Prognostic significance of neutrophil to lymphocyte ratio in pancreatic cancer: A meta-analysis

AIM:To conduct a meta-analysis evaluating theassociation between the peripheral blood neutrophil to lymphocyte ratio(NLR) and the outcome of patients with pancreatic cancer.METHODS:Studies evaluating the relationship between the peripheral blood NLR and outcome of patients with pancreatic cancer published up to May 2014 were searched using electronic databases, including Pub Med, Web of Science, Embase and Ovid.A meta-analysis was performed to pool the hazard ratios(HRs) or odds ratios(ORs) and their 95% confidence intervals(CIs) using either a fixed-effects model or a random-effects model to quantitatively assess the prognostic value of NLR and its association with clinicopathological parameters.RESULTS:Eleven studies containing a total of 1804 patients were eligible according to our selection criteria, and combined hazard ratios indicated that high NLR was a poor prognostic marker for pancreatic cancer patients because it had an unfavorable impact on the overall survival(OS)(HR =2.61, 95%CI:1.68-4.06, P =0.000) and cancer specific survival(HR =1.66, 95%CI:1.08-2.57, P =0.021).Subgroup analysis revealed that high NLR was associated with poor OS in patients with mixed treatment(HR =4.36, 95%CI:2.50-7.61, P =0.000), chemotherapy(HR =2.08, 95%CI:1.49-2.9, P =0.000), or surgical resection(HR =1.2, 95%CI:1.00-1.44, P =0.048).Additionally, high NLR was significantly correlated with tumor metastasis(OR =1.69, 95%CI:1.10-2.59, P =0.016), poor tumor differentiation(OR =2.75, 95%CI:1.19-6.36, P =0.016), poor performance status(OR =2.56, 95%CI:1.63-4.03, P =0.000), high cancer antigen 199(OR =2.62, 95%CI:1.49-4.60, P =0.000), high C-reactive protein(OR =4.32, 95%CI:2.71-6.87, P =0.000), and low albumin(OR =3.56, 95%CI:1.37-9.27, P =0.009).CONCLUSION:High peripheral blood NLR suggested a poor prognosis for patients with pancreatic cancer,and it could be a novel marker of survival evaluation and could help clinicians develop therapeutic strategies for pancreatic cancer patients.

Relationship between autophagy and perineural invasion, clinicopathological features, and prognosis in pancreatic cancer

AIM To investigate the relationship between autophagy and perineural invasion(PNI), clinical features, and prognosis in patients with pancreatic cancer. METHODS Clinical and pathological data were retrospectively collected from 109 patients with pancreatic ductal adenocarcinoma who underwent radical resection at the First Affiliated Hospital of Zhengzhou University from January 2011 to August 2016. Expression levels of the autophagy-related protein microtubuleassociated protein 1 A/1 B-light chain 3(LC3) and PNI marker ubiquitin carboxy-terminal hydrolase(UCH) in pancreatic cancer tissues were detected by immunohistochemistry. The correlations among LC3 expression, PNI, and clinical pathological features in pancreatic cancer were analyzed. The patients were followed for further survival analysis. RESULTS In 109 cases of pancreatic cancer, 68.8%(75/109) had evidence of PNI and 61.5%(67/109) had high LC3 expression. PNI was associated with lymph node metastasis, pancreatitis, and CA19-9 levels(P < 0.05). LC3 expression was related to lymph node metastasis(P < 0.05) and was positively correlated with neural invasion(P < 0.05, r = 0.227). Multivariate logistic regression analysis indicated that LC3 expression, lymph node metastasis, pancreatitis, and CA19-9 level were factors that influenced neural invasion, whereas only neural invasion itself was an independent factor for high LC3 expression. Univariate analysis showed that LC3 expression, neural invasion, and CA19-9 level were related to the overall survival of pancreatic cancer patients(P < 0.05). Multivariate COX regression analysis indicated that PNI and LC3 expression were independent risk factors for poor prognosis in pancreatic cancer(P < 0.05). CONCLUSION PNI in patients with pancreatic cancer is positively related to autophagy. Neural invasion and LC3 expression are independent risk factors for pancreatic cancer with a poor prognosis.

