Poor Prognosis In Hepatocellular Carcinoma Research Articles

Inhibition of DTYMK significantly restrains the growth of HCC and increases sensitivity to oxaliplatin

Most patients with hepatocellular carcinoma (HCC) are in the middle or advanced stage at the time of diagnosis, and the therapeutic effect is limited. Therefore, this study aimed to verify whether deoxythymidylate kinase (DTYMK) increased in HCC and was an effective therapeutic target in HCC. The findings revealed that the DTYMK level significantly increased and correlated with poor prognosis in HCC. However, nothing else is known, except that DTYMK could catalyze the phosphorylation of deoxythymidine monophosphate (dTMP) to form deoxythymidine diphosphate (dTDP). A number of experiments were performed to study the function of DTYMK in vitro and in vivo to resolve this knowledge gap. The knockdown of DTYMK was found to significantly inhibit the growth of HCC and increase the sensitivity to oxaliplatin, which is commonly used in HCC treatment. Moreover, DTYMK was found to competitively combine with miR-378a-3p to maintain the expression of MAPK activated protein kinase 2 (MAPKAPK2) and thus activate the phospho-heat shock protein 27 (phospho-HSP27)/nuclear factor NF-kappaB (NF-κB) axis, which mediated the drug resistance, proliferation of tumor cells, and infiltration of tumor-associated macrophages by inducing the expression of C-C motif chemokine ligand 5 (CCL5). Thus, this study demonstrated a new mechanism and provided a new insight into the role of mRNA in not only encoding proteins to regulate the process of life but also regulating the expression of other genes and tumor microenvironment through the competing endogenous RNA (ceRNA) mechanism.

Fanconi Anemia Complementation Group E, a DNA Repair-Related Gene, Is a Potential Marker of Poor Prognosis in Hepatocellular Carcinoma

Introduction: Fanconi anemia complementation group E (FANCE) is a Fanconi anemia (FA) pathway gene that regulates DNA repair. We evaluated the clinical relevance of FANCE expression in hepatocellular carcinoma (HCC). Methods: First, the associations between the expression of FA pathway genes including FANCE and clinical outcomes in HCC patients were analyzed in 2 independent cohorts: The Cancer Genome Atlas (TCGA, n = 373) and our patient cohort (n = 53). Localization of FANCE expression in HCC tissues was observed by immunohistochemical staining. Gene set enrichment analysis (GSEA) and gene network analysis (SiGN_BN) were conducted using the TCGA dataset. Next, an in vitro proliferation assay was performed using FANCE-knockdown HCC cell lines (HuH7 and HepG2). The association between mRNA expression of FANCE and that of DNA damage response genes in HCC was analyzed using TCGA and Cancer Cell Line Encyclopedia datasets. Finally, the association between FANCE mRNA expression and overall survival (OS) in various digestive carcinomas was analyzed using TCGA data. Results: FANCE was highly expressed in HCC cells. Multivariate analysis indicated that high FANCE mRNA expression was an independent factor predicting poor OS. GSEA revealed a positive relationship between enhanced FANCE expression and E2F and MYC target gene expression in HCC tissues. FANCE knockdown attenuated the proliferation of HCC cells, as well as reduced cdc25A expression and elevated histone H3 pSer10 expression. SiGN_BN revealed that FANCE mRNA expression was positively correlated with DNA damage response genes (H2A histone family member X and checkpoint kinase 1) in HCC tissues. Significant effects of high FANCE expression on OS were observed in hepatobiliary pancreatic carcinomas, including HCC. Conclusions: FANCE may provide a potential therapeutic target and biomarker of poor prognosis in HCC, possibly by facilitating tumor proliferation, which is mediated partly by cell cycle signaling activation.

Integrated Analysis of FAM57A Expression and Its Potential Roles in Hepatocellular Carcinoma.

