MXR7 facilitates liver cancer metastasis via epithelial-mesenchymal transition

MXR7 is a cell-surface protein and highly expressed in hepatocellular carcinoma(HCC). The aim of this study is to determine the expression profile of MXR7 in HCC and investigate the influence of MXR7 on invasion and metastasis of HCC cells. For this purpose, immunohistochemical assay was used to identify the differential expression of MXR7 in 94 HCC specimens. Expression of MXR7 in 4 pairs of HCC and portal vein tumor thrombus(PVTT) was also tested. The motility of HCC cells were characterized by transwell migration and matrigel invasion assays. In vivo metastasis potential was determined via tail vein injection assay.Moreover, compared with noninvasive HCC tumors or human HCC cell lines with low metastatic potential, invasive HCC samples and HCC cell lines with high metastatic potential exhibited higher MXR7 expression. Furthermore, forced expression of MXR7 in SMMC-7721 promoted cell proliferation, migration and invasion in vitro and accelerated tumor growth and metastasis in vivo. Conversely, knockdown of MXR7 expression in HuH7 cells inhibited proliferation and motility of cells. Mechanically,overexpression of MXR7 promoted epithelial-mesenchymal transition(EMT) progress, and MXR7 depletion repressed the EMT phenotype. In conclusion, MXR7 is a mediator of EMT and metastasis in HCC and may serve as a novel therapeutic target.

An RNA-RNA crosstalk network involving HMGB1 and RICTOR facilitates hepatocellular carcinoma tumorigenesis by promoting glutamine metabolism and impedes immunotherapy by PD-L1+ exosomes activity

Hepatocellular carcinoma(HCC)is the global leading cause of cancer-related deaths due to the deficiency of targets for precision therapy.A new modality of epigenetic regulation has emerged involving RNA-RNA crosstalk networks where two or more competing endogenous RNAs(ceRNAs)bind to the same microRNAs.However,the contribution of such mechanisms in HCC has not been well studied.Herein,potential HMGB1-driven RNA-RNA crosstalk networks were evaluated at different HCC stages,identifying the mT0RC2 component RICTOR as a potential HMGB1 ceRNA in HBV^(+)early stage HCC.Indeed,elevated HMGB1 mRNA was found to promote the expressio n of RICTOR mRNA through competitively bin ding with the miR-200 family,especially miR-429.Functio nal assays emplo ying overexpressi on or in terference strategies dem on strated that the HMGB1 and RICTOR 3zuntra nslated regions(UTR)epigenetically promoted the malignant proliferation,self-renewal,and tumorigenesis in HCC cells.Intriguingly,in terference agai nst HMGB1 and RICTOR in HCC cells promoted a stron ger an ti-PD-L1 immuno therapy resp on se,which appeared to associate with the production of PD-L1^(+)exosomes.Mechanistically,the HMGB1-driven RNA-RNA crosstalk network facilitated HCC cell glutamine metabolism via dual mechanisms,activating a positive feedback loop involving mT0RC2-AKT-C-MYC to upregulate glutamine synthetase(GS)expression,and inducing mTORCI signaling to derepress SIRT4 on glutamate dehydrogenase(GDH).Meanwhile,this crosstalk network could impede the efficacy of immunotherapy through mTORCI-P70S6K dependent PD-L1 production and PD-L1^(+)exosomes activity.In conclusion,our study highlights the non-coding regulatory role of HMGB1 with implicatio ns for RNA-based therapeutic targeting together with a predictio n of an ti-PD-L1 immuno therapy in HCC.