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.

Is concomitant radiotherapy necessary with gemcitabinebased chemotherapy in pancreatic cancer?

AIM:To evaluate the efficacy and safety of gemcitabine(GEM)plus radiotherapy compared with GEM alone for pancreatic cancer(PC).METHODS:A systematic search for eligible studies comparing gemcitabine plus radiotherapy with gemcitabine alone for PC was performed using MEDLINE,EMBASE,and the Cochrane Library.A quality assessment was performed in each study.Meta-analyses were performed to study the pooled effects of relative risk with 95%confidence interval(CI).RESULTS:A total of 336 participants from four original studies were included.Gemcitabine plus radiotherapy resulted in comparable overall survival(HR=0.84,95%CI:0.53-1.34,P=0.48)and progress freesurvival(HR=0.99,95%CI:0.97-1.01,P=0.36)to gemcitabine alone.Moreover,concomitant radiotherapy was associated with a significantly higher incidence of severe(grade 3 or greater)toxicities,mainly anemia,leukocytopenia,thrombocytopenia,anorexia,nausea/vomiting,and asthenia/fatigue.CONCLUSION:Radiotherapy is not beneficial with gemcitabine-based chemotherapy for PC.Further exploration for better radiotherapy approaches and therapeutic regimens for the treatment of PC is warranted.