BackgroundFamily with sequence similarity 57 member A (FAM57A) is a membrane associated gene contributing to lung carcinogenesis. In hepatocellular carcinoma (HCC) and other cancers, whether FAM57A exerts similar roles has been rarely reported. Herein, the biological functions and clinical significance of FAM57A in HCC were explored.MethodsInitially the differential expression of FAM57A between nontumor and HCC tissues was validated using a number of publicly accessible databases and immunohistochemistry (IHC). Then, the Kruskal–Wallis rank sum test or the Wilcoxon rank sum test as well as logistic regression were employed to analyze the association of FAM57A expression with clinical characteristics of HCC. The Cox regression and Kaplan–Meier analyses were conducted to assess the prognostic significance. Besides, with the coexpression analysis, Gene Ontology (GO), Gene Set Enrichment Analysis (GSEA), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, the molecular pathomechanisms that were mediated by FAM57A in HCC were elucidated. Furthermore, the correlations between FAM57A expression and tumor-infiltrating immune cells (TIICs) or immune checkpoint genes were analyzed. Finally, in vitro cell functional assay was carried out to preliminarily verify the role of FAM57A in HCC.ResultsFAM57A expression was demonstrated to be higher in HCC samples than in nontumor samples (all p-values <0.05), statistically correlated with clinicopathological characteristics (clinical stage, T stage, pathological grade), and inversely correlated to HCC patient survival. Univariate and multivariate Cox regression analyses showed that FAM57A expression could independently predict prognosis in HCC patients. Functional enrichment analyses further indicated that FAM57A was involved in multiple tumor-related pathways. FAM57A expression was positively correlated with TIICs, gene markers of TIICs, as well as immune checkpoint genes. Also, high expression of FAM57A predicted a poor prognosis for HCC based on immune cell subgroups. Functional assay of FAM57A knockdown significantly inhibited cell proliferation and induced cell apoptosis in HCC cells.ConclusionsOur results indicated that FAM57A could be used as a biomarker to predict the prognosis and immunotherapy response for HCC patients and might function as an oncogene to promote HCC progression.

Identification and characterization of a 25-lncRNA prognostic signature for early recurrence in hepatocellular carcinoma

BackgroundEarly recurrence is the major cause of poor prognosis in hepatocellular carcinoma (HCC). Long non-coding RNAs (lncRNAs) are deeply involved in HCC prognosis. In this study, we aimed to establish a prognostic lncRNA signature for HCC early recurrence.MethodsThe lncRNA expression profile and corresponding clinical data were retrieved from total 299 HCC patients in TCGA database. LncRNA candidates correlated to early recurrence were selected by differentially expressed gene (DEG), univariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. A 25-lncRNA prognostic signature was constructed according to receiver operating characteristic curve (ROC). Kaplan-Meier and multivariate Cox regression analyses were used to evaluate the performance of this signature. ROC and nomogram were used to evaluate the integrated models based on this signature with other independent clinical risk factors. Gene set enrichment analysis (GSEA) was used to reveal enriched gene sets in the high-risk group. Tumor infiltrating lymphocytes (TILs) levels were analyzed with single sample Gene Set Enrichment Analysis (ssGSEA). Immune therapy response prediction was performed with TIDE and SubMap. Chemotherapeutic response prediction was conducted by using Genomics of Drug Sensitivity in Cancer (GDSC) pharmacogenomics database.ResultsCompared to low-risk group, patients in high-risk group showed reduced disease-free survival (DFS) in the training (p < 0.0001) and validation cohort (p = 0.0132). The 25-lncRNA signature, AFP, TNM and vascular invasion could serve as independent risk factors for HCC early recurrence. Among them, the 25-lncRNA signature had the best predictive performance, and combination of those four risk factors further improves the prognostic potential. Moreover, GSEA showed significant enrichment of “E2F TARGETS”, “G2M CHECKPOINT”, “MYC TARGETS V1” and “DNA REPAIR” pathways in the high-risk group. In addition, increased TILs were observed in the low-risk group compared to the high-risk group. The 25-lncRNA signature negatively associates with the levels of some types of antitumor immune cells. Immunotherapies and chemotherapies prediction revealed differential responses to PD-1 inhibitor and several chemotherapeutic drugs in the low- and high-risk group.ConclusionsOur study proposed a 25-lncRNA prognostic signature for predicting HCC early recurrence, which may guide postoperative treatment and recurrence surveillance in HCC patients.