Novel index for the prediction of significant liver fibrosis and cirrhosis in chronic hepatitis B patients in China

BACKGROUND Noninvasive,practical,and convenient means of detection for the prediction of liver fibrosis and cirrhosis in China are greatly needed.AIM To develop a precise noninvasive test to stage liver fibrosis and cirrhosis.METHODS With liver biopsy as the gold standard,we established a new index,[alkaline phosphatase(U/L)+gamma-glutamyl transpeptidase(U/L)/platelet(109/L)(AGPR)],to predict liver fibrosis and cirrhosis.In addition,we compared the area under the receiver operating characteristic curve(AUROC)of AGPR,gammaglutamyl transpeptidase to platelet ratio,aspartate transaminase to platelet ratio index,and FIB-4 and evaluated the accuracy of these routine laboratory indices in predicting liver fibrosis and cirrhosis.RESULTS Correlation analysis revealed a significant positive correlation between AGPR and liver fibrosis stage(P<0.001).In the training cohort,the AUROC of AGPR was 0.83(95%CI:0.78-0.87)for predicting fibrosis(≥F2),0.84(95%CI:0.79-0.88)for predicting extensive fibrosis(≥F3),and 0.87(95%CI:0.83-0.91)for predicting cirrhosis(F4).In the validation cohort,the AUROCs of AGPR to predict≥F2,≥F3 and F4 were 0.83(95%CI:0.77-0.88),0.83(95%CI:0.77-0.89),and 0.84(95%CI:0.78-0.89),respectively.CONCLUSION The AGPR index should become a new,simple,accurate,and noninvasive marker to predict liver fibrosis and cirrhosis in chronic hepatitis B patients.

hMex-3A is associated with poor prognosis and contributes to the progression of hepatocellular carcinoma

Background:HMex-3A,an RNA-binding protein,was found to be associated with tumorigenesis.However,the roles of h Mex-3A in hepatocellular carcinoma(HCC)progression remained unclear.Methods:The different expression of h Mex-3A between HCC tissues and non-tumor tissues was evaluated using The Cancer Genome Atlas database.Thereafter,the h Mex-3A expression was evaluated in HCC tissues using Western blotting and q RT-PCR.Immunohistochemistry was performed to investigate the association between h Mex-3 A level and clinicopathological features including prognosis in HCC patients.In addition,we used si-h Mex-3A to knockdown h Mex-3A in HCC cells to test Cell Counting Kit-8,colony formation,cell migration and invasion.Results:The h Mex-3A expression was significantly elevated in HCC tissues.Analysis of the clinicopathological parameters suggested that h Mex-3A expression was significantly associated with pathological grade(P=0.019)and TNM stage(P=0.001)in HCC.Moreover,univariate and multivariate Coxregression analyses revealed that high h Mex-3A expression(HR=1.491,95%CI:1.107–2.007;P=0.009)was an independent risk factor for overall survival in HCC patients.Finally,we confirmed that si-h Mex-3A could significantly inhibit HCC cell proliferation,migration,and invasion in vitro.Conclusions:HMex-3A may contribute to the progression of HCC and might be used as a novel therapeutic target and prognostic marker in HCC.

Complement activation targeted inhibitor C2-FH ameliorates acetaminophen-induced liver injury in mice

BACKGROUND Complement activation is recognized as an important factor in the progression of liver damage caused by acetaminophen(APAP).However,the role of the complement inhibitor C2-FH in APAP-induced liver injury remains unclear.AIM To explore C2-FH in protecting against APAP-induced liver injury by inhibiting complement activation.METHODS A model of APAP-induced liver injury was used to study the protective effect of C2-FH on liver injury.C2-FH was administered through intraperitoneal injection 30 minutes after APAP treatment.We detected the effects of C2-FH on liver function,inflammatory response and complement activation.Additionally,RNA-sequencing(RNA-Seq)analysis was conducted to understand the mechanism through which C2-FH provides protection against APAP-induced liver injury.RESULTS C2-FH inhibited the increase in serum alanine aminotransferase activity,aspartate aminotransferase activity and lactate dehydrogenase,and reduced liver tissue necrosis caused by APAP.Moreover,it attenuated the inflammatory response and inhibited complement activation in APAP-induced liver injury.RNA-Seq analysis provided additional explanations for the protective role of C2-FH against APAP-induced liver injury.CONCLUSION C2-FH attenuates APAP-induced liver injury by inhibiting complement activation.

