了关键的代谢物以产生能量（ 16 ）。在核质中，BCAT2 参与调节过程，影响基因表达或核信号通路，可能将代谢状态与涉及肿瘤细胞增殖和生存的核功能联系起来（ 17,18 ）。
Finally, our analysis of the protein-protein interaction (PPI) network indicated that BCAT2 interacts with multiple metabolic proteins, such as GCLC and BCK (Fig. 3E). These interactions highlight the potential involvement of BCAT2 in key metabolic pathways, further supporting its role in cancer metabolism and progression.
最后，我们对蛋白质-蛋白质相互作用（PPI）网络的分析表明，BCAT2 与多种代谢蛋白相互作用，如 GCLC 和 BCK（图 E）。这些相互作用突显了 BCAT2 在关键代谢途径中潜在的作用，进一步支持了其在癌症代谢和进展中的作用。
The correlation of BCAT2 with pan-cancer prognosis
BCAT2 与泛癌预后的相关性
After conducting an in-depth bioinformatics analysis of BCAT2, we further analyzed the significance of BCAT2 in pan-cancer clinical prognosis. Initially, we scrutinized the BCAT2 gene expression across different stages of tumors, guided by WHO cancer staging criteria. BCAT2 exhibited decreased expression in later stages of BLCA (P = 0.009, Fig. 4A), in contrast to increased expression in advanced stages of UVM and HNSC (P = 0.035 and 0.040 respectively, Fig. 4B,D). For THCA tumors, a unique expression pattern was observed: BCAT2 gene expression levels increased in stage II (P = 0.009) but decreased in advanced stages (P = 0.004 and 0.008 respectively, Fig. 4C). After adjusting the p-values, we still observed a significant expression pattern indicating progression in both THCA and HNSC. Additionally, we fitted a linear regression for UVM, revealing a significant increasing linear trend (P = 0.0044), indicating that as the tumor progressed, BCAT2 expression steadily increased.
在深入进行 BCAT2 的生物信息学分析后，我们进一步分析了 BCAT2 在泛癌种临床预后中的重要性。首先，我们根据 WHO 癌症分期标准，审视了不同肿瘤阶段的 BCAT2 基因表达情况。BCAT2 在 BLCA 晚期阶段的表达量降低（P=0.009，图 4 A），而在 UVM 和 HNSC 的晚期阶段表达量增加（P=0.035 和 0.040，图 4 B、D）。对于 THCA 肿瘤，观察到一种独特的表达模式：BCAT2 基因表达水平在第二阶段增加（P=0.009），但在晚期阶段减少（P=0.004 和 0.008，图 4 C）。在调整 p 值后，我们仍然观察到 BCAT2 在 THCA 和 HNSC 中的显著表达模式，表明其与肿瘤进展相关。此外，我们为 UVM 拟合了一条线性回归，结果显示有显著的线性增加趋势（P=0.0044），表明随着肿瘤的进展，BCAT2 的表达量稳步增加。
Fig. 4. 图 4.
Variations in BCAT2 expression across different stages. *P < 0.05; **P < 0.01; ***P < 0.001; ns: non-significant.
不同阶段 BCAT2 表达量的变化。*P < 0.05; **P < 0.01; ***P < 0.001; ns: 无统计学意义。
We then aimed to elucidate the relationship between BCAT2 gene expression and the survival of cancer patients, after leveraging significant findings from prior research and using available data from relevant databases. The top three quartiles of BCAT2 gene expression were defined high expression category19. The divergence in survival outcomes across different cancers suggests that BCAT2 may play contrasting roles, either as a pro-survival factor or as a driver of tumor progression, depending on the cancer type. For instance, the association between high BCAT2 expression and better OS in KIRP and PAAD could indicate that BCAT2 supports metabolic processes that sustain tumor homeostasis without driving aggressive tumor behavior. In contrast, poorer OS in GBMLGG, LGG, and UVM patients with high BCAT2 expression suggests that BCAT2 may contribute to a more aggressive tumor phenotype in these cancer types, possibly through enhanced BCAA metabolism and cell proliferation (Fig. 5).
