Dysregulation Of Tristetraprolin And Human Antigen R Promotes Gastric Cancer Progressions Partly By Upregulation Of The High-mobility Group Box 1

Objective:Aberrant expression of ARE-binding proteins(ARE-BPs)plays an important role in several diseases,including cancer.Both tristetraprolin(TTP)and human antigen R(HuR)are important ARE-BPs,and always play opposite roles in regulating target mRNAs.Our previous work has demonstrated that TTP expression is decreased in gastric cancer(GC).In this study,we aimed to investigate whether HuR was elevated or showed aberrant nuclear/cytoplasmic translocation in GC.We also explored the relationship between HuR and TTP in GC.Furthermore,we investigated the relationship of TTP-HuR axis and the high-mobility group box 1(HMGB1).Methods:Western blotting and qRT-PCR were performed to assess the protein and mRNA expression levels of HuR in GC cell lines.Next we used qRT-PCR and immunohistochemistry to detect HuR expression in GC tissues.Plasmids or si-RNAs of TTP and HuR were transfected into cells to study the relationship among TTP,HuR and HMGB1,Then,we used CCK-8 and transwell assays to evaluate the effects of HuR on the proliferation,migration,and invasion of GC cells in vitro.To investigate whether overexpression of HuR promotes GC growth in vivo,we established xenograft tumor models in nude mice by subcutaneous injection of GC cells.Lastly,we measured the expression of HuR in GC specimens by immunohistological staining and analyzed the correlation between the HuR expression levels and clinicopathological features and survival of GC.Results:In this study,we reported that HuR was elevated in GC cell lines and gastric cancer patients,and that decreased TTP expression partly contributed to the elevated HuR levels by regulating its mRNA turnover.We also observed that dysregulation of TTP and HuR elevated the high-mobility group box 1(HMGB1)expression in different ways.HuR had no effect on HMGB1 mRNA,while decreased expression of TTP increased HMGB1 levels by affecting its mRNA stability.Increased HuR promoted cancer cells proliferation and the metastasis potential partly by HMGB1.Using immunohistochemistry,we observed that both positive cytoplasmic and high-expression of nuclear HuR were associated with poor pathologic features and survival of GC patients.Conclusions:Dysregulation of the TTP-HuR axis plays an important role in GC.Moreover,high HuR nuclear expression or aberrant cytoplasmic distribution may serve as a predictor of poor survival.Furthermore,elevated HMGB1 expression in GC was correlated with an aberrant TTP-HuR axis.Our study indicated that the TTP-HuR axis may serve as a potential therapeutic target for GC therapy.