High level of intercellular adhesion molecule-1 affects prognosis of patients with hepatocellular carcinoma

AIM: To determine the cut-off value of intercellular adhesion molecule-1(ICAM-1) and assess the correlation of ICAM-1 with clinicopathological features and the prognosis of hepatocellular carcinoma(HCC)patients who underwent surgical resection.METHODS: We prospectively collected clinicopathological data from 236 HCC patients who had undergone successful hepatectomy. Receiver operating characteristic curve analysis was performed to determine the optimal cut-off value of ICAM-1. Enzymelinked immunosorbent assay was used to measure the concentration of ICAM-1 in 236 serum samples isolated from HCC patients and the stratified analysis was used to compare the serum level of ICAM-1 in different HCC subgroups. Immunohistochemistry was performed to test the expression level of the ICAM-1 protein in76 cases of HCC tissues and their adjacent normal liver tissues(ANLT). The survival probability of HCC patients was estimated using Kaplan-Meier plots and differences between the groups were obtained using the log-rank test. Furthermore, independent indicatorsof the prognosis were acquired using a stepwise Cox proportional hazard model to analyze a series of predictors that were associated with disease-free survival(DFS) and overall survival(OS) in HCC patients.RESULTS: Our findings suggested that ICAM-1promotes HCC metastasis and high serum ICAM-1 is significantly associated with alpha-fetoprotein(AFP)(P = 0.022), clinical tumor-node-metastasis stage(P< 0.001), portal vein tumor thrombus(P = 0.005),distant metastasis(P = 0.016) and recurrence(P= 0.034). We further detected the ICAM-1 protein in HCC specimens and found that 56 of 76(73.7%)HCC tissues had ICAM-1 positive staining while only23 of 76(30.3%) ANLT were positively stained(P <0.0001). Survival analysis indicated that HCC patients with increased ICAM-1 concentrations had significantly shorter DFS and OS after resection. A multivariate analysis showed that ICAM-1 > 684 ng/mL was an independent factor for DFS(HR = 1.643; 95%CI:1.125-2.401; P = 0.010) and OS(HR = 1.692; 95%CI:1.152-2.486; P = 0.007).CONCLUSION: ICAM-1 may be a promising serological biomarker for HCC diagnosis and an independent predictor of DFS and OS after surgical resection and may provide a useful reference for the prediction of intra- and extrahepatic metastasis.

Anti-hepatoma Effect of DC2.4 Cells Transfected with Tumor-Associated Antigen Cdc25C In Vitro

