Protein convertase subtilisin/Kexin type 9 inhibits hepatocellular carcinoma growth by interacting with GSTP1 and suppressing the JNK signaling pathway

Objective:Protein convertase subtilisin/Kexin type 9(PCSK9)has been found to be closely associated with the occurrence and development of numerous tumors.However,the precise role of PCSK9 and its relationship to the development of hepatocellular carcinoma(HCC)remain largely unknown.This study aimed to clarify these issues.Methods:The expression levels of PCSK9 in HCC tissues and HCC cell lines were determined by the quantitative reverse transcription polymerase chain reaction,Western blot,and immunohistochemical analyses,and the effects of PCSK9 expression on HCC cell biological traits were investigated by overexpressing and downregulating PCSK9 expression in vivo and in vitro.Additionally,the mechanism by which PCSK9 mediated dissociation of glutathione S-transferase Pi 1(GSTP1)dimers and phosphorylation of the Jun N-terminal kinase(JNK)pathway components were investigated.Results:PCSK9 expression levels were significantly lower in HCC tissues than in adjacent non-tumor samples.In vivo and in vitro experiments suggested that PCSK9 inhibited HCC cell proliferation and metastasis.Further analysis showed that PCSK9 interacted with GSTP1 and promoted GSTP1 dimer dissociation and JNK signaling pathway inactivation in HCC cells.Moreover,the relationships between PCSK9 protein expressions and clinical outcomes were investigated.The PCSK9-lo group displayed a significantly shorter overall survival(OS;median OS:64.2 months vs.83.2 months;log-rank statistic:4.237;P=0.04)and recurrencefree survival(RFS;median RFS:26.5 months vs.46.6 months;log-rank statistic:10.498;P=0.001)time than the PCSK9-hi group.Conclusions:PCSK9 inhibited HCC cell proliferation,cell cycle progression,and apoptosis by interacting with GSTP1 and suppressing JNK signaling,suggesting that PCSK9 might act as a tumor suppressor and be a therapeutic target in HCC patients.

Comprehensive Metabolic Profiling and Genome-wide Analysis Reveal Therapeutic Modalities for Hepatocellular Carcinoma

Understanding the details of metabolic reprogramming in hepatocellular carcinoma(HCC)is critical to improve stratification for therapy.Both multiomics analysis and cross-cohort validation were performed to investigate the metabolic dysregulation of 562 HCC patients from 4 cohorts.On the basis of the identified dynamic network biomarkers,227 substantial metabolic genes were identified and a total of 343 HCC patients were classified into 4 heterogeneous metabolic clusters with distinct metabolic characteristics:cluster 1,the pyruvate subtype,associated with upregulated pyruvate metabolism;cluster 2,the amino acid subtype,with dysregulated amino acid metabolism as the reference;cluster 3,the mixed subtype,in which lipid metabolism,amino acid metabolism,and glycan metabolism are dysregulated;and cluster 4,the glycolytic subtype,associated with the dysregulated carbohydrate metabolism.These 4 clusters showed distinct prognoses,clinical characteristics and immune cell infiltrations,which was further validated by genomic alterations,transcriptomics,metabolomics,and immune cell profiles in the other 3 independent cohorts.Besides,the sensitivity of different clusters to metabolic inhibitors varied depending on their metabolic features.Importantly,cluster 2 is rich in immune cells in tumor tissues,especially programmed cell death protein 1(PD-1)-expressing cells,which may be due to the tryptophan metabolism disorders,and potentially benefiting more from PD-1 treatment.In conclusion,our results suggest the metabolic heterogeneity of HCC and make it possible to treat HCC patients precisely and effectively on specific metabolic characteristics.

Hepatic SIRT6 deficit promotes liver tumorigenesis in the mice models

SIRT6 belongs to class III sirtuin family with NAD+-dependent histone deacetylase activities and controls multiple processes including aging,metabolism and inflammation.In recent years,increasing studies showed tumor suppressor role of SIRT6 in HCC development.We established a two-stage DEN followed CC14 induced liver carcinogenesis in the hepatic-specific SIRT6 HKO mice models and found that hepatic S1RT6 deficit significantly promotes liver injury and liver cancer through inhibition of the ERK1/2 pathway.SIRT6 was compensatory up-regulated in mice tumor tissues and human HCC cells and overexpressed SIRT6 inhibits tumor growth both in vitro and in vivo.Taken together,we provide a useful mouse model for delineating the molecular pathways involved in chronic liver diseases and primary liver cancer and suggest that SIRT6 can be a promising target for HCC therapies.

Acquired resistance to third-generation EGFR-TKIs and emerging next-generation EGFR inhibitors

The discovery that mutations in the EGFR gene are detected in up to 50%of lung adenocarcinoma patients,along with the development of highly efficacious epidermal growth factor receptor(EGFR)tyrosine kinase inhibitors(TKIs),has revolutionized the treatment of this frequently occurring lung malignancy.Indeed,the clinical success of these TKIs constitutes a critical milestone in targeted cancer therapy.Three generations of EGFR-TKIs are currently approved for the treatment of EGFR mutation-positive non-small cell lung cancer(NSCLC).The first-generation TKIs include erlotinib,gefitinib,lapatinib,and icotinib;the second-generation ErbB family blockers include afatinib,neratinib,and dacomitinib;whereas osimertinib,approved by the FDA on 2015,is a third-generation TKI targeting EGFR harboring specific mutations.Compared with the first-and second-generation TKIs,third-generation EGFR inhibitors display a significant advantage in terms of patient survival.For example,the median overall survival in NSCLC patients receiving osimertinib reached 38.6 months.Unfortunately,however,like other targeted therapies,new EGFR mutations,as well as additional drug-resistance mechanisms emerge rapidly after treatment,posing formidable obstacles to cancer therapeutics aimed at surmounting this chemoresistance.In this review,we summarize the molecular mechanisms underlying resistance to third-generation EGFR inhibitors and the ongoing efforts to address and overcome this chemoresistance.We also discuss the current status of fourthgeneration EGFR inhibitors,which are of great value in overcoming resistance to EGFR inhibitors that appear to have greater therapeutic benefits in the clinic.

RAS Signaling Targeted Cancer Therapy

Mutated and activated RAS is a key oncogene that drives various human cancers.RAS-targeted therapy has been an extensive research focus but has made little progress given its long history.Several novel binding sites,especially the Cys12 mutation in KRAS G12C,have been identified,paving the way for irreversible inhibitor development.A series of clinical trials have proven their efficacies,and the first RAS G12C-targeting drug sotorasib(AMG-510)received approval for non-small cell lung cancer treatment in May,2021.In another approach,the development of indirect RAS inhibitors that target components of the RAS signaling pathway,including the upstream enzyme farnesyl transferase and the downstream effector molecules SOS1,MEK,AKT,and SHP2,has also made significant progress.This review systematically summarizes the latest progress in RAS signaling pathway-targeted drugs,discusses clinical challenges,and proposes beneficial strategies for RAStargeted therapy.