A race to uncover a panoramic view of primary liver cancer

Introduction Primary liver cancer,the second most common cause of cancer related death worldwide1,presents ethnic,etiological,sex,and geographical diversity2(Figure 1A).At the histological level,liver cancer includes two major types:hepatocellular carcinoma(HCC,about 80%)and cholangiocarcinoma(CCA,about 15%).Many etiological factors contribute to HCC development,such as hepatitis

Bone morphogenetic protein-7 represses hepatic stellate cell activation and liver fibrosis via regulation of TGF-β/Smad signaling pathway

BACKGROUND Liver fibrosis is a refractory disease whose persistence can eventually induce cirrhosis or even liver cancer.Early liver fibrosis is reversible by intervention.As a member of the transforming growth factor-beta(TGF-β)superfamily,bone morphogenetic protein 7(BMP7)has anti-liver fibrosis functions.However,little is known about BMP7 expression changes and its potential regulatory mechanism as well as the relationship between BMP7 and TGF-βduring liver fibrosis.In addition,the mechanism underlying the anti-liver fibrosis function of BMP7 needs to be further explored.AIM To investigate changes in the dynamic expression of BMP7 during liver fibrosis,interactions between BMP7 and TGF-β1,and possible mechanisms underlying the anti-liver fibrosis function of BMP7.METHODS Changes in BMP7 expression during liver fibrosis and the interaction between BMP7 and TGF-β1 in mice were observed.Exogenous BMP7 was used to treat mouse primary hepatic stellate cells(HSCs)to observe its effect on activation,migration,and proliferation of HSCs and explore the possible mechanism underlying the anti-liver fibrosis function of BMP7.Mice with liver fibrosis received exogenous BMP7 intervention to observe improvement of liver fibrosis by using Masson’s trichrome staining and detecting the expression of the HSC activation indicator alpha-smooth muscle actin(α-SMA)and the collagen formation associated protein type I collagen(Col I).Changes in the dynamic expression of BMP7 during liver fibrosis in the human body were further observed.RESULTS In the process of liver fibrosis induced by carbon tetrachloride(CCl4)in mice,BMP7 protein expression first increased,followed by a decrease;there was a similar trend in the human body.This process was accompanied by a sustained increase in TGF-β1 protein expression.In vitro experiment results showed that TGF-β1 inhibited BMP7 expression in a time-and dose-dependent manner.In contrast,high doses of exogenous BMP7 inhibited TGF-β1-induced activation,migration,and proliferation of HSCs;this inhibitory effect was associated with upregulation of pSmad1/5/8 and downregulation of phosphorylation of Smad3 and p38 by BMP7.In vivo experiment results showed that exogenous BMP7 improved liver fibrosis in mice.CONCLUSION During liver fibrosis,BMP7 protein expression first increases and then decreases.This changing trend is associated with inhibition of BMP7 expression by sustained upregulation of TGF-β1 in a time-and dose-dependent manner.Exogenous BMP7 could selectively regulate TGF-β/Smad pathway-associated factors to inhibit activation,migration,and proliferation of HSCs and exert antiliver fibrosis functions.Exogenous BMP7 has the potential to be used as an antiliver fibrosis drug.

Gasdermin D-mediated hepatocyte pyroptosis expands inflammatory responses that aggravate acute liver failure by upregulating monocyte chemotactic protein 1/CC chemokine receptor-2 to recruit macrophages