Objective Cell division cyclin 25 homolog C(Cdc25C)is a tumor-associated antigen candidate gene,and this may be used as an effective target in cancer treatment.The present study aims to evaluate the lysis effect of cytotoxic T lymphocytes(CTLs)induced by dendritic cell line DC2.4 overexpressing Cdc25C,and the feasibility of Cdc25C as a component in hepatoma immunotherapy.Methods The mouse Cdc25C gene was ligated into a lentiviral vector,and transfected into DC2.4 cells.The DC2.4 cell phenotype and cytokine secretion were determined by flow cytometry and ELISA,respectively.CD8^(+)T cells were sorted from the spleens of C57BL/6 mice using a magnetic bead sorting kit obtained from Miltenyi Biotech,Germany,and co-cultured with DC2.4 cells for one week as effector cells.Then,IL-2,granzyme B and perforin were detected in the CTL culture medium by ELISA.Next,time-resolved fluorescence immunoassay was used to detect the immune killing effect of Cdc25C-specific CTLs on target cells.Meanwhile,the effect of blocking MHC-I sites on target cells with a monoclonal anti-MHC-I antibody was evaluated.Results The results revealed that Cdc25C could be stably overexpressed in DC2.4 cells by LV-Cdc25C infection.DC2.4 cells transfected with LV-Cdc25C secreted more IL-6,IL-12,TNF-αand IFN-γ,and had higher expression levels of CD40,CD86,CCR7 and MHC-II than unaltered DC2.4 cells.The elevated Cdc25C in dendritic cells also further increased the secretion of IL-2,granzyme B and perforin to elicit Cdc25C-specific CTLs,and induced the higher cytotoxicity in Hepa1-6 cell lines(P<0.05),but this had no effect on the target cells when MHC-I monoclonal antibodies were blocked.Conclusion DC2.4 cells transfected with LV-Cdc25C can induce specific CTLs,and result in a strong cellular immune response.The dendritic cells that overexpress Cdc25C may be useful for hepatoma immunotherapy.

Sphingolipid metabolism affects the anticancer effect of cisplatin

Cisplatin,a DNA crosslinking agent,is widely used for the treatment of a variety of solid tumors.Numerous studies have demonstrated that sphingolipid metabolism,which acts as a target for cisplatin treatment,is a highly complex network that consists of sphingolipid signaling molecules and related catalytic enzymes.Ceramide(Cer),which is the central molecule of this network,has been established to induce apoptosis.However,another molecule,sphingosine-1-phosphate(S1P),exerts the opposite function,i.e.,serves as a regulator of pro-survival.Other sphingolipid molecules,including dihydroceramide,ceramide-1-phosphate,glucosylceramide(Glu Cer),and sphingosine(Sph),or sphingolipid catalytic enzymes such as Sph kinase(Sph K),Cer synthase(Cer S),and S1 P lyase,have also attracted considerable attention,particularly Cer,Glu Cer,Sph K,Cer S,and S1 P lyase,which have been implicated in cisplatin resistance.This review summarizes specific molecules involved in sphingolipid metabolism and related catalytic enzymes affecting the anticancer effect of cisplatin,particularly in relation to induction of apoptosis and drug resistance.

Radiomics model based on contrast-enhanced computed tomography to predict early recurrence in patients with hepatocellular carcinoma after radical resection

BACKGROUND Radical resection remains an effective strategy for patients with hepatocellular carcinoma(HCC).Unfortunately,the postoperative early recurrence(recurrence within 2 years)rate is still high.AIM To develop a radiomics model based on preoperative contrast-enhanced computed tomography(CECT)to evaluate early recurrence in HCC patients with a single tumour.METHODS We enrolled a total of 402 HCC patients from two centres who were diagnosed with a single tumour and underwent radical resection.First,the features from the portal venous and arterial phases of CECT were extracted based on the region of interest,and the early recurrence-related radiomics features were selected via the least absolute shrinkage and selection operator proportional hazards model(LASSO Cox)to determine radiomics scores for each patient.Then,the clinicopathologic data were combined to develop a model to predict early recurrence by Cox regression.Finally,we evaluated the prediction performance of this model by multiple methods.RESULTS A total of 1915 radiomics features were extracted from CECT images,and 31 of them were used to determine the radiomics scores,which showed a significant difference between the early recurrence and nonearly recurrence groups.Univariate and multivariate Cox regression analyses showed that radiomics scores and serum alphafetoprotein were independent indicators,and they were used to develop a combined model to predict early recurrence.The area under the receiver operating characteristic curve values for the training and validation cohorts were 0.77 and 0.74,respectively,while the C-indices were 0.712 and 0.674,respectively.The calibration curves and decision curve analysis showed satisfactory accuracy and clinical utilities.Kaplan-Meier curves based on recurrence-free survival and overall survival showed significant differences.CONCLUSION The preoperative radiomics model was shown to be effective for predicting early recurrence among HCC patients with a single tumour.

