He Yi, Zhang Haiyang, Zhang Yan, Wang Peiyun, Zhu Kegan, Ba Yi
Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, People's Republic of China.
Department of Gastroenterology, Tianjin Haihe Hospital, Tianjin, 300350, People's Republic of China.
Int J Gen Med. 2022 Mar 25;15:3375-3391. doi: 10.2147/IJGM.S353879. eCollection 2022.
Stomach adenocarcinoma (STAD) ranks as the third leading cause of cancer death worldwide. TGF‑β receptor 1 (TGFBR1), serving important roles in the TGF‑β family, the mechanisms whereby TGFBR1 governs tumor progression, immune cell infiltration in STAD remains unintelligible.
We used the TCGA, GEPIA, and HPA databases to explore TGFBR1 expression in STAD, the correlation between TGFBR1 expression and the clinical features. A receiver operating characteristic (ROC) curve and nomogram were constructed, and LASSO (the Least Absolute Shrinkage and Selection Operator)-selected features were used to build the TGFBR1 prognostic signature. GSEA is used to find the potential mechanism of TGFBR1 to promote the malignant process of STAD. We explored the influence of the TGFBR1 on the immune microenvironment of STAD through the TIMER2.0 and GEPIA database.
In our study, TGFBR1 expression was significantly elevated in STAD and positively co-expression with pathologic stage, lymph node metastases (LNM) stage and histopathological grade. Nine factors with non-zero coefficients were identified by LASSO-selected features. Survival analysis revealed that patients with high TGFBR1 had shorter OS, FP, and PPS. Multivariate Cox analysis revealed that TGFBR1 was an independent prognostic factor for OS in STAD. The ROC analysis suggested that high diagnostic value with the AUC of TGFBR1 was 0.739. GSEA revealed that high TGFBR1 expression was correlated with pathway in cancer, MAPK signaling pathway, NOTCH signaling pathway, and VEGF-C production. ssGSEA showed that TGFBR1 is correlated with NK cells, Tem and Th17 cells. Furthermore, elevated TGFBR1 expression was found to be significantly correlated with several immune checkpoint and immune markers associated with immune cell subsets.
In summary, TGFBR1 could be a prognostic biomarker and an important regulator of immune cell infiltration in STAD. The present study revealed the probable underlying molecular mechanisms of TGFBR1 in STAD and provided a potential target for improving the prognosis.
胃腺癌（STAD）是全球癌症死亡的第三大主要原因。转化生长因子β受体1（TGFBR1）在转化生长因子β家族中发挥重要作用，TGFBR1调控STAD肿瘤进展及免疫细胞浸润的机制仍不清楚。
我们使用TCGA、GEPIA和HPA数据库来探究STAD中TGFBR1的表达情况，以及TGFBR1表达与临床特征之间的相关性。构建了受试者工作特征（ROC）曲线和列线图，并使用最小绝对收缩和选择算子（LASSO）选择的特征来构建TGFBR1预后特征。基因集富集分析（GSEA）用于寻找TGFBR1促进STAD恶性进程的潜在机制。我们通过TIMER2.0和GEPIA数据库探究了TGFBR1对STAD免疫微环境的影响。
在我们的研究中，STAD中TGFBR1表达显著升高，且与病理分期、淋巴结转移（LNM）分期及组织病理学分级呈正共表达。LASSO选择的特征确定了9个非零系数的因素。生存分析显示，TGFBR1高表达的患者总生存期（OS）、无进展生存期（FP）和无进展生存期（PPS）较短。多因素Cox分析显示，TGFBR1是STAD患者OS的独立预后因素。ROC分析表明，TGFBR1的曲线下面积（AUC）具有较高的诊断价值，为0.739。GSEA显示，TGFBR1高表达与癌症通路、丝裂原活化蛋白激酶（MAPK）信号通路、Notch信号通路及血管内皮生长因子C（VEGF-C）产生相关。单样本基因集富集分析（ssGSEA）显示，TGFBR1与自然杀伤（NK）细胞、效应记忆T细胞（Tem）和辅助性T细胞17（Th17）细胞相关。此外，发现TGFBR1表达升高与几种免疫检查点及与免疫细胞亚群相关的免疫标志物显著相关。
总之，TGFBR1可能是STAD的预后生物标志物及免疫细胞浸润的重要调节因子。本研究揭示了TGFBR1在STAD中可能的潜在分子机制，并为改善预后提供了一个潜在靶点。
