FABP4 Acts As A Suppressor Gene In Gastric Cancer Invasion And Metastasis And Its Molecular Mechanism

Objective: Gastric cancer is one of the most common cancers in East Asia,including China,and its mortality is high.At present,most patients are diagnosis at an advanced stage.The highly invasive tumors,such as tumor recurrence and metastasis,are the main causes of death of gastric cancer patients.A major problem is the lack of specific and efficient interventions in clinical practice and the potential mechanism has not been clarified.FABP4,a member of the fatty acid binding protein family,mainly distributed in macrophages and adipocytes.Recent studies have shown that FABP4 involved in tumor progression,but its role and molecular mechanism in gastric cancer remain unclear.At first this study investigated the expression of FABP4 in gastric cancer,and analyzed the correlation between FABP4 expression and the prognosis of gastric cancer patients.Secondly,we investigated the relationship between FABP4 and gastric cancer progression in in vivo and in vitro.Finally,we explored the potential molecular mechanisms of FABP4 in gastric cancer.This study aims to clarify the role of FABP4 and its molecular mechanism in gastric cancer,and to provide more theoretical basis for the development of new treatment strategies for gastric cancer.Methods: 1.Using IHC,q RT-PCR and Western Blotting assays to detect the expression of FABP4 in human gastric cancer samples,and analyzed the correlation between FABP4 and prognosis of gastric cancer patients.2.Lentivirus was used to build the gastric cancer cell lines MGC-803,BGC-823,SNU-216 and AGS with stable overexpressed or silenced FABP4.3.Transwell and CCK-8 assays were performed to elucidate the relationship between FABP4 expression and the proliferation,invasion,and migration of gastric cancer cells.4.By constructing the nude mice model to investigate the effect of FABP4 on the biological behavior of MGC-803 in vivo.5.Using RNA-sequencing analysis,luciferase reporter assays,immunofluorescence and other techniques to discuss the molecular mechanism of FABP4 in gastric cancer.Results: 1.FABP4 expression in gastric cancer tissues at m RNA and protein levels were significantly lower than that in corresponding adjacent tissues(both P < 0.05).2.The expression of FABP4 was significantly related to the prognosis,TNM stage and histological differentiation of gastric cancer patients.3.Overexpression of FABP4 inhibited the invasion and metastasis of gastric cancer cells,while stably silencing of FABP4 had the opposite results.4.RNA-sequencing analysis showed that FABP4 expression positively correlated with CADM3 expression and related to the PPAR signal pathway.5.PPARγ,a subtype of PPAR,promoted CADM3 expression.6.Overexpression of CADM3 suppressed the invasion and metastasis of gastric cancer cells,while stably silencing of CADM3 had the opposite result.7.FABP4 promoted the Translocation of PPARγ to affect CADM3 expression,and inhibited the invasion and migration of gastric cancer.Conclusions: 1.FABP4 closely associated with gastric cancer metastasis,which is suggested to be a new biomarker for predicting the prognosis of patients with gastric cancer.2.FABP4 inhibits the gastric cancer cell invasion and migration ability in vivo and in vitro,but does not affect the proliferation capacity of gastric cancer cells.3.FABP4,as a ligand,binds to PPARγ,activates PPARγtranscriptional activity and incorporates into the nucleus;FABP4 promotes the downstream target gene CADM3 transcription of PPARγ,maintains the adhesion ability of gastric cancer cells,thereby acting as a tumor suppressor gene.