BACKGROUND Massive hepatocyte death is the core event in acute liver failure(ALF).Gasdermin D(GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death.However,the role of hepatocyte pyroptosis and its mechanisms of expanding inflammatory responses in ALF are unclear.AIM To investigate the role and mechanisms of GSDMD-mediated hepatocyte pyroptosis through in vitro and in vivo experiments.METHODS The expression of pyroptosis pathway-associated proteins in liver tissues from ALF patients and a hepatocyte injury model was examined by Western blot.GSDMD short hairpin RNA(shRNA)was used to investigate the effects of downregulation of GSDMD on monocyte chemotactic protein 1(MCP1)and its receptor CC chemokine receptor-2(CCR2)in vitro.For in vivo experiments,we used GSDMD knockout mice to investigate the role and mechanism of GSDMD in a D-galactose/lipopolysaccharide(D-Galn/LPS)-induced ALF mouse model.RESULTS The levels of pyroptosis pathway-associated proteins in liver tissue from ALF patients and a hepatocyte injury model increased significantly.The level of GSDMD-N protein increased most obviously(P<0.001).In vitro,downregulation of GSDMD by shRNA decreased the cell inhibition rate and the levels of MCP1/CCR2 proteins(P<0.01).In vivo,GSDMD knockout dramatically eliminated inflammatory damage in the liver and improved the survival of DGaln/LPS-induced ALF mice(P<0.001).Unlike the mechanism of immune cell pyroptosis that involves releasing interleukin(IL)-1βand IL-18,GSDMDmediated hepatocyte pyroptosis recruited macrophages via MCP1/CCR2 to aggravate hepatocyte death.However,this pathological process was inhibited after knocking down GSDMD.CONCLUSION GSDMD-mediated hepatocyte pyroptosis plays an important role in the pathogenesis of ALF,recruiting macrophages to release inflammatory mediators by upregulating MCP1/CCR2 and leading to expansion of the inflammatory responses.GSDMD knockout can reduce hepatocyte death and inflammatory responses,thus alleviating ALF.

Systematic screening reveals synergistic interactions that overcome MAPK inhibitor resistance in cancer cells

Objective:Effective adjuvant therapeutic strategies are urgently needed to overcome MAPK inhibitor(MAPKi)resistance,which is one of the most common forms of resistance that has emerged in many types of cancers.Here,we aimed to systematically identify the genetic interactions underlying MAPKi resistance,and to further investigate the mechanisms that produce the genetic interactions that generate synergistic MAPKi resistance.Methods:We conducted a comprehensive pair-wise sgRNA-based high-throughput screening assay to identify synergistic interactions that sensitized cancer cells to MAPKi,and validated 3 genetic combinations through competitive growth,cell viability,and spheroid formation assays.We next conducted Kaplan-Meier survival analysis based on The Cancer Genome Atlas database and conducted immunohistochemistry to determine the clinical relevance of these synergistic combinations.We also investigated the MAPKi resistance mechanisms of these validated synergistic combinations by using co-immunoprecipitation,Western blot,qRTPCR,and immunofluorescence assays.Results:We constructed a systematic interaction network of MAPKi resistance and identified 3 novel synergistic combinations that effectively targeted MAPKi resistance(ITGB3+IGF1R,ITGB3+JNK,and HDGF+LGR5).We next analyzed their clinical relevance and the mechanisms by which they sensitized cancer cells to MAPKi exposure.Specifically,we discovered a novel protein complex,HDGF-LGR5,that adaptively responded to MAPKi to enhance cancer cell stemness,which was up-or downregulated by the inhibitors of ITGB3+JNK or ITGB3+IGF1R.Conclusions:Pair-wise sgRNA library screening provided systematic insights into elucidating MAPKi resistance in cancer cells.ITGB3-+IGF1R-targeting drugs(cilengitide+linsitinib)could be used as an effective therapy for suppressing the adaptive formation of the HDGF-LGR5 protein complex,which enhanced cancer stemness during MAPKi stress.

The advanced development of molecular targeted therapy for hepatocellular carcinoma

Hepatocellular carcinoma(HCC),one of the most common malignant tumors in China,severely threatens the life and health of patients.In recent years,precision medicine,clinical diagnoses,treatments,and innovative research have led to important breakthroughs in HCC care.The discovery of new biomarkers and the promotion of liquid biopsy technologies have greatly facilitated the early diagnosis and treatment of HCC.Progress in targeted therapy and immunotherapy has provided more choices for precise HCC treatment.Multiomics technologies,such as genomics,transcriptomics,and metabolomics,have enabled deeper understanding of the occurrence and development mechanisms,heterogeneity,and genetic mutation characteristics of HCC.The continued promotion and accurate typing of HCC,accurate guidance of treatment,and accurate prognostication have provided more treatment opportunities and prolonged survival timelines for patients with HCC.Innovative HCC research providing an in-depth understanding of the biological characteristics of HCC will be translated into accurate clinical practices for the diagnosis and treatment of HCC.