然后我们旨在通过利用前期研究的重要发现，并利用相关数据库中的可用数据，阐明 BCAT2 基因表达与癌症患者生存之间的关系。BCAT2 基因表达的前三四分位数被定义为高表达类别 19 。不同癌症中生存结果的差异表明，BCAT2 可能在不同癌症类型中扮演着不同的角色，既可以作为促进生存的因素，也可以作为肿瘤进展的驱动因素。例如，在 KIRP 和 PAAD 中，高 BCAT2 表达与更好的总生存期（OS）相关，这可能表明 BCAT2 支持维持肿瘤稳态的代谢过程，而不促进肿瘤的侵袭性行为。相反，在 GBMLGG、LGG 和 UVM 中，高 BCAT2 表达与较差的 OS 相关，这表明 BCAT2 可能在这些癌症类型中促进更具侵袭性的肿瘤表型，可能是通过增强支链氨基酸（BCAA）代谢和细胞增殖（图 5 ）。
Fig. 5. 图 5.
BCAT2 gene expression and the overall survival of pan-cancer patients. (A–E) The correlation between BCAT2 expression and OS of indicated cancer patients was discovered using data from TCGA database.
BCAT2 基因表达与泛癌种患者总生存期的关系。（A-E）通过 TCGA 数据库数据发现，BCAT2 表达与特定癌种患者总生存期之间的相关性。
Delving deeper, univariate Cox regression analysis using TCGA data linked high BCAT2 expression with decreased OS in LGG, PCPG, and UVM patients, but a favorable OS in BLCA, BRCA, KIRP, and PAAD cases (Fig. 6A). Disease-specific survival (DSS) analysis classified high BCAT2 expression as a protective biomarker for BLCA, KIRP, and PAAD, and as a risk marker for LGG, PCPG, PRAD, THCA, THYM, and UVM (Fig. 6B). Disease-free interval (DFI) assessments, defined as time from treatment completion to disease recurrence or death, showed BCAT2 acting as a contributor in DLBC, LGG, PCPG, and UVM and as an inhibitor in BLCA, KIRP, and PAAD (Fig. 6C). Additionally, BCAT2 was established as a protective factor for KIRP patients in progression-free interval (PFI), defined as time from the start of treatment to disease progression or death, reflecting treatment effectiveness, analysis (Fig. 6D).
进一步分析，使用 TCGA 数据进行单变量 Cox 回归分析发现，BCAT2 表达在 LGG、PCPG 和 UVM 患者中与 OS 降低相关，但在 BLCA、BRCA、KIRP 和 PAAD 患者中与 OS 改善相关（图 6 A）。疾病特异性生存（DSS）分析将 BCAT2 高表达分类为 BLCA、KIRP 和 PAAD 的保护性生物标志物，而 LGG、PCPG、PRAD、THCA、THYM 和 UVM 的危险性生物标志物（图 6 B）。无病间隔期（DFI）评估，定义为从治疗完成到疾病复发或死亡的时间，显示 BCAT2 在 DLBC、LGG、PCPG 和 UVM 中起促进作用，在 BLCA、KIRP 和 PAAD 中起抑制作用（图 6 C）。此外，BCAT2 在进展自由间隔期（PFI）中被确定为 KIRP 患者的保护因素，PFI 定义为从治疗开始到疾病进展或死亡的时间，反映了治疗效果（图 6 D）。
Fig. 6. 图 6.
Cox regression analysis of BCAT2. (A–D) The univariate Cox regression of BCAT2 for the OS, DSS, DFI and PFI in TCGA pan-cancer patients was presented by forest maps. After adjusting for p-values, we still observe significant correlations between OS and BCAT2 expression in KIRP, LGG, PAAD, and UVM. For DSS, significant correlations are found in KIRP, LGG, PAAD, PCPG, THCA, THYM, and UVM. No significant correlations were observed for DFI, while for PFI, significant associations remain for LGG, KIRP, PAAD, PCPG, and UVM.
BCAT2 的 Cox 回归分析。（A–D）通过森林图展示了 BCAT2 在 TCGA 泛癌种患者中对 OS、DSS、DFI 和 PFI 的单变量 Cox 回归分析结果。经过调整 p 值后，我们仍然观察到 BCAT2 表达与 OS 在 KIRP、LGG、PAAD 和 UVM 中存在显著相关性。对于 DSS，显著相关性出现在 KIRP、LGG、PAAD、PCPG、THCA、THYM 和 UVM 中。未观察到 DFI 的显著相关性，而对于 PFI，显著关联仍然存在于 LGG、KIRP、PAAD、PCPG 和 UVM 中。
Overall, these findings highlight a complex, cancer-type-specific role for BCAT2, underscoring the need for a deeper understanding of its mechanisms in different cancer types. Further studies are necessary to explore the biological underpinnings of these associations, particularly the metabolic and signaling pathways that BCAT2 regulates in distinct tumor environments. Understanding these mechanisms will be crucial for developing targeted therapies that could modulate BCAT2 activity in a context-dependent manner.