HNRNPU promotes the progression of hepatocellular carcinoma by enhancing CDK2 transcription

The nuclear matrix-associated protein Heterogeneous Nuclear Ribonucleoprotein U (HNRNPU), also known as SAF-A, is known to maintain active chromatin structure in mouse hepatocytes. However, the functional roles and molecular mechanisms of HNRNPU in the development of hepatocellular carcinoma (HCC) remain largely unknown. Herein, we found that HNRNPU was upregulated in HCC, and the proliferation of HCC cells was inhibited in vitro and in vivo upon HNRNPU knockdown. Moreover, the upregulation of HNRNPU was correlated with poor prognosis in HCC. Mechanistically, HNRNPU bound to the CDK2 gene locus, a key factor in cell cycle regulation, where it was enriched with H3K27 acetylation (H3K27ac), H3K9 acetylation (H3K9ac), and H3K4 mono-methylation (H3K4me1). Furthermore, HNRNPU knockdown reduced the levels of H3K27ac and H3K9ac at the binding site, where the levels of H3K27 tri-methylation (H3K27me3) were increased, eventually leading to the downregulation of CDK2. Collectively, our results provide a new mechanism whereby HNRNPU promotes HCC development by enhancing the transcription of CDK2.

PRCC reduces the sensitivity of cancer cells to DNA damage by inhibiting JNK and ATM/ATR pathways and results in a poor prognosis in hepatocellular carcinoma

Background and aimThe proline rich mitotic checkpoint control factor (PRCC) is involved in the splicing process of pre-mRNA. This study aims to elucidate PRCC molecular function, regulatory mechanism and diagnostic value in hepatocellular carcinoma (HCC).MethodsThe tissue microarray and serum samples from HCC patients were used to investigate the clinical value of PRCC. The biological function and molecular mechanism of PRCC were demonstrated by cell biology, biochemical and animal experiments. The relationship between PRCC and intratumoral heterogeneity (ITH) was analyzed by bioinformatics.ResultsPRCC was highly expressed in HCC tissues and related to the poor prognosis of HCC patients, its contents were elevated in the preoperative sera of HCC patients. PRCC exhibited high application potential as a substitute or adjuvant of alpha-fetoprotein (AFP) for clinical diagnosis of HCC. It had no significant effect on the proliferation of cancer cells, but could inhibit spheroid formation and metastasis of HCC cells in vitro and in vivo. The high ectopic expression of PRCC made cancer cells insensitive to DNA damage, and enhanced the heterogeneity of HCC cells by inhibiting the JNK/ATM/ATR/ATF2 axis. The HCC patients with high PRCC expression had high ITH, which corresponded to a short overall survival in patients.ConclusionsPRCC has high application potential as a substitute or adjuvant of AFP for clinical diagnosis of HCC. The high ectopic expression of PRCC not only caused HCC cells to resist to cell death induced by DNA damage, but also endowed cancer cells with numerous DNA mutations to become increasingly heterogeneous, finally leading to a poor prognosis in HCC patients. These data suggested PRCC could be a promising therapeutic target in HCC patients.

Bioinformatic Evidence Reveals that Cell Cycle Correlated Genes Drive the Communication between Tumor Cells and the Tumor Microenvironment and Impact the Outcomes of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is an aggressive cancer type with poor prognosis; thus, there is especially necessary and urgent to screen potential prognostic biomarkers for early diagnosis and novel therapeutic targets. In this study, we downloaded target data sets from the GEO database, and obtained codifferentially expressed genes using the limma R package and identified key genes through the protein–protein interaction network and molecular modules, and performed GO and KEGG pathway analyses for key genes via the clusterProfiler package and further determined their correlations with clinicopathological features using the Oncomine database. Survival analysis was completed in the GEPIA and the Kaplan–Meier plotter database. Finally, correlations between key genes, cell types infiltrated in the tumor microenvironment (TME), and hypoxic signatures were explored based on the TIMER database. From the results, 11 key genes related to the cell cycle were determined, and high levels of these key genes' expression were focused on advanced and higher grade status HCC patients, as well as in samples of TP53 mutation and vascular invasion. Besides, the 11 key genes were significantly associated with poor prognosis of HCC and also were positively related to the infiltration level of MDSCs in the TME and the HIF1A and VEGFA of hypoxic signatures, but a negative correlation was found with endothelial cells (ECs) and hematopoietic stem cells. The result determined that 11 key genes (RRM2, NDC80, ECT2, CCNB1, ASPM, CDK1, PRC1, KIF20A, DTL, TOP2A, and PBK) could play a vital role in the pathogenesis of HCC, drive the communication between tumor cells and the TME, and act as probably promising diagnostic, therapeutic, and prognostic biomarkers in HCC patients.

CXCR4 promotes gefitinib resistance of Huh7 cells by activating the c-Met signaling pathway.