Calycosin attenuates severe acute pancreatitis-associated acute lung injury by curtailing high mobility group box 1-induced inflammation

BACKGROUND Acute lung injury(ALI)is a common and life-threatening complication of severe acute pancreatitis(SAP).There are currently limited effective treatment options for SAP and associated ALI.Calycosin(Cal),a bioactive constituent extracted from the medicinal herb Radix Astragali exhibits potent anti-inflammatory properties,but its effect on SAP and associated ALI has yet to be determined.AIM To identify the roles of Cal in SAP-ALI and the underlying mechanism.METHODS SAP was induced via two intraperitoneal injections of L-arg(4 g/kg)and Cal(25 or 50 mg/kg)were injected 1 h prior to the first L-arg challenge.Mice were sacrificed 72 h after the induction of SAP and associated ALI was examined histologically and biochemically.An in vitro model of lipopolysaccharide(LPS)-induced ALI was established using A549 cells.Immunofluorescence analysis and western blot were evaluated in cells.Molecular docking analyses were conducted to examine the interaction of Cal with HMGB1.RESULTS Cal treatment substantially reduced the serum amylase levels and alleviated histopathological injury associated with SAP and ALI.Neutrophil infiltration and lung tissue levels of neutrophil mediator myeloperoxidase were reduced in line with protective effects of Cal against ALI in SAP.Cal treatment also attenuated the serum levels and mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α,interleukin-6,IL-1β,HMGB1 and chemokine(CXC motif)ligand 1 in lung tissue.Immunofluorescence and western blot analyses showed that Cal treatment markedly suppressed the expression of HMGB1 and phosphorylated nuclear factor-kappa B(NF-κB)p65 in lung tissues and an in vitro model of LPSinduced ALI in A549 cells suggesting a role for HGMB1 in the pathogenesis of ALI.Furthermore,molecular docking analysis provided evidence for the direct interaction of Cal with HGMB1.CONCLUSION Cal protects mice against L-arg-induced SAP and associated ALI by attenuating local and systemic neutrophil infiltration and inflammatory response via inhibition of HGMB1 and the NF-κB signaling pathway.

Preoperative contrast-enhanced computed tomography-based radiomics model for overall survival prediction in hepatocellular carcinoma

BACKGROUND Hepatocellular carcinoma(HCC)is the most common primary liver malignancy with a rising incidence worldwide.The prognosis of HCC patients after radical resection remains poor.Radiomics is a novel machine learning method that extracts quantitative features from medical images and provides predictive information of cancer,which can assist with cancer diagnosis,therapeutic decision-making and prognosis improvement.AIM To develop and validate a contrast-enhanced computed tomography-based radiomics model for predicting the overall survival(OS)of HCC patients after radical hepatectomy.METHODS A total of 150 HCC patients were randomly divided into a training cohort(n=107)and a validation cohort(n=43).Radiomics features were extracted from the entire tumour lesion.The least absolute shrinkage and selection operator algorithm was applied for the selection of radiomics features and the construction of the radiomics signature.Univariate and multivariate Cox regression analyses were used to identify the independent prognostic factors and develop the predictive nomogram,incorporating clinicopathological characteristics and the radiomics signature.The accuracy of the nomogram was assessed with the concordance index,receiver operating characteristic(ROC)curve and calibration curve.The clinical utility was evaluated by decision curve analysis(DCA).Kaplan–Meier methodology was used to compare the survival between the low-and high-risk subgroups.RESULTS In total,seven radiomics features were selected to construct the radiomics signature.According to the results of univariate and multivariate Cox regression analyses,alpha-fetoprotein(AFP),neutrophil-to-lymphocyte ratio(NLR)and radiomics signature were included to build the nomogram.The C-indices of the nomogram in the training and validation cohorts were 0.736 and 0.774,respectively.ROC curve analysis for predicting 1-,3-,and 5-year OS confirmed satisfactory accuracy[training cohort,area under the curve(AUC)=0.850,0.791 and 0.823,respectively;validation cohort,AUC=0.905,0.884 and 0.911,respectively].The calibration curve analysis indicated a good agreement between the nomogram-prediction and actual survival.DCA curves suggested that the nomogram had more benefit than traditional staging system models.Kaplan-Meier survival analysis indicated that patients in the low-risk group had longer OS and disease-free survival(all P<0.0001).CONCLUSION The nomogram containing the radiomics signature,NLR and AFP is a reliable tool for predicting the OS of HCC patients.