总体而言，这些发现突显了 BCAT2 在不同癌症类型中复杂而特定的作用，强调了对其在不同癌症类型中机制进行更深入理解的必要性。有必要进一步研究这些关联的生物学基础，特别是 BCAT2 在不同肿瘤环境中调节的代谢和信号通路。了解这些机制对于开发能够根据具体环境调节 BCAT2 活性的靶向疗法至关重要。
Analysis of BCAT2 and immune cell infiltration
BCAT2 和免疫细胞浸润分析
Building on our previous investigations, we conducted a correlation analysis using the TIMER2 database to evaluate the association between BCAT2 expression and immune cell infiltration across various cancer types. Our analysis revealed diverse interactions between BCAT2 expression and different subsets of immune cells.
在我们之前的研究所基础上，我们使用 TIMER2 数据库进行了相关性分析，评估 BCAT2 表达与不同癌症类型中免疫细胞浸润之间的关联。我们的分析揭示了 BCAT2 表达与不同免疫细胞亚群之间多种多样的相互作用。
Specifically, BCAT2 expression positively correlated with naïve CD4+ T cells in BLCA, SKCM, and THCA; with both CD4+ T cells and CD4+ Th cells in HNSC; and with CD4+ Th cells in LGG, SARC, and READ. Conversely, a negative correlation was observed with non-regulatory CD4+ T cells in GBM; with CD4+ Th cells in BLCA and TGCT; and with CD4+ memory cells in BRCA, KIRC, and THCA (Fig. 7A). Regarding CD8+ T cells, BCAT2 expression exhibited a significant positive correlation in CESC, HNSC-HPV(+), and UVM. However, negative correlations were identified in BRCA, KIRC, KIRP, PCPG, SKCM, and THYM (Fig. 7B). In the context of Treg cells, BCAT2 expression was positively associated with Treg cells in HNSC-HPV(+), LUAD, and TGCT, but negatively correlated with Treg cells in KIRP and THCA (Fig. 7C).
具体而言，在 BLCA、SKCM 和 THCA 中，BCAT2 表达与初始 CD4+ T 细胞呈正相关；在 HNSC 中，BCAT2 表达与 CD4+ T 细胞和 CD4+ Th 细胞呈正相关；在 LGG、SARC 和 READ 中，BCAT2 表达与 CD4+ Th 细胞呈正相关。相反，在 GBM 中，BCAT2 表达与非调节性 CD4+ T 细胞呈负相关；在 BLCA 和 TGCT 中，BCAT2 表达与 CD4+ Th 细胞呈负相关；在 BRCA、KIRC 和 THCA 中，BCAT2 表达与 CD4+ 记忆细胞呈负相关（图 7 A）。关于 CD8+ T 细胞，BCAT2 表达在 CESC、HNSC-HPV+和 UVM 中与 CD8+ T 细胞呈显著正相关。然而，在 BRCA、KIRC、KIRP、PCPG、SKCM 和 THYM 中，BCAT2 表达与 CD8+ T 细胞呈负相关（图 7 B）。在调节性 T 细胞（Treg 细胞）方面，BCAT2 表达在 HNSC-HPV+、LUAD 和 TGCT 中与 Treg 细胞呈正相关，但在 KIRP 和 THCA 中与 Treg 细胞呈负相关（图 7 C）。
Fig. 7. 图 7.
Immune infiltration analysis of BCAT2. (A) The expression of BCAT2 was correlated with CD4+ T cell infiltration by analyzing on TIMER2 database. (B) The correlation between BCAT2 expression and the infiltration of CD8+ T cells on TIMER2 database. (C) BCAT2 expression was associated to Treg cells infiltration in pan-cancer using data from TIMER2 database. *P < 0.05; **P < 0.01; ***P < 0.001.
