RMP In Tumor Progression

RMP(RPB5 Mediating Protein)is the binding protein of RPB5 which is the 5th subunit of RNA polymerase II.Recent studies have uncovered that RMP was a key regulator in several human cancers.In this study,we explored the mechanism of carcinogensis of RMP in 3 parts.Epithelial-mesenchymal transition(EMT)was that epithelial cells acquire high migration and invasion ability which belongs to mesenchymal cells.This process contributes a lot to normal development and tumor metastasis.Even though there were sequential studies report the relevance of EMT and tumor metastasis,the molecular mechanism was still elusive.In this study,we demonstrate the key role of RPB5-mediating protein(RMP)in EMT of HCC cells and the mechanism by which RMP promote EMT.Based on our results,RMP directly interact with NF-)kB subunit p65,increaseits phosphorylation and nuclear translocation,NF-κB is activated by RMP,which directly promotes the expression of COP9 signalosome 2(CSN2)to repress the degradation of Snail.The accumulation of Snail eventually promotes EMT by inhibit the expression of E-cadherin.Moreover,pulmonary metastases mouse model demonstrates that RMP induces metastasis in vivo.Immunohistochemical analysis of human HCC tissues confrms the negative correlation of RMP with the expression of E-cadherin in vivo.In summary,these findings indicate the key role of RMP in EMT and metastasis of HCC.Turn down the expression of RMP may effectively suppress the metastasis of tumor.After DNA breaks,series of DNA repair factorswill recognizethe DNA break sites and be recruited into it as soon as possible.In our previous study,we found RMP as a potential DNA repair factor could abnormally upgrade the DNA repair in HCC,and promote tumor cell survival by endowing cells with radioresistance.In this study,we report that RMP rapidly translocate into nuclear and subsequently promote the phosphorylation of ATM after DNA breaks.The phosphorylated ATM directly binds to RMP and recruits repair factors into DNA break sites.Though this mechanism,RMP significantly accelerate the DNA double strain repair.These results explain basically how RMP promotes DSB repair,and provide basis for overcoming radioresistance in clinic.We also investigate hsa-miR-598-3p mediated the malignant phenotype of tumor by directly repressing RMP through its 3’UTR.Specifically,knockdown of miR-598-3p in cancer cell line significantly reduced the activity of NF-κB andp70s6kl/bad pathways,thereby increase cell proliferation and metastasis.In turn,overexpression of miR-598-3p reversed these malignant phenotype.Moreover,upregulation of RMP in cell overexpressed miR-598-3p remarkably release the activity of NF-κB and Bad,thus disrupt the inhibition of proliferation and metastasis which caused by miR-598-3p.The analysis of human lung and gastric cancer specimen confirms the negative correlation of RMP with the expression of miR-598-3p in vivo.These results demonstrate miR-598-3p suppress carcinogenesis by inhibited expression of RMP.Collectively,our studies uncovered the importance of RMP in EMT and DSB repair of HCC,and as a repressor of RMP,miR-598-3p could rescue the malignant phenotype induced by RMP.