C‐X‐C chemokine receptor type 4 (CXCR4) expression is associated with poor prognosis of hepatocellular carcinoma (HCC). The aim of this study was to explore the biological role of CXCR4 in gefitinib resistance of HCC. Compared with a normal, non‐gefitinib‐resistant, human HCC cell line (Huh7), CXCR4 mRNA and protein were highly expressed in gefitinib‐resistant Huh7 cells (Huh7‐R). Cell proliferation was decreased, and apoptosis was enhanced in Huh7 cells in the presence of gefitinib. These influences conferred by gefitinib treatment on proliferation and apoptosis of Huh7 cells were abolished by CXCR4 overexpression. CXCR4 knockdown reduced the proliferation ability of HuH‐7R cells after gefitinib treatment. Importantly, CXCR4 overexpression had no influence on caveolin 1 (Cav‐1) expression; similarly, Cav‐1 silencing did not cause a substantive change in CXCR4 expression. However, CXCR4 activated Cav‐1, c‐Met, and Raf‐1 in Huh7 cells, whereas Cav‐1 silencing repressed the expression of Raf‐1 and phosphorylated c‐Met in Huh7 cells. CXCR4 overexpression promoted proliferation and repressed apoptosis in gefitinib‐treated Huh7 cells, which was partly rescued by PHA‐665752 (a c‐Met inhibitor) treatment or c‐Met deficiency. Finally, we constructed a tumor xenograft model to determine the influence of CXCR4 overexpression on tumor growth of HCC. CXCR4 overexpression accelerated tumor growth of HCC, which was abrogated by c‐Met deficiency. These findings demonstrate that CXCR4 overexpression activates c‐Met via the Cav‐1 signaling pathway, thereby promoting gefitinib resistance of Huh7 cells. Thus, this study highlights novel insights into the mechanism of gefitinib resistance of HCC and CXCR4 may become a potential target for HCC treatment.

Upregulation of Nei-Like DNA Glycosylase 3 Predicts Poor Prognosis in Hepatocellular Carcinoma.

Background Accumulating evidence has suggested that Nei-like DNA glycosylase 3 (NEIL3) is associated with human tumors. However, there are few studies on the role of NEIL3 in hepatocellular carcinoma (HCC). The aim of this study was to investigate the expression profile of NEIL3 and its clinical relevance in HCC. Materials and Methods A total of 130 HCC and corresponding nontumor tissues were collected to perform immunohistochemistry (IHC). The clinical relevance and prognostic value of NEIL3 in HCC were analyzed by the chi-square test, Kaplan–Meier analysis, the Cox proportional hazard model, and nomogram. Results IHC showed that the NEIL3 protein level was remarkably upregulated in tumor tissues compared with nontumor tissues (fold change = 1.24; P < 0.001). High NEIL3 expression was significantly correlated with BCLC stage (P=0.004) and TNM stage (P=0.005). Overall survival (OS) and disease-free survival (DFS) rates in the high NEIL3 expression group were significantly worse than those in the low NEIL3 expression group (P=0.007 and P=0.004, respectively). Furthermore, subgroup analysis showed that high NEIL3 expression predicted worse OS and DFS for HCC patients with advanced TNM stage, poorly differentiated tumor, HBsAg positive, or cirrhosis. Multivariate analysis and the prognostic nomograms revealed that tumor NEIL3 level may serve as a promising prognostic indicator for OS and DFS in HCC patients. Conclusion Our findings suggested that NEIL3 might be a potential prognosis assessment marker and therapeutic target for HCC patients.

Serum LAG-3 Predicts Outcome and Treatment Response in Hepatocellular Carcinoma Patients With Transarterial Chemoembolization.

BackgroundTransarterial chemoembolization (TACE) stands for the most commonly utilized therapy for hepatocellular carcinoma (HCC) worldwide. This study was to explore the potential predictive and prognostic roles of LAG-3 and PD-L1 as serum biomarkers in HCC patients underwent TACE treatment.MethodsA total of 100 HCC patients receiving TACE as well as 30 healthy controls were enrolled in the study. Serum LAG-3 and PD-L1 levels were determined at baseline and 3 day after TACE using enzyme-linked immunosorbent assay (ELISA).ResultsWe found serum levels of LAG-3 and PD-L1 were significantly elevated in HCC patients compared with healthy controls. Interestingly, patients with low pre-TACE and post-TACE levels of LAG-3 but not PD-L1 had a high probability of achieving an objective response (OR) after TACE treatment. Additionally, high pre-TACE LAG-3 level was correlated with poor disease outcome, and the patients with both high serum LAG-3 and PD-L1 level had the shorter overall survival (OS) than patients who are either PD-L1 or LAG-3 high or both PD-L1 and LAG-3 low. High pre-TACE serum LAG-3 level was positively associated with more cirrhosis pattern, advanced BCLC stage, pre-TACE alanine aminotransferase (ALT) level, and pre-TACE aspartate aminotransferase (AST) level. Furthermore, in 50 patients who underwent TACE, the serum LAG-3 level was significantly decreased at 3 day after TACE.ConclusionBoth pre-TACE and post-TACE serum LAG-3 levels could serve as powerful predictors for tumor response of TACE, and high pre-TACE serum LAG-3 level was an indicator for poor prognosis in HCC.

