CD31 promotes diffuse large B cell lymphoma metastasis by upregulating OPN and mTOR

Abstract Background Diffuse large B cell lymphoma (DLBCL) will progress to recurrence/ refractory because of ongoing metastasis in various organizations (including the brain and testicles) and it is difficult for first-line chemotherapy agents to cross the physical barriers (Such as the blood-brain barrier and blood-testosterone barrier). At present, the mechanism of invasion is unknow and there is no effective drugs to effectively inhibit the metastasis of DLBCL. Methods In this study, 40 newly diagnosis DLBCL patients samples were analyzed by real-time PCR. Western-blot, immunofluorescence staining, immunohistochemical staining and RNA sequence were used to identify diferentially expressed genes of different invasive DLBCL cells. Xenograft models were constructed to validate the different invasive DLBCL cells in vivo. Scanning electron microscope were used to detect the effect of overexpression CD31 DLBCL cells on integrity of blood brain barrier. Results Osteopontin (OPN) was upregulated in multiple metastases patients compared with single or less metastases patients. Overexpression OPN DLBCL cells didn’t respond to R-CHOP and more easily progress to recurrence/refractory. In vivo experiments, the DLBCL cells aggressiveness positively correlated with OPN. Overexpression OPN DLBCL cells formed more tumor metastases over time in mice and it also shortened mice survival time. Using RNA sequencing and in vitro studies, we showed that OPN was obviously upregulated by Platelet endothelial cell adhesion molecule-1 (CD31) through AKT pathway. CD31 also helped DLBCL foci hide from immune cells by recruiting function suppressed CD31 + memory T cells in xenografts. CD31 inhibited CD31 + memory T cells to synthetic INF-γ, TNF-α and perforin effectively by abnormally activated mTOR pathway. Finally, CD31 disrupted the tight junctions (TJ) between endothelial cells of blood-brain barrier by activating OPN-EGFR-ZO-1/ZO-2 axis, allowing DLBCL cells to metastasize to brain. Conclusions Overall, CD31 is a marker for DLBCL metastasis and targeting CD31 may be a valuable strategy to reduced DLBCL cells aggressiveness and prevent patients progress to recurrence/ refractory because of ongoing metastasis.