Silencing profilin-1 inhibits gastric cancer progression via integrin β1/focal adhesion kinase pathway modulation

AIM:To investigate the role of profilin-1(PFN1)in gastric cancer and the underlying mechanisms.METHODS:Immunohistochemical analysis,quan-titative real-time polymerase chain reaction(q RTPCR)and Western blot were performed to detect PFN1expression in clinical gastric carcinoma and adjacent tissues,and the association of PFN1 expression with patient clinicopathological characteristics was analyzed.PFN1 was knocked down to investigate the role of this protein in cell proliferation and metastasis in the SGC-7901 cell line.To explore the underlying mechanisms,the expression of integrinβ1 and the activity of focal adhesion kinase(FAK)and the downstream proteins extracellular-regulated kinase(ERK)1/2,P38 mitogen-activated protein kinase(MAPK),phosphatidylinositol 3-kinase(PI3K),AKT and mammalian target of rapamycin(m TOR)were measured through Western blot or q RT-PCR analysis.Fibronectin(FN),a ligand of integrinβ1,was used to verify the correlation between alterations in the integrinβ1/FAK pathway and changes in tumor cell aggressiveness upon PFN1 perturbation.RESULTS:Immunohistochemical,Western blot and q RT-PCR analyses revealed that PFN1 expression was higher at both the protein and m RNA levels in gastric carcinoma tissues compared with the adjacent tissues.In addition,high PFN1 expression(53/75,70.4%)was correlated with tumor infiltration,lymph node metastasis and TNM stage in gastric cancer,but not with gender,age,location,tumor size,or histological differentiation.In vitro experiments showed that PFN1knockdown inhibited the proliferation of SGC-7901cells through the induction G0/G1 arrest.Silencing PFN1 inhibited cell migration and invasion and downregulated the expression of matrix metalloproteinase(MMP)-2 and MMP9.Moreover,silencing PFN1 reduced the expression of integrinβ1 at the protein level and inhibited the activity of FAK,and the downstream effectors ERK1/2,P38MAPK,PI3K,AKT and m TOR.FN-promoted cell proliferation and metastasis via the integrinβ1/FAK pathway was ameliorated by PFN1silencing.CONCLUSION:These findings suggest that PFN1 plays a critical role in gastric carcinoma progression,and these effects are likely mediated through the integrinβ1/FAK pathway.

Safety and efficacy of meplazumab in healthy volunteers and COVID-19 patients: a randomized phase 1 and an exploratory phase 2 trial

Recent evidence suggests that CD147 serves as a novel receptor for severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)infection.Blocking CD147 via anti-CD147 antibody could suppress the in vitro SARS-CoV-2 replication.Meplazumab is a humanized anti-CD147 IgG_(2) monoclonal antibody,which may effectively prevent SARS-CoV-2 infection in coronavirus disease 2019(COVID-19)patients.Here,we conducted a randomized,double-blinded,placebo-controlled phase 1 trial to evaluate the safety,tolerability,and pharmacokinetics of meplazumab in healthy subjects,and an open-labeled,concurrent controlled add-on exploratory phase 2 study to determine the efficacy in COVID-19 patients.In phase 1 study,59 subjects were enrolled and assigned to eight cohorts,and no serious treatment-emergent adverse event(TEAE)or TEAE grade≥3 was observed.The serum and peripheral blood Cmax and area under the curve showed non-linear pharmacokinetic characteristics.No obvious relation between the incidence or titer of positive anti-drug antibody and dosage was observed in each cohort.The biodistribution study indicated that meplazumab reached lung tissue and maintained>14 days stable with the lung tissue/cardiac blood-pool ratio ranging from 0.41 to 0.32.In the exploratory phase 2 study,17 COVID-19 patients were enrolled,and 11 hospitalized patients were involved as concurrent control.The meplazumab treatment significantly improved the discharged(P=0.005)and case severity(P=0.021),and reduced the time to virus negative(P=0.045)in comparison to the control group.These results show a sound safety and tolerance of meplazumab in healthy volunteers and suggest that meplazumab could accelerate the recovery of patients from COVID-19 pneumonia with a favorable safety profile.