NLRP6 is correlated with the progression and therapeutic outcome of hepatocellular carcinoma and inhibits the function of CD14^+ cells

Objective:Inflammasomes promote carcinogenesis through an extrinsic pathway and maintain the malignant cancer microenvironment through an intrinsic pathway.Moreover,inflammasomes exert anticancer effects by pyroptosis and immune regulatory functions.Until now,there have been few studies about how inflammasomes contribute to hepatocellular carcinoma(HCC)development.

Abnormal accumulation of RNA helicase DDX5 protein promotes malignancy of hepatocellular carcinoma

Objective:Hepatocellular carcinoma(HCC),the most common type of liver cancer,has a high morbidity and mortality rate,and poor prognosis.There is currently no effective treatment for HCC.RNA helicase DDX5,which acts as a transcriptional co-regulator,is overexpressed in most malignant tumors and promotes cancer cell activities.

Lymph node metastasis of hepatocellular carcinoma is associated with gut microbiota, bile acid metabolism and inflammation

Objective:Hepatocellular carcinoma(HCC)is the most common primary liver cancer and is the second leading cause of cancer-related death globally.Lymph node metastasis(LNM)is negatively correlated with prognosis of HCC patients.The gut microbiota has an important role in development and progression of HCC.In this study.

Serum CA125, CA199, CEA, CA724, and AFP for diagnosis and prognosis prediction in patients with intrahepatic cholangiocarcinoma

Objective:Intrahepatic cholangiocarcinoma(ICC)is a malignancy that involves difficulties in early diagnosis and has extremely poor prognosis.This study aimed to evaluate serum carbohydrate antigen 125(CA125),serum carbohydrate antigen 199(CA199),carcinoembryonic antigen(CEA),carbohydrate antigen 724(CA724)and alpha-fetoprotein(AFP)as biomarkers for diagnosis and prognosis of ICC patients.

Exploratory study of highly susceptible to SARS-CoV-2 populations

The coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),is threatening public health.The human angiotensin-converting enzyme 2(ACE2)has a remarkably high affinity binding to SARS-CoV-2.This study explored whether certain populations,including obese and cancer patients,are susceptible to SARS-CoV-2.The expression pattern of ACE2 in normal and tumor tissues of cancer patients was compared by the search for network database and re-analysis of pubic data.The level of ACE2 expression in normal adipose tissue was higher than that in normal lung tissue,which indicated the adipose tissue might be vulnerable to SARS-CoV-2;the levels of ACE2 expressed by adipocytes and adipose progenitor cells were similar between non-obese individuals and obese individuals(BMI>29),but obese individuals have more adiposes so as to increase the number of ACE2-expressing cells;the expression of ACE2 in tumor tissues posed by five different types of cancers increased significantly compared with that in adjacent tissues.Therefore,we proposed the following hypothesis:the obese individuals and five types of cancer patients might have a higher risk of SARS-CoV-2 infection,which might become the target population of SARS-CoV-2 infection in the future.

A novel strategy for identifying biomarker in serum of patient with COVID-19 using immune complex

Dear Editor,COVID-19(Coronavirus Disease 2019)is a disease caused by the single-stranded sense RNA virus SARS-CoV-2(severe acute respiratory syndrome coronavirus 2),which has caused a global public health crisis.1 However,so far no effective serum marker has been found as a biomarker for COVID-19 diagnosis,except that viral nucleic acid detection is an effective evidence of SARS-CoV-2 infection.

Molecular deconvolution of the neutralizing antibodies in duced by an in activated SARS-CoV-2 virus vaccine

Dear Editor,The rapid emerge nee and persistence of the pan demic caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)has had enormous impacts on global health and the economy.Effective vaccines against SARS-CoV-2 are urgently needed to control the coronavirus disease 2019(COVID-19)pandemic,and multiple vaccines have been found to be efficacious in preventing symptomatic COVID-19(Polack et al.,2020;Wu et al.,2020;Jones and Roy,2021).