BCAT2 的免疫浸润分析。（A）通过分析 TIMER2 数据库，BCAT2 的表达与 CD4+ T 细胞浸润呈正相关。（B）通过分析 TIMER2 数据库，BCAT2 的表达与 CD8+ T 细胞浸润呈正相关。（C）通过 TIMER2 数据库的数据，在泛癌种中 BCAT2 的表达与调节性 T 细胞浸润相关。*P < 0.05；**P < 0.01；***P < 0.001。
These findings underscore the complex role of BCAT2 in modulating the immune microenvironment across different cancer types. By influencing the infiltration and activity of various immune cell subsets, BCAT2 may play a pivotal role in tumor immunity and progression. This highlights the importance of further investigating the mechanisms of BCAT2 in immune regulation to better understand its potential as a therapeutic target in cancer.
这些发现强调了 BCAT2 在不同癌症类型中调节免疫微环境的复杂作用。通过影响各种免疫细胞亚群的浸润和活性，BCAT2 可能在肿瘤免疫和进展中发挥关键作用。这突显了进一步研究 BCAT2 在免疫调节机制中的重要性，以便更好地理解其作为癌症治疗靶点的潜力。
Discussion 讨论
Early identification and successful therapy are crucial factors in enhancing the outcomes in cancer patients. The accumulation of diverse genetic changes that manifest novel antigens on cancer cell surfaces is critical to tumor development. By conducting pan-cancer analysis, we can uncover the commonalities and distinctions among various types of cancer, offering valuable insights for crafting tailored strategies for cancer prevention and personalized treatment. Recent studies have increasingly concentrated on multi-omics pan-cancer analysis to uncover gene mutations, RNA alterations, and cancer-promoting genes linked to cancer initiation and progression. These findings are important in facilitating early cancer detection and pinpointing influential biomarkers.
早期识别和成功治疗是提高癌症患者预后的关键因素。癌细胞表面出现的新抗原是多种遗传变化累积的结果，对于肿瘤的发展至关重要。通过进行泛癌分析，我们可以发现不同类型的癌症之间的共性和差异，为制定个性化的癌症预防和治疗策略提供宝贵见解。近年来，越来越多的研究集中在泛癌多组学分析上，以揭示与癌症发生和进展相关的基因突变、RNA 改变和致癌基因。这些发现对于早期癌症检测和确定关键生物标志物具有重要意义。
In this study, we identified that BCAT2 was significantly upregulated in several cancer types, including BRCA, CHOL, HNSC, KIRP, LIHC, and PRAD, while it was notably downregulated in THCA tumors. The upregulation of BCAT2 in these cancers may reflect its critical role in metabolic reprogramming, where cancer cells rely on BCAA metabolism to fuel tumor growth and survival. By promoting BCAA catabolism, BCAT2 supports mitochondrial respiration and provides essential metabolites for energy production, which may be particularly important in metabolically active tumors like BRCA and HNSC17,20. Conversely, the downregulation of BCAT2 in THCA suggests a distinct metabolic dependency in thyroid cancers, possibly indicating a unique regulatory mechanism that warrants further investigation.
在本研究中，我们发现 BCAT2 在包括 BRCA、CHOL、HNSC、KIRP、LIHC 和 PRAD 等多种癌症类型中显著上调，而在 THCA 肿瘤中则显著下调。BCAT2 在这些癌症中的上调可能反映了其在代谢重编程中的关键作用，癌细胞依赖 BCAA 代谢来促进肿瘤生长和存活。通过促进 BCAA 的分解代谢，BCAT2 支持线粒体呼吸并提供能量生产所需的代谢物，这在 BRCA 和 HNSC 等代谢活跃的肿瘤中尤为重要。相反，THCA 中 BCAT2 的下调表明甲状腺癌可能存在不同的代谢依赖性，这可能表明一种独特的调节机制，值得进一步研究。
Additionally, our findings align with previous studies showing that BCAT2 overexpression is linked to poorer prognosis in some cancer types20, such as GBMLGG, LGG, and UVM, likely due to its role in enhancing tumor cell proliferation and invasiveness through increased metabolic activity. However, we also observed a contrasting trend in other cancer types21, like KIRP and PAAD, where high BCAT2 expression was associated with improved survival, suggesting a more regulatory or protective role in these tumors, potentially supporting tumor homeostasis. These contrasting outcomes highlight the cancer-type-specific role of BCAT2, and further mechanistic investigation is needed to clarify how BCAT2 contributes to tumor progression and prognosis across different cancers.
