Sun Meiyun, Xie Jinjing, Zhang Dongze, Chen Chunyang, Lin Simin, Chen Yan, Zhang Guangbo
Medical College of Soochow University, 199 Ren ai Road, Suzhou, Jiangsu Province, 215100, China.
Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, 708 Ren min Road, Suzhou, Jiangsu Province, 215100, China.
J Cancer. 2021 Nov 8;12(24):7518-7526. doi: 10.7150/jca.59263. eCollection 2021.
Anti-apoptosis has been widely accepted as a hallmark of malignancy. B7-H3, a type I transmembrane protein, plays a key role in anti-apoptosis and immune escape, but its regulation during cancer development remains unclear. To investigate how the effect of anti-apoptosis is regulated by B7-H3 in gastric cancer, we stably knocked down B7-H3 gene by shRNA in MGC-803 and MKN-45 cells. The correlation between B7-H3 and Fibronectin (FN) expression were investigated by bioinformatics in public data from TCGA (The Cancer Genome Atlas). Here, we reported that B7-H3 expression is positively correlated with FN in clinical gastric cancer samples, and B7-H3 promoted adhesion and inhibited apoptosis of gastric cancer cell through an FN-dependent pathway. Mechanistically, B7-H3 interacted with FN and subsequently activated PI3K/AKT signaling pathway, a critical mediator of oncogenic signaling. In addition, exogenous FN could inhibit the expression of pro-apoptosis-related proteins such as Caspase 3, Caspase 8, Caspase 9, Bax , p53, Apaf-1 and Cleaved PARP, and upregulated the levels of signal molecule p-PI3K, p-AKT and anti-apoptotic proteins Bcl-2 in B7-H3 group, as compared with those in B7-H3 group. In conclusion, we here for the first time revealed that B7-H3 inhibits apoptosis of gastric cancer cell through regulation of FN-mediated PI3K/AKT signaling pathways.
抗凋亡已被广泛认为是恶性肿瘤的一个标志。B7-H3是一种I型跨膜蛋白，在抗凋亡和免疫逃逸中起关键作用，但其在癌症发生发展过程中的调控机制仍不清楚。为了研究B7-H3在胃癌中如何调节抗凋亡作用，我们利用短发夹RNA（shRNA）在MGC-803和MKN-45细胞中稳定敲低B7-H3基因。通过生物信息学分析来自癌症基因组图谱（TCGA）的公开数据，研究了B7-H3与纤连蛋白（FN）表达之间的相关性。在此，我们报道在临床胃癌样本中B7-H3表达与FN呈正相关，并且B7-H3通过FN依赖的途径促进胃癌细胞的黏附并抑制其凋亡。机制上，B7-H3与FN相互作用，随后激活致癌信号的关键介质PI3K/AKT信号通路。此外，与B7-H3敲低组相比，外源性FN可抑制B7-H3组中促凋亡相关蛋白如半胱天冬酶3、半胱天冬酶8、半胱天冬酶9、Bax、p53、凋亡蛋白酶激活因子-1（Apaf-1）和裂解的聚（ADP-核糖）聚合酶（Cleaved PARP）的表达，并上调信号分子p-PI3K、p-AKT和抗凋亡蛋白Bcl-2的水平。总之，我们首次揭示B7-H3通过调节FN介导的PI3K/AKT信号通路抑制胃癌细胞凋亡。
