Functional And Mechanistic Research On The Roles Of RelB/NF-?B In Endometrioid Endometrial Adenocarcinoma

[BACKGROUND] Previous study hinted that the key NF-?B transcriptional factors operated oncogenic role in the area of carcinogenesis of endometrial tissue mainly by abnormally modulating the proliferation and apoptosis activities.However,the particular expression profile and relative functional mechanisms in endometrial carcinoma(EC)have still been unlarified as yet.[OBJECTIVES]The protein levels of key NF-?B transcriptional factors(RelB and RelA)in primary EC specimen relative to normal endometrial tissues were detected.The correlations among the key NF-?B transcriptional factors with differentiated expression,EC subtypes and FIGO stages were statistically analyzed.The particular functions and relevant mechanisms of individual NF-?B subunits with differentiated expression were further explored to provide some theoretical and experimental foundations based on specific pathological types for clinical prevention and treatment of endometrial carcinoma.[CONTENTS AND METHODS](1)The protein levels of NF-?B-RelB/RelA in primary EC specimen relative to normal endometrium tissues were detected by immunohistochemistry(IHC);the differentially expressional profiles and their correlations with EC subtypes/FIGO stages were statistically analyzed.(2)When RelB was stably knocked down by the technique of short-hairpin RNA,the CCK-8,growth curve,clone formation assays and subcutaneous nude mice xenograft experiments were used to test the changes of growth ability in vitro and tumor formation capacity in vivo of endometrioid endometrial adenocarcinoma(EEC)cell lines.(3)The effects of RelB on proliferation and apoptosis activities were analyzed by flow cytometry.(4)The crucial signaling pathways and closely-related target genes were searched for by RNA-array mainly in HEC-1A cells.[RESULTS](1)Non-canonical NF-?B/RelB rather than canonical NF-?B/RelA was dramatically up-regulated in EC tissues when compared to normal controls.And especially,this elevated expression was prominent in type I EC---EEC subtype,with extradinary manifestation in early-stage(FIGO stage I)EEC.(2)Stable RelB silence resulted in great arrests of growth abilities in vitro and subcutaneous nude mice xenograft capacities in vivo of EEC cells.(3)The growth-promoting function of RelB was positively and inversely dependent on the G1-to-S entry induction and cell apoptosis evasion at the same time.And in this perspective,RelB attenuation up-regulated the expression of p27 while down-regulated the expression of Bcl3/CyclinD1/c-Myc.All those were critical modulators of G1-to-S cell cycle progression.Moreover,RelB was shown to protect EC cells from apoptosis,manifested by the corresponding changes of Bcl-2,Bcl-X l/s and cleaved PARP-1.[CONCLUSIONS]Our study established the critical "oncogenic" part of RelB in the area of hyperproliferation of EEC by both the induction of G1/S cell cycle transition and the protection of cell-type dependent apoptosis.Accordingly,non-canonnical NF-?B/RelB and its regulatory components could be potential therapeutic targets for EC,EEC particularly.