Identification of heterogeneous nuclear ribonucleoprotein as a candidate biomarker for diagnosis and prognosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer with a high mortality rate. However, spliceosomal genes are still lacking in the diagnosis and prognosis of HCC. Identification of differentially expressed genes (DEGs) was performed using the limma package in R software. Modules highly related to HCC were obtained by weighted gene co-expression network analysis (WGCNA), and the module genes were analyzed using the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The biomarker for diagnosing HCC was determined by receiver operating characteristic (ROC) curve analysis, and the effect of the biomarker in the diagnosis of HCC was evaluated by performing five-fold cross-validation with logistic regression. HCC specimens from preoperatively treated patients were tested for biomarker by real-time quantitative polymerase chain reaction (RT-qPCR). Kaplan-Meier analysis was used to assess the relationship between biomarker and patient survival. The role of biomarker was evaluated using ESTIMATE analysis in the tumor microenvironment. In this study, 389 DEGs were screened out from three Gene Expression Omnibus (GEO) datasets. We also found that the turquoise module of 123 genes from The Cancer Genome Atlas (TCGA) data was the key module with the highest correlation with HCC traits. Then, 123 genes were analyzed using the KEGG enrichment pathway, and eight genes were found to be most significantly related to the spliceosome pathway. We selected 8 genes and 389 DEGs shared genes, and finally got the only gene, heterogeneous nuclear ribonucleoprotein (hnRNPU). The high expression of hnRNPU was associated with poor prognosis of HCC, and hnRNPU was a biomarker for diagnosing HCC. In the tissues of patients with excellent HCC treatment hnRNPU messenger RNA (mRNA) was lower than in the tissues of patients with poor HCC treatment. High expression of hnRNPU was significantly increased in HCC patients with low stromal (P<0.05), low immune (P<0.05), and low estimation scores (P<0.05), and with high tumor purity (P<0.05) and high malignant progression (P<0.05) of the HCC. The hnRNPU gene identified in this study may become a new biomarker for the diagnosis and prognosis of HCC.

High FITM2 expression promotes cell migration ability of hepatocellular carcinoma by regulating the formation of caveolae and indicates poor patient survival.

Hepatocellular carcinoma (HCC) is among the most malignant tumors with high recurrence and low 5-year survival rate. Lipid metabolism is essential in tumor metastasis, although how altered lipid metabolism promotes HCC progression has not been well elucidated. Fat Storage Inducing Transmembrane Protein 2 (FITM2) is a gene involved in lipid homeostasis and cytoskeletal organization; however, its role in regulating tumor biological behavior has not been evaluated. In this study, immunohistochemistry was performed to evaluate the expression of FITM2 in HCC. Univariate and multivariate analysis was performed to identify the prognostic factors. RNA interference wound healing and transwell experiments were performed to analyze the biological role of FITM2. Western blot analysis was performed to investigate the potential downstream signaling. The results revealed that FITM2 was highly expressed in the intratumoral tissues of HCC. Expression of intratumoral FITM2 was associated with microvascular invasion. FITM2 is an independent risk factor of HCC disease-free survival and overall survival. In vitro studies revealed that knockdown of FITM2 significantly inhibited the migration ability of HCC cells. FITM2 promotes HCC cell migration by regulating the expression of caveolin-1 and promoting the formation of caveolae. These results indicate that high intratumoral expression of FITM2 is associated with poor HCC prognosis, which may be applied to develop a new adjuvant therapy.