Degradation of helicase-like transcription factor(HLTF)byβ-TrCP promotes hepatocarcinogenesis via activation of the p62/mTOR axis

Helicase-like transcription factor (HLTF) has been found to be involved in the maintenance of genome stability and tumoursuppression, but whether its downregulation in cancers is associated with posttranslational regulation remains unclear. Here, weobserved that HLTF was significantly downregulated in hepatocellular carcinoma (HCC) tissues and positively associated with thesurvival of HCC patients. Mechanistically, the decreased expression of HLTF in HCC was attributed to elevated β-TrCP-mediated ubiquitination and degradation. Knockdown of HLTF enhanced p62 transcriptional activity and mammalian target of rapamycin (mTOR)activation, leading to HCC tumourigenesis. Inhibition of mTOR effectively blocked β-TrCP overexpression- or HLTF knockdownmediated HCC tumourigenesis and metastasis. Furthermore, in clinical tissues, decreased HLTF expression was positively correlatedwith elevated expression of β-TrCP, p62, or p-mTOR in HCC patients. Overall, our data not only uncover new roles of HLTF in HCCcell proliferation and metastasis, but also reveal a novel posttranslational modification of HLTF by β-TrCP, indicating that theβ-TrCP/HLTF/p62/mTOR axis may be a new oncogenic driver involved in HCC development. This finding provides a potentialtherapeutic strategy for HCC patients by targeting the β-TrCP/HLTF/p62/mTOR axis.

Effect of Upregulated DNA Replication and Sister Chromatid Cohesion 1 Expression on Proliferation and Prognosis in Hepatocellular Carcinoma

Background: DNA replication and sister chromatid cohesion 1 (DSCC1) (also called DCC1) is a component of an alternative replication factor C complex that loads proliferating cell nuclear antigen onto DNA during S phase of the cell cycle. It is located at 8q24 and frequently amplified in hepatocellular carcinoma (HCC). However, the role of DSCC1 in the carcinogenesis and progress of HCC has not been fully investigated. Here, we aimed to assert the importance of DSCC1 in the HCC. Methods: In this study, copy number variation data and RNA sequencing data were used to calculate the DNA copy number and mRNA expression of DSCC1 in HCC. Quantitative polymerase chain reaction, Western blotting, and immunohistochemistry analysis were used to determine the mRNA and protein level of DSCC1 in HCC. The Kaplan–Meier analysis and univariate and multivariate Cox regression analysis were used to assess the association of DSCC1 with the overall survival (OS) of HCC patients. Moreover, lentiviral shRNA was used to knockdown DSCC1, and then, colony?forming assay, cell cycle assay, and cell proliferation assay were performed to evaluate the impact of DSCC1 silencing on HCC cell lines. Results: We found that DSCC1 was amplified and highly expressed in HCC tumor tissues than in nontumor tissues. We then found that the overexpression of both mRNA and protein of DSCC1 was linked to the bad prognosis of HCC patients. Astonishingly, the protein level of DSCC1 was an independent prognostic factor for OS (hazard ratio, 1.79; 95% confidence interval, 1.17–2.74; P = 0.007). Furthermore, the clonogenic capacity of DSCC1?amplified HCC cell lines (MHCC?97H, MHCC?97L, and Hep3B) was significantly inhibited by transduction of a lentiviral shRNA that targets DSCC1. We also showed that knockdown of DSCC1 induced G0–G1 cell cycle arrest (increased from 60% to more than 80%) and greatly inhibited the proliferation of HCC cell lines. Conclusion: These results suggest that DSCC1 is a putative HCC driver gene that promotes proliferation and is associated with poor prognosis in HCC.

