Detection of telomerase activity in biopsy samples for predicting prognosis in cirrhotic patients with hepatocellular carcinoma after laparoscopic radiofrequency ablation therapy

Objective: To explore the role of telomerase activity detected in biopsy samples for evaluating the efficacy of lapa- roscopic radiofrequency ablation (RFA) therapy in patients with hepatocellular carcinoma (HCC) and liver cirrhosis. Methods: From August 2001 to October 2004, 34 cirrhotic patients with HCC were treated by laparoscopic RFA under general anesthe- sia. A total of 34 tumors, with a mean maximum tumor diameter of 4.0 ± 1.0 cm, were all located on the liver surface or adja- cent to the gallbladder. Laparoscopic ultrasound-guided core biopsy for liver lesions was performed before and immediately after RFA therapy. In these biopsy samples, telomerase activity was detected by the ELISA-based telomeric repeat amplifica- tion protocol (ELISA-TRAP) assay, and pathological examination was routinely performed. Results: Laparoscopic RFA was successfully performed in all the 34 patients. A complete tumor necrosis was achieved in all patients on the contrast-enhanced helical CT scanning one month after laparoscopic RFA. The positive rates of telomerase activity and histopathologic diagnosis in biopsy samples were 91.2% (31/34) and 100% (34/34) respectively before RFA, and 26.5% (9/34) and 0% respectively after RFA. During a median follow-up period of 35 months (range, 18–51 months), the rates of local tumor recurrence at the ablation sites in post-RFA telomerase-positive and negative patients were 88.9% (8/9) and 4% (1/25) respectively (P < 0.01), and the rates of distant recurrence within the livers were 0% (0/9) and 12% (3/25) respectively (P > 0.05). Conclusion: For cirrhotic patients with HCC treated by laparoscopic RFA, detection of telomerase activity in biopsy samples may be useful for evaluating the therapeutic efficacy of RFA and predicting postoperative local tumor recurrence.

Mesenchymal stromal cells in hepatic fibrosis/cirrhosis:from pathogenesis to treatment

Hepatic fibrosis/cirrhosis is a significant health burden worldwide,resulting in liver failure or hepatocellular carcinoma(HCC)and accounting for many deaths each year.The pathogenesis of hepatic fibrosis/cirrhosis is very complex,which makes treatment challenging.Endogenous mesenchymal stromal cells(MsCs)have been shown to play pivotal roles in the pathogenesis of hepatic fibrosis.Paradoxically,exogenous MsCs have also been used in clinical trials for liver cirrhosis,and their effectiveness has been observed in most completed clinical trials.There are still many issues to be resolved to promote the use of MsCs in the clinic in the future.In this review,we will examine the controversial role of MsCs in the pathogenesis and treatment of hepatic fibrosis/cirrhosis.We also investigated the clinical trials involving MsCs in liver cirrhosis,summarized the parameters that need to be standardized,and discussed how to promote the use of MsCs from a clinical perspective.

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.