此外，我们的研究结果与之前的研究一致，这些研究显示 BCAT2 的过表达与某些癌症类型（如 GBMLGG、LGG 和 UVM）较差的预后相关，这可能是因为 BCAT2 在增强肿瘤细胞增殖和侵袭性方面发挥了作用，通过增加代谢活性。然而，在其他癌症类型（如 KIRP 和 PAAD）中，我们观察到 BCAT2 表达水平较高与更好的生存率相关，这表明 BCAT2 在这些肿瘤中可能具有更调节性或保护性的作用，可能支持肿瘤稳态。这些不同的结果突显了 BCAT2 在不同癌症类型中的特定作用，进一步的机制研究是必要的，以阐明 BCAT2 在不同癌症中如何促进肿瘤进展和预后。
Previous research has focused on the role of BCAT2 in PAAD. For example, Li et al. demonstrated that BCAT2 stabilization contributed to PAAD development in mice22, and other studies hightlighted that degradation of BCAT2 could inhibit PAAD tumor growth6,13. This prior evidence points to BCAT2 acting as an oncogene in PAAD progression. However, our findings, showing BCAT2 as a positive prognostic factor in PAAD, suggest a more complex role that needs further investigation.
先前的研究主要关注 BCAT2 在胰腺腺癌（PAAD）中的作用。例如，李等人证明 BCAT2 的稳定化促进了小鼠 PAAD 的发展 22 ，而其他研究则强调 BCAT2 的降解可以抑制 PAAD 肿瘤的生长 6,13 。这些先前的证据表明，BCAT2 在 PAAD 进展中可能是一种致癌基因。然而，我们的发现表明，BCAT2 在 PAAD 中是一个有利的预后因素，这暗示其作用可能更为复杂，需要进一步研究。
Moreover, our study aligns with some aforementioned works. Samuel and colleagues found that inhibiting BCAT2 impaired the progression of GBM23. High BCAT2 expression in estrogen receptor-positive BRCA was associated with poor survival outcomes24, and Zhang et al. reported that BCAT2 downregulation correlated with a worse prognosis in patients with STAD25. These findings are consistent with our results, inhibiting BCAT2 expression will contribute to the diagnosis and therapy of pan-cancer.
此外，我们的研究与一些先前的研究结果一致。萨缪尔及其同事发现抑制 BCAT2 会阻碍胶质母细胞瘤（GBM）的进展 23 。雌激素受体阳性乳腺癌（BRCA）中 BCAT2 高表达与较差的生存预后相关 24 ，而张等人报告称，BCAT2 下调与胃癌（STAD）患者较差的预后相关 25 。这些发现与我们的结果一致，抑制 BCAT2 的表达将有助于泛癌种的诊断和治疗。
We further explored the interaction between BCAT2 and tumor microenvironment (TME), which encompasses a sophisticated arrangement of tumor cells, noncancerous cells, blood vessels, extracellular matrix, and other substances26. Intriguingly, our study showed that BCAT2 correlates significantly with the infiltration of CD4+ T cells, CD8+ T cells, and regulatory T (Treg) cells across various cancers, which suggests its potential role in modulating immune responses within the TME. This aligns with existing research and underscores the importance of BCAT2 as a promising biomarker in cancer immunotherapy, guiding the development of more effective and personalized treatment strategies27,28.
我们进一步探讨了 BCAT2 与肿瘤微环境（TME）之间的相互作用，TME 包括复杂的肿瘤细胞、非癌细胞、血管、细胞外基质和其他物质 26 。有趣的是，我们的研究显示 BCAT2 与多种癌症中 CD4+ T 细胞、CD8+ T 细胞和调节性 T（Treg）细胞的浸润显著相关，这表明 BCAT2 可能在调节 TME 中的免疫反应中发挥作用。这与现有研究一致，并强调了 BCAT2 作为癌症免疫治疗潜在生物标志物的重要性，有助于指导更有效和个性化的治疗策略的发展 27,28 。
In conclusion, our comprehensive study validated that BCAT2 expression was dramatically altered in pan-cancer and had a significant correlation with cancer progression and survival outcomes. Additionally, BCAT2 showed obvious association with the infiltrations of CD4+ T cells, CD8+ T cells and Treg cells, suggesting its potential involvement in modulating the immune microenvironment. While these findings highlight BCAT2 as a promising biomarker for cancer prognosis and immune-targeted therapies, it is important to acknowledge that our analysis is primarily based on correlations. Therefore, further investigation into the causal relationships and detailed mechanistic studies are necessary to validate these findings and fully understand the role of BCAT2 in cancer progression.