The hepatic senescence-associated secretory phenotype promotes hepatocarcinogenesis through Bcl3-dependent activation of macrophages

BackgroundLiver cancer is one of the most common malignancies in the world with a poor prognosis. Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer, accounting for 80–90% of cases. The initiation and progression of HCC are closely associated with chronic liver inflammation. In addition, HCC is often accompanied by cell senescence. Senescent hepatocytes can secrete various inflammatory factors, collectively called the senescence-associated secretory phenotype (SASP). The SASP has been confirmed to promote the occurrence of liver cancer by affecting the inflammatory microenvironment. However, its role and the underlying mechanism of hepatic SASP in hepatocarcinogenesis are not clearly understood. Therefore, a better understanding of the pathogenic mechanisms of the effect of the hepatic SASP on the occurrence of HCC is still needed.MethodsThe study aims to explore the role of SASP factors and the underlying mechanism in tumorigenesis and the progression of HCC in vivo. We used diethylnitrosamine (DEN) combined with carbon tetrachloride (CCl4) (DEN-CCl4) to establish liver cancer model in wild-type (WT) mice and Bcl3 knockout (Bcl3−/−) mice. β-galactosidase (β-gal) staining was performed to evaluate the degree of cellular senescence. Immunohistochemistry (IHC) were used to detect the degree of cellular senescence and the activation of macrophage. PCR chip and clinical tissue chip assays were used to estimate the RNA levels of SASP factors and NF-κB related genes, and their protein levels were examined by Western blot assays.ResultsDEN-CCl4 induced cellular senescence in mouse hepatocytes. In addition, senescent hepatocytes might release a variety of inflammatory factors that further activate macrophages, thereby changing the microenvironmental state and promoting the occurrence of HCC. Mechanistically, the NF-κB pathway is important because it regulates the SASP. Therefore, we used a PCR chip to detect the expression of NF-κB-related genes in senescent liver tissue. Our results showed that the expression of Bcl3 was increased in senescent hepatocytes, and knocking out Bcl3 significantly inhibited the secretion of hepatocyte SASP factors and the activation of macrophages, thereby inhibiting hepatocarcinogenesis. Finally, in clinical tissues adjacent to HCC tissues in patients, the expression of Bcl3 and IL-8 correlated with poor prognosis in HCC patients.ConclusionThe hepatic SASP can further induce the activation of macrophages during hepatocarcinogenesis, thereby promoting the occurrence of HCC, and that this process is closely related to the expression of Bcl3 in hepatocytes.

LncRNA SNHG17 Contributes to Proliferation, Migration, and Poor Prognosis of Hepatocellular Carcinoma.

Long noncoding RNAs (lncRNAs) have been substantially reported to have critical roles in regulating tumorigenesis in recent years. However, the expression pattern and biological function of SNHG17 in hepatocellular carcinoma (HCC) remain unclear. Bioinformatics analysis and qRT-PCR were performed to detect the expression pattern of SNHG17 in HCC tissues, adjacent nontumorous tissues, and cell lines. The effect of SNHG17 on proliferation, migration, and apoptosis of HCC was investigated by knockdown and overexpressing SNHG17 in HCC cell lines. RNA sequencing was utilized to explore the underlying mechanism. Utilizing publicly available TCGA-LIHC, GSE102079 HCC datasets, and qRT-PCR, we found SNHG17 was significantly upregulated in HCC tissues and cell lines and was notably associated with larger tumor size, poorly differentiation, presence of vascular invasion, and advanced TNM stage. Furthermore, gain- and loss-of-function studies demonstrated that SNHG17 promoted cell proliferation and migration and inhibited apoptosis of HCC. By employing RNA sequencing, we found knockdown of SNHG17 caused 1037 differentially expressed genes, highly enriched in several pathways, including metabolic, PI3K-Akt, cell adhesion, regulation of cell proliferation, and apoptotic pathway; among them, 92 were overlapped with SNHG17-related genes in the TCGA-LIHC dataset. Furthermore, ERH, TBCA, TDO2, and PDK4 were successfully validated and found significantly dysregulated in HCC tissues. Moreover, HCC patients with higher SNHG17 expression had a relatively poor overall survival and disease-free survival, and ERH and PDK4 also played a marked role in the prognosis of HCC. Broadly, our findings illustrate that SNHG17 acts as a noncoding oncogene in HCC progression, suggesting its potential value as a novel target for HCC therapy.

Antiviral Therapy Improves Survival in Hepatocellular Carcinoma with Microvascular Invasion: A Propensity Score Analysis.

