目的:抑制素B(INHB)是TGF-β超家族成员之一,由α(INHA)和βB(INHBB)亚基组成。研究发现TGF-β受体3(TGFBR3)与INHB表面的凸α亚基结合,并增强激活素受体2型(ACVR2A/B)与INHβ亚基的结合亲和力。本研究试图评估INHB亚基及其受体(INHA,ACVR2A,ACVR2B,INHBB,TGFBR3)作为有效治疗肺腺癌(LUAD)的预后生物标志物和治疗靶标。
方法:我们分析了INHB亚基及其受体的表达以及Oncomine对LUAD的影响,GEPIA,HCMDB,CancerSEA,TIMER数据库等等。然后,应用免疫组化法检测LUAD患者41例癌组织和41例癌旁上皮。
结果:INHA,ACVR2A,ACVR2B,在LUAD中,INHBB上调,而TGFBR3下调。INHA,发现ACVR2A和TGFBR3与高级别恶性肿瘤和晚期TNM密切相关。只有TGFBR3表达与LUAD转移呈负相关,可能主要通过细胞粘附分子和PI3K-Akt信号通路,单因素和多因素分析显示,TGFBR3水平较低的LUAD患者的总生存率较低.进一步的分析表明,低TGFBR3表达与免疫细胞向LUAD的浸润减少有关,促进LUAD细胞转移。TGFBR3的表达与LUAD患者的淋巴结转移和临床分期呈负相关。
结论:TGFBR3可能是LUAD潜在的新的转移生物标志物,具有作为LUAD的预后标志物和免疫治疗的潜在应用。
OBJECTIVE: Inhibin B (INHB) is one of the TGF-β superfamily member, consisting of α (INHA) and βB (INHBB) subunits. Studies have found that TGF-β receptor 3 (TGFBR3) binds to a convex α subunit on the surface of INHB, and enhances the binding affinity of activin receptor type-2 (ACVR2A/B) to INHβ subunit. This study tried to evaluate the roles of INHB subunits and its receptors (INHA, ACVR2A, ACVR2B, INHBB, TGFBR3) as prognostic biomarkers and therapeutic targets for the effective treatment of lung adenocarcinoma (LUAD).
METHODS: We analyzed INHB subunits and its receptors\' expression and the influence of LUAD from Oncomine, GEPIA, HCMDB, CancerSEA, TIMER databases and so on. Then, 41 cases of cancer tissue and 41 cases of adjacent epithelium were detected in LUAD patients by immunohistochemistry.
RESULTS: INHA, ACVR2A, ACVR2B, INHBB were up-regulated while TGFBR3 was down-regulated in LUAD. INHA, ACVR2A and TGFBR3 were found to be strongly associated with high-grade malignancies and advanced TNM, only TGFBR3 expression was negatively correlated with LUAD metastasis probably mainly through cell adhesion molecules and the PI3K-Akt signaling pathway, univariate and multivariate analysis suggested that overall survival was lower in LUAD cases with low TGFBR3 levels. Further analysis revealed that low TGFBR3 expression was related to reduced infiltration of immune cells into the LUAD, promoting metastasis of LUAD cells. TGFBR3 expression negatively correlates with lymphatic metastasis and clinical stage in patients with LUAD.
CONCLUSIONS: TGFBR3 could be a potential new metastatic biomarker for LUAD, with potential application as a prognostic marker and for immunotherapy of LUAD.