Promoting Role And The Underlying Mechanisms Of P2-HNF4α In The Growth And Metastasis Of Invasive Mucinous Lung Adenocarcinoma

Invasive mucinous adenocarcinoma of lung(IMA)is a highly malignant subty pe of lung adenocarcinoma.Due to the frequent misdiagnosis,IMA is ususally diagnosed at an advanced stage,receiving non-operative treatments such as radiotherapy and chemotherapy which result in serious side effects and poor prognosis.In recent years,molecular-targeted antineoplastic drugs,such as EGFR inhibitors,have achieved encouraging outcomes in the treatment of lung adenocarcinoma.However,since lung adenocarcinoma can be subdivided into more than ten subtypes with high genetic and histological heterogeneity,individual therapy is still in great unmet need.For example,IMA frequently carrying mutations in KRAS rather than EGFR does not response to EGFR inhibitors,whilst KRAS mutations remain undruggable except KRASG12C whose incidence is low in lung cancer.Therefore,new IMA targets and the corresponding drgus are urgently needed to be developed.Nuclear receptor HNF4α is silenced in normal lung tissues and most lung cancer;however,it is abnormally expressed in approximately 90%of IMA and serves as a diagnostic marker for IMA.However,the role of HNF4α in IMA development and the underlying molecular mechanisms remain unclear.In this thesis,we reported that P2 promoter-driven HNF4α(P2-HNF4α)was expressed in IMA cell lines and clinic samples.P2-HNF4α depends on its transactivational activity to regulate the growth,migration and invasion of IMA in vitro and in vivo.Mechanistically,HNF4α transcriptionally increased the expression of lncRNA BC200,which mediated the IMA-promoting function of HNF4α through acting as a scaffold for FMR1 to bind and regulate the stability of mRNAs for cancerrelated genes such as Twist and EGFR.BC200 in turn upregulated HNF4α expression by facilitating the FMR1-bound state and stabilization of HNF4α mRNA.Based on these findings,mycophenolic acid,the active metabolite of FDA-approved drug mycophenolate mofetil,was further screened out and identified as HNF4α antagonist,which inhibited BC200 expression and the growth and metastasis of IMA via HNF4αmediation in vitro and in vivo.Therefore,mycophenolate mofetil has the potential to be developed as a therapeutic agent against IMA.In summary,we thoroughly investigated the role and the underlying molecular mechanisms of P2-HNF4α in IMA development,and identified a novel HNF4αantagonist that effectively inhibited the growth and metastasis of IMA from the FDAapproved drug library,thus providing a new strategy for the trearment of IMA.