To investigate the effect of postoperative adjuvant antiviral therapy (AVT) on hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) with microvascular invasion (MVI) after R0 liver resection. A total of 1008 patients with HBV-related HCC with MVI were recruited, which comprises 378 non-AVT groups and 630 AVT groups. Propensity score matching (PSM) was developed to reduce any bias in patient selection. Independent risk factors were identified by Cox regression analysis. After PSM, the 1-, 3-, and 5-year overall survival rates in the AVT group and non-AVT group were 89.2%, 62.4%, 42.1%, and 73.3%, 46.3%, 22.1%, (p < 0.01), respectively. The 1-, 3-, and 5-year recurrence-free survival rates in the AVT group and non-AVT group were 52.5%, 30.4%, 22.1%, and 46.3%, 26.8%, 13.2% (p = 0.02), respectively. Multivariate Cox analysis revealed that postoperative adjuvant AVT was the independent protective factor associated with mortality (HR = 0.55, 95%CI = 0.46-0.67, p < 0.01) and tumor recurrence (HR = 0.81, 95%CI = 0.69-0.96, p = 0.01). Among patients who underwent curative hepatectomy for HBV-related HCC with MVI, postoperative adjuvant AVT was the independent protective factor associated with mortality and tumor recurrence. Given the high rate of postoperative recurrence and poor prognosis of HBV-related HCC with MVI, our findings may have useful clinical significance in the prevention of tumor recurrence in these patients.

Elevated LncRNA TRERNA1 correlated with activation of HIF-1α predicts poor prognosis in hepatocellular carcinoma

BackgroundTranslation regulatory long non-coding RNA 1 (TRERNA1) has been reported to be upregulated in several cancers and accelerate tumor metastasis by inducing epithelial-to-mesenchymal transition (EMT). However, it remains unclear how TRERNA1 is upregulated and whether the upregulation of TRERNA1 influences the prognosis of HCC patients. In this study, we aimed to investigate the prognostic value of TRERNA1 in HCC and the regulatory mechanism underlying TRERNA1 upregulation. MethodsIn situ hybridization was adopted to analyze the expression level of TRERNA1, and immunohistochemistry technique was employed to evaluate the expression level of HIF-1α and E-cadherin. χ2 test was used to assess the association between TRERNA1 level and clinicopathological characteristics of HCC cases, whereas Kaplan-Meier survival analysis, ROC curve analysis and Cox proportional hazards regression model were performed to evaluate the prognostic significance of TRERNA1 expression level in HCC. ResultsTRERNA1 was substantially upregulated in HCC tissues, which was accompanied by aberrant decreased expression of E-cadherin. Elevated TRERNA1 level was correlated with high tumor grade, high recurrence rate and poor survival in patients with HCC. Moreover, TRERNA1 expression level was positively correlated with the activation of HIF-1α. Importantly, high TRERNA1 expression level can be an independent risk factor for poor prognosis in HCC, especially combining elevated TRERNA1 and HIF-1α with decreased E-cadherin predicted a worst prognosis of patients with HCC. ConclusionTRERNA1 is not only a biomarker for predicting poor prognosis in HCC patients, but also can categorize HCC patients into different risk groups for survival when combined with HIF-1α and E-cadherin.

Long non-coding RNA SNHG16 as a potential biomarker in hepatocellular carcinoma: A meta-analysis.

Small nucleolar RNA host gene 16 (SNHG16) has recently been reported as a potential biomarker in various cancers. However, the prognostic value of SNHG16 in hepatocellular carcinoma (HCC) has not been investigated yet. Therefore, the purpose of this study was to reveal the association between SNHG16 expression and clinicopathological characteristics of HCC.Standards-compliant literature was retrieved from multiple public databases, and data on overall survival, disease-free survival, and clinicopathological characteristics related to SNGH16 were extracted and meta-analysis was performed. Additionally, the Cancer Genome Atlas data were analyzed through the gene expression profiling interactive analysis database to verify previous results.A total of 5 reports involving 410 patients with HCC were enrolled. The high expression of SNHG16 indicated worse overall survival (hazard ratio, 2.10; 95% CI, 1.22–3.60; P = .007) and disease-free survival (hazard ratio, 3.38; 95% CI, 1.10–10.40; P = .03). Additionally, the high expression of SNHG16 predicted a larger tumor size, metastasis, and advanced TNM stage.SNHG16 could serve as a potential biomarker of poor prognosis in HCC.