综上所述，我们全面的研究验证了 BCAT2 在泛癌种中的表达显著改变，并且与癌症进展和生存结果有显著的相关性。此外，BCAT2 与 CD4+ T 细胞、CD8+ T 细胞和 Treg 细胞的浸润明显相关，表明其可能参与调节免疫微环境。虽然这些发现突显了 BCAT2 作为癌症预后和免疫靶向治疗的有前景的生物标志物的重要性，但值得注意的是，我们的分析主要基于相关性。因此，进一步探讨因果关系和详细的机制研究是必要的，以验证这些发现并全面理解 BCAT2 在癌症进展中的作用。
Methods 方法
Data sources 数据来源
In total, we included 32 cancer types for this study. The expression profile of BCAT2 and clinical information of pan-cancer patients were sourced from The Cancer Genome Atlas (TCGA)29 and Genotype-Tissue Expression (GTEx)30 databases, utilizing the Genomic Data Commons platform (GDC)31 for data retrieval. The cBioPortal database32 was employed to analyze BCAT2 genetic alterations.
本研究共纳入 32 种癌症类型。BCAT2 的表达谱和泛癌患者的临床信息来源于 The Cancer Genome Atlas (TCGA) 29 和 Genotype-Tissue Expression (GTEx) 30 数据库，利用 Genomic Data Commons 平台（GDC） 31 获取数据。我们使用 cBioPortal 数据库 32 分析 BCAT2 的遗传变异。
To explore BCAT2 protein abundance and its subcellular localization in tumor versus normal tissues, we utilized resources from The Human Protein Atlas database33, along with the String database34 for protein-protein interaction (PPI) analysis, and the Uniprot platform35 to determine the subcellular structure of BCAT2.
为了探索 BCAT2 在肿瘤组织与正常组织中的蛋白丰度及其亚细胞定位，我们利用了 The Human Protein Atlas 数据库 33 的资源，结合 String 数据库 34 进行蛋白质-蛋白质相互作用（PPI）分析，并使用 Uniprot 平台 35 确定 BCAT2 的亚细胞结构。
Along with TIMER2 database36, the information of immune cell infiltration from TCGA cohorts were collected and used to analyze the correlation with BCAT2 expression in pan-cancer patients.
除了使用 TIMER2 数据库 36 收集 TCGA 队列中免疫细胞浸润的信息外，我们还利用这些数据来分析 BCAT2 表达与泛癌患者免疫细胞浸润的相关性。
Statistical analysis 统计分析
The statistical analysis was performed using R software, version 3.6.2. We employed Student’s t-test to compare groups, considering a P value of less than 0.05 as statistically significance. Additionally, the Benjamini-Hochberg procedure was applied to adjust p-values when performing multiple testing to control for false discovery rates. Data were presented as means ± standard deviation (SD). For survival analysis, we utilized the Kaplan–Meier method and univariate Cox regression analysis. Furthermore, we used the RSEM tool, version 1.3.314, for accurate quantification of gene and isoform expression from RNA-Seq data. Across all tumors in the TCGA dataset, we utilized the Tumor Immune Estimation Resource 2.0 (TIMER2.0, http://timer.cistrome.org/) to analyze the partial Spearman’s correlations between BCAT2 expression and various immune cell populations, including CD4+ T cells, CD8+ T cells, and Treg cells. Multiple estimation algorithms were employed for this analysis, including TIMER, EPIC, TIDE, CIBERSORT, CIBERSORT-ABS, QUANTISEQ, XCELL, and MCPCOUNTER.
