The Effect Of Overexpressing DNAJB6 On B Ogical Behavior Of Esophageal Squamous Cell Carcinoma A Its Mechanism Studies

Background:Esophageal carcinoma is a quite common digestive tumor in the world It has two main pathological types including esophageal adenocarcinoma（EAC）and esophageal squamous cell carcinoma（ESCC）.EAC is common in western countries,while ESCC is the dominant pathological type in Asia including China.ESCC progresses rapidly and metastasizes early.Hence,it is of great importance to research the molecular mechanism of ESCC for treatment and prognosis.DnaJ/Hsp40 homolog,subfamily B,member 6（DNAJB6）also known as mammalian relative of DnaJ（MRJ）.Human DNAJB6 has two spliced isoforms:isoform a（2.5 kb,NM 058246）and isoform b（1.6 kb,NM₀05494）.The isoform a of DNAJB6 comprises 326 amino acids,while the isoform b includes 242 amino acids.A lot of nervous system diseases,for example,Parkinson’s disease and Huntington disease show protein aggregation of DNAJB6.Nevertheless,the function of DNAJB6 in carcinoma has not been clear.Recent research has shown there is a iron-dependent form of cell death termed ferroptosis in some cancer cells.Unlike cell necrosis and apoptosis,ferroptosis is caused by lipid peroxides when ferrous iron reacts it.To inhibit the defensive protein called glutathione peroxidase 4（GPX4,an antioxidant enzyme）may active ferroptosis selectively.GPX4 plays an important character in holding back ferroptosis through decreasing phospholipid hydroperoxide and hence inhibiting lipid peroxidation.Some scholars had hypothesized that ferroptosis would be a treatment method of malignancies.Objective:To investigate the effect of DNAJB6 on biological behavior of esophageal squamous cell carcinoma,and to further clarify the molecular biological mechanism of esophageal squamous cell carcinoma and provide a new target for the treatment of esophageal squamous cell carcinoma.Methods:The expression of DNAJB6 was detected in ESCC patient by western blot and immunohistochemistry.To overexpress DNAJB6a by lentivirus infection.Colony-forming,CCK-8,transwell,mouse xenograft assays were utilized to verify the proliferous,invasive and migratory role of DNAJB6a in ESCC cells.The MDA and GSH assays determine whether DNAJB6a participate in cell redox reaction.The variation of AKT and GPX4 was detected by western blot.Results:The correlation between DNAJB6 level and lymph node metastasis in ESCC patient was negative.Overexpressing DNAJB6a shows tumor-suppressive effects in vitro and vivo.In addition,DNAJB6a overexpression together with a remarkable reduction in the protein levels of GPX4 and phosphorylated AKT（p-AKT）.Conclusion:In summary,DNAJB6 is down-regulated in ESCC tissues.Our data suggest that DNAJB6 plays an important anti-oncogenic role in ESCC evolvement via ferroptosis.DNAJB6 may be a potential therapeutic target for the therapy of ESCC.