Regulatory factor X5 promotes hepatocellular carcinoma progression by transactivating tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta and suppressing apoptosis

Background:Our previous studies have shown that regulatory factor X5(RFX5),a classical transcription regulator of MHCⅡ genes,was obviously overexpressed in hepatocellular carcinoma(HCC)tumors.However,the role of RFX5 in the carcinogenesis and progress of HCC remains unknown.This study aimed to reveal its biological significance and the underlying mechanism in HCC.Methods:RFX5 mRNA expression level and copy number variation in HCC tumors and cell lines were determined by analyzing deposited data sets in the Cancer Genome Atlas and Gene Expression Omnibus database.The biological significance of RFX5 in HCC was investigated by monitoring the colony formation and subcutaneous tumor growth capacity when RFX5 was silenced with lentiviral short hairpin RNA and CRISPR7Cas9 system in HCC cell lines.The downstream gene transcriptionally activated by RFX5 in HCC cells was determined by chromatin immunoprecipitation and luciferase reporter assay.The involvement of tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein theta(YWHAQ)in HCC development was further determined by performing colony formation rescue assay and subcutaneous tumor growth rescue experiment.The association of YWHAQ with recurrence-free survival of patients with HCC was assessed by Kaplan-Meier analysis.Moreover,apoptosis level and the protein level of p53 pathway were determined to reveal the mechanism of RFX5 in driving HCC development.Results:RFX5 was amplified and highly overexpressed in HCC tumor tissues compared with the corresponding non-tumor tissues.The mRNA expression level of RFX5 was significantly correlated with its DNA copy number(r=0.4,P<0.001).Functional study demonstrated that RFX5 was required for both clonogenic forming in vitro and subcutaneous tumor growth in vivo of HCC cells.Further study identified YWHAQ,namely 14-3-3 tau,as a key downstream transcriptional target gene of RFX5,which was tightly regulated by RFX5 in HCC.Moreover,overexpression of YWHAQ largely rescued the clonogenic growth of HCC cells that was suppressed by RFX5 knockdown.In addition,overexpression of YWHAQ in primary tumor was linked to poor prognosis of patients with HCC.These results demonstrated that YWHAQ was a downstream effector of RFX5 in HCC.Notably,RFX5-YWHAQ pathway could protect cells from apoptosis by suppressing the p53 and Bax in HCC.Conclusion:RFX5 is a putative HCC driver gene that plays an important role in the development and progression of HCC by transactivating YWHAQ and suppressing apoptosis.

Chinese expert consensus on conversion therapy for hepatocellular carcinoma(2021 edition)

Recent advances in systemic and locoregional treatments for patients with unresectable or advanced hepatocellular carcinoma(HCC)have resulted in improved response rates.This has provided an opportunity for selected patients with initially unresectable HCC to achieve adequate tumor downstaging to undergo surgical resection,a‘conversion therapy’strategy.However,conversion therapy is a new approach to the treatment of HCC and its practice and treatment protocols are still being developed.Review the evidence for conversion therapy in HCC and develop consensus statements to guide clinical practice.Evidence review:Many research centers in China have accumulated significant experience implementing HCC conversion therapy.Preliminary findings and data have shown that conversion therapy represents an important strategy to maximize the survival of selected patients with intermediate stage to advanced HCC;however,there are still many urgent clinical and scientific challenges for this therapeutic strategy and its related fields.In order to summarize and learn from past experience and review current challenges,the Chinese Expert Consensus on Conversion Therapy for Hepatocellular Carcinoma(2021 Edition)was developed based on a review of preliminary experience and clinical data from Chinese and non-Chinese studies in this field and combined with recommendations for clinical practice.Sixteen consensus statements on the implementation of conversion therapy for HCC were developed.The statements generated in this review are based on a review of clinical evidence and real clinical experience and will help guide future progress in conversion therapy for patients with HCC.