Decreased DHRS1 Expression Is A Novel Predictor of Poor Survival in Patients with Hepatocellular Carcinoma

Aim: To investigate the effect of aberrant expression of DHRS1 on hepatocellular carcinoma (HCC). Materials & methods: Kaplan-Meier and Cox regression analyses were performed to evaluate the correlation between DHRS1 and overall survival. Gene set enrichment analysis was performed to explore the potential function of DHRS1 in HCC. Results: Multiple data analysis revealed that DHRS1 mRNA and protein expression level were remarkably lower in HCC than that in normal tissues. In survival analysis, patients with low DHRS1 expression presented a poorer prognosis, and was an independent risk factor for HCC. Conclusion: Decreased DHRS1 expression may be a potential predictor of poor prognosis in HCC.

Identification of Three Key Genes Associated with Hepatocellular Carcinoma Progression Based on Co-expression Analysis.

Hepatocellular carcinoma (HCC) is the fifth most common cancer and one of the leading causes of cancer-related death in the world. Due to the recurrence of HCC, its survival rate is still low. Therefore, it is vital to seek prognostic biomarkers for HCC. In this study, differential analysis was conducted on gene expression data in The Cancer Genome Atlas -LIHC, and 4482 differentially expressed genes in tumor tissue were selected. Then, weighted gene co-expression network analysis was used to analyze the co-expression of the gained differential genes. By module-trait correlation analysis, the turquoise gene module that was significantly related to tumor grade, pathologic_T stage, and clinical stage was identified. Thereafter, enrichment analysis of genes in this module uncovered that the genes were mainly enriched in the signaling pathways involved in spliceosome and cell cycle. After that, through correlation analysis, 18 hub genes highly correlated with tumor grade, clinical stage, pathologic_T stage, and the turquoise module were selected. Meanwhile, protein-protein interaction (PPI) network was constructed by using genes in the module. Finally, three key genes, heterogeneous nuclear ribonucleoprotein L, serrate RNA effector molecule, and cyclin B2, were identified by intersecting the top 30 genes with the highest connectivity in PPI network and the previously obtained 18 hub genes in the turquoise module. Further survival analysis revealed that high expression of the three key genes predicted poor prognosis of HCC. These results indicated the direction for further research on clinical diagnosis and prognostic biomarkers of HCC.

CISD2 Promotes Resistance to Sorafenib-Induced Ferroptosis by Regulating Autophagy in Hepatocellular Carcinoma.

PurposeSorafenib is a multi-kinase inhibitor that is used as a standard treatment for advanced hepatocellular carcinoma (HCC). However, the mechanism of sorafenib resistance in HCC is still unclear. It has been shown that CISD2 expression is related to the progression and poor prognosis of HCC. Here, we show a new role for CISD2 in sorafenib resistance in HCC.MethodsBioinformatic analysis was used to detect the expression of negative regulatory genes of ferroptosis in sorafenib-resistant samples. The concentration gradient method was used to establish sorafenib-resistant HCC cells. Western blot was used to detect the protein expression of CISD2, LC3, ERK, PI3K, AKT, mTOR, and Beclin1 in HCC samples. Quantitative real-time PCR (qPCR) was used to detect gene expression. CISD2 shRNA and Beclin1 shRNA were transfected to knock down the expression of the corresponding genes. Cell viability was detected by a CCK-8 assay. ROS were detected by DCFH-DA staining, and MDA and GSH were detected with a Lipid Peroxidation MDA Assay Kit and Micro Reduced Glutathione (GSH) Assay Kit, respectively. Flow cytometry was used to detect apoptosis and the levels of ROS and iron ions.ResultsCISD2 was highly expressed in HCC cells compared with normal cells and was associated with poor prognosis in patients. Knockdown of CISD2 promoted a decrease in the viability of drug-resistant HCC cells. CISD2 knockdown promoted sorafenib-induced ferroptosis in resistant HCC cells. The levels of ROS, MDA, and iron ions increased, but the change in GSH was not obvious. Knockdown of CISD2 promoted uncontrolled autophagy in resistant HCC cells. Inhibition of autophagy attenuated CISD2 knockdown-induced ferroptosis. The autophagy promoted by CISD2 knockdown was related to Beclin1. When CISD2 and Beclin1 were inhibited, the effect on ferroptosis was correspondingly weakened.ConclusionInhibition of CISD2 promoted sorafenib-induced ferroptosis in resistant cells, and this process promoted excessive iron ion accumulation through autophagy, leading to ferroptosis. The combination of CISD2 inhibition and sorafenib treatment is an effective therapeutic strategy for resistant HCC.