统计分析使用了 R 软件，版本 3.6.2。我们使用了学生 t 检验来比较组间差异，将 P 值小于 0.05 视为统计学显著性。此外，在进行多重检验时，我们应用了本德-霍奇伯格程序来调整 P 值，以控制假发现率。数据以均值±标准差（SD）的形式呈现。在生存分析中，我们使用了 Kaplan-Meier 方法和单变量 Cox 回归分析。此外，我们使用了 RSEM 工具，版本 1.3.3，对 RNA-Seq 数据中的基因和 isoform 表达进行了准确量化。在 TCGA 数据集中，我们使用了 TIMER2.0 资源（TIMER2.0， http://timer.cistrome.org/ ）来分析 BCAT2 表达与各种免疫细胞群体之间的部分 Spearman 相关性，包括 CD4+ T 细胞、CD8+ T 细胞和 Treg 细胞。此分析使用了多种估计算法，包括 TIMER、EPIC、TIDE、CIBERSORT、CIBERSORT-ABS、QUANTISEQ、XCELL 和 MCPCOUNTER。
Author contributions 作者贡献
Q.C. and J.F. curated the data, analyzed the results, and created the visualization. Q.C. wrote the original draft. J.Z. and W.W. reviewed and edited the manuscript and supervised the project.
Q.C. 和 J.F. 整理了数据，分析了结果，并创建了可视化图表。Q.C. 撰写了原始草稿。J.Z. 和 W.W. 审阅并编辑了手稿，并监督了整个项目。
Data availability statement
数据可用性声明
BCAT2 expression and clinical data across various cancers were sourced from The Cancer Genome Atlas (TCGA, https://www.cancer.gov/tcga) and Genotype-Tissue Expression (GTEx, http://commonfund.nih.gov/GTEx), via the Genomic Data Commons (GDC, https://gdc.cancer.gov/). BCAT2 genomic alterations data were obtained from the cBioPortal database (http://www.cbioportal.org/). Protein expression analysis, including interaction networks and subcellular localization, was conducted using The Human Protein Atlas (https://www.proteinatlas.org/), STRING database (https://cn.string-db.org/), and UniProt (https://www.uniprot.org/).
BCAT2 在各种癌症中的表达和临床数据来源于 The Cancer Genome Atlas (TCGA, https://www.cancer.gov/tcga ) 和 Genotype-Tissue Expression (GTEx, http://commonfund.nih.gov/GTEx )，并通过 Genomic Data Commons (GDC, https://gdc.cancer.gov/ ) 获取。BCAT2 的基因变异数据来自 cBioPortal 数据库（http://www.cbioportal.org/）。蛋白质表达分析，包括相互作用网络和亚细胞定位，使用了 The Human Protein Atlas (https://www.proteinatlas.org/)、STRING 数据库 (https://cn.string-db.org/) 和 UniProt (https://www.uniprot.org/)。
Footnotes 脚注
Publisher’s note 出版商声明
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Contributor Information 贡献者信息
Jian Zou, Email: jianzou@cqmu.edu.cn.
周健，邮箱: jianzou@cqmu.edu.cn。
Wei Wang, Email: wwzqbc@cqmu.edu.cn.
王威，邮箱: wwzqbc@cqmu.edu.cn。
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Associated Data 相关数据
This section collects any data citations, data availability statements, or supplementary materials included in this article.
本节收集了本文中包含的任何数据引用、数据可用性声明或补充材料。
Data Availability Statement
数据可用性声明
BCAT2 expression and clinical data across various cancers were sourced from The Cancer Genome Atlas (TCGA, https://www.cancer.gov/tcga) and Genotype-Tissue Expression (GTEx, http://commonfund.nih.gov/GTEx), via the Genomic Data Commons (GDC, https://gdc.cancer.gov/). BCAT2 genomic alterations data were obtained from the cBioPortal database (http://www.cbioportal.org/). Protein expression analysis, including interaction networks and subcellular localization, was conducted using The Human Protein Atlas (https://www.proteinatlas.org/), STRING database (https://cn.string-db.org/), and UniProt (https://www.uniprot.org/).
BCAT2 在各种癌症中的表达和临床数据来源于 The Cancer Genome Atlas (TCGA, https://www.cancer.gov/tcga ) 和 Genotype-Tissue Expression (GTEx, http://commonfund.nih.gov/GTEx )，并通过 Genomic Data Commons (GDC, https://gdc.cancer.gov/ ) 获取。BCAT2 的基因变异数据来自 cBioPortal 数据库（http://www.cbioportal.org/）。蛋白质表达分析，包括相互作用网络和亚细胞定位，使用了 The Human Protein Atlas (https://www.proteinatlas.org/)、STRING 数据库 (https://cn.string-db.org/) 和 UniProt (https://www.uniprot.org/)。