B7-H3 inhibits apoptosis of gastric cancer cell by interacting with Fibronectin

Abstract

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 high group, as compared with those in B7-H3 low 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.

High expression of B7-H3 on monocyte/macrophages in tumor microenvironment promotes lung cancer progression by inhibiting apoptosis

“…Since the discovery of B7-H3 in 2001 [28] , B7-H3 has been widely investigated in a variety of cancers, including but not limited to breast, kidney and gastric cancers [29] , [30] , [31] . However, evidence on whether B7-H3 expressed on monocyte/macrophages in TME was involved in tumor progression was still limited.…”

MCRS1 Expression Regulates Tumor Activity and Affects Survival Probability of Patients with Gastric Cancer

“…Inhibiting the expression of fibronectin inhibited the growth of breast cancer cells [ 69 ]. Stable knockout of the B7-H3 gene in MGC-803 and MKN-45 gastric cancer cell lines has been shown; B7-H3 is a type I transmembrane protein that affects the PI3K/AKT signaling pathway by regulating fibronectin to inhibit gastric cancer cell apoptosis [ 70 ]. In a mouse model, inhibition of miR-1278 increased fibronectin 1 expression and promoted gastric cancer progression [ 71 ].…”

B7-H3 at the crossroads between tumor plasticity and colorectal cancer progression: a potential target for therapeutic intervention

“…Thus, B7-H3 confers resistance to apoptosis induced by anticancer drugs. This observation also applies to pancreatic and gastric carcinoma, where B7-H3 has shown similar anti-apoptotic features [ 43 , 44 ]. Sun et al described an alternative mechanism associated with the anti-apoptotic effect of B7-H3.…”

“…Sun et al described an alternative mechanism associated with the anti-apoptotic effect of B7-H3. As reported in gastric cancer, B7-H3 interacts with fibronectin, which consequently activates the oncogenic signaling pathway phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT), inhibiting apoptosis [ 44 ]. Two downstream targets in PI3K/AKT pathway related to apoptosis (Bcl-2 was upregulated) and cell cycle progression (p53 was downregulated) were dysregulated by the direct interaction of B7-H3 with fibronectin [ 44 ].…”