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• Retraction pp undefined-undefined

  Retraction for: The cross-talk between DDR1 and STAT3 promotes the development of hepatocellular carcinoma

  Relevance score: 6.452524

  Ye Lin, Haosheng Jin, Xianqiu Wu, Zhixiang Jian, Xiongfeng Zou, Jianfeng Huang, Renguo Guan, Xiangling Wei

  Keywords: hepatocellular carcinoma, DDR1, STAT3, EMT, glutamine metabolism

  Published in Aging on June 15, 2024

• Correction

  Correction for: Comprehensive analysis of prognostic value, relationship to cell cycle, immune infiltration and m6A modification of ZSCAN20 in hepatocellular carcinoma

  Relevance score: 6.452524

  Fang Jiayu, Yike Jiang, Xuanrui Zhou, Minqin Zhou, Jingying Pan, Yun Ke, Jing Zhen, Da Huang, Weifan Jiang

  Keywords: hepatocellular carcinoma, ZSCAN20, biomarker, prognosis, immune infiltrates

  Published in Aging on April 29, 2023

• Research Paper Volume 14, Issue 7 pp 3276-3292

  An immune subtype-related prognostic signature of hepatocellular carcinoma based on single-cell sequencing analysis

  Relevance score: 5.2042146

  Jiaheng Xie, Liang Chen, Qingmei Sun, Haobo Li, Wei Wei, Dan Wu, Yiming Hu, Zhechen Zhu, Jingping Shi, Ming Wang

  Keywords: hepatocellular carcinoma, single-cell sequencing analysis, differential expression analysis, immune microenvironment, prognostic model

  Published in Aging on April 12, 2022

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  Hepatocellular carcinoma (HCC) is one of the most common cancers in the world and is often associated with a poor prognosis. The main reason for this poor prognosis is that inconspicuous early symptoms lead to delayed diagnosis. Treatment options for advanced HCC remain limited and ineffective. In this context, the exploration of the immune microenvironment in HCC becomes attractive. In this study, we divided HCC into immune cell and non-immune cell subtypes, by single-cell sequencing analysis of GEO dataset GSE146115. We found differentially expressed genes in the two subtypes, which we used to construct a prognostic model for HCC through Cox and Lasso regressions. Our prognostic model can accurately evaluate the prognosis of HCC patients, and provide a reference for the design of immunotherapy for HCC.

• Research Paper Volume 14, Issue 6 pp 2855-2867

  Cyclin B2 overexpression promotes tumour growth by regulating jagged 1 in hepatocellular carcinoma

  Relevance score: 6.5921803

  Yening Xiao, Jiamei Ma, Chunliu Guo, Danni Liu, Jing Pan, Xiaoxi Huang

  Keywords: hepatocellular carcinoma, CCNB2, JAG1, proliferation, migration

  Published in Aging on March 29, 2022

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  Background: Our previous study showed that Cyclin B2 (CCNB2) is closely related to the occurrence and progression of hepatocellular carcinoma (HCC).

  Aim of the study: This study aimed to clarify the effect of CCNB2 gene silencing on tumorigenesis in nude mice and to detect the potential mechanism.

  Methods: The effect of CCNB2 on HCC was tested in vivo. The downstream target genes of CCNB2 were predicted by proteomics and confirmed by western blot assay. The regulatory functions of CCNB2 in the proliferation and migration of HCC cells were determined through functional recovery experiments. The expression of the downstream target genes of CCNB2 was detected by immunohistochemistry.

  Results: Knockdown of CCNB2 decreased tumour formation rate and tumour volume and weight and inhibited tumour proliferation. A total of 130 differentially expressed proteins were detected by proteomics, and Jagged 1 (JAG1) was predicted as the potential downstream target of CCNB2. Western blot assay revealed that CCNB2 and JAG1 expression was significantly correlated in HCC cells. The results of functional recovery experiments suggested that CCNB2 knockdown weakened the proliferation and migration ability of HCC cells, while JAG1 overexpression restored this ability of HCC cells that was weakened by CCNB2 knockdown. Immunohistochemistry showed that JAG1 expression was higher in HCC tissues than in paracancerous tissues and was related to tumour size and number and tumour thrombus formation.

  Conclusions: The proliferation of HCC cells in vivo was inhibited by CCNB2 knockdown. CCNB2 may accelerate the proliferation and metastasis of HCC cells by increasing JAG1 expression.

• Research Paper Volume 14, Issue 6 pp 2645-2664

  Clinical utility of serum fucosylated fraction of alpha-fetoprotein in the diagnostic of hepatocellular carcinoma: a comprehensive analysis with large sample size

  Relevance score: 6.4233923

  Aibin Liu, Yanyan Li, Lin Shen, Liangfang Shen, Zhanzhan Li

  Keywords: hepatocellular carcinoma, biomarkers, molecular diagnosis, meta-analysis, alpha-fetoprotein

  Published in Aging on March 20, 2022

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  We conducted a comprehensive meta-analysis of the utility of AFP-L3 for the diagnosis of hepatocellular carcinoma, to provide a more accurate estimation for the clinical utility of AFP-L3. We performed online searches in five databases (PubMed, China National Knowledge Infrastructure, Wanfang, Web of Science, and Embase), from inception to December 31, 2021. Pooled sensitivity, specificity, and area under the curve (AUC) with the matching 95% confidence intervals (95% CIs) were calculated to estimate the diagnostic value of AFP-L3. Thirty-four studies were included in the meta-analysis. The pooled sensitivity was 0.70 [95% confidence interval (CI): 0.63–0.77], and the specificity was 0.91 (95% CI: 0.88–0.94). The estimated area under the curve (AUC) was 0.90 (95% CI: 0.87–0.92). The positive likelihood ratio and negative likelihood ratio were 7.78 (95% CI: 5.7–10.7) and 0.33 (95% CI: 0.26–0.41), respectively. The diagnostic odds ratio was 24 (95% CI: 16–37). The subgroup analysis indicated moderate sensitivity (0.79) and high specificity (0.89) for the Asian population (AUC = 0.89), and similar specificity (0.95) but lower sensitivity (0.35) for Caucasians (AUC = 0.80). Deeks’ funnel plot asymmetry test detected no publication bias (P = 0.460). The sensitivity analysis showed that the pooled results were stable. Taken together, our results indicated that AFP-L3 demonstrates high diagnostic ability for HCC, especially among Asian populations. AFP-L3 is a useful means for high-volume screening, which can help doctors optimize diagnosis workflow, reduce workload, and improve detection sensitivity. The combination of multiple biomarkers may provide more accurate diagnostic tools for HCC in the future.

• Research Paper Volume 14, Issue 5 pp 2367-2382

  Centrosomal protein 290 is a novel prognostic indicator that modulates liver cancer cell ferroptosis via the Nrf2 pathway

  Relevance score: 6.266476

  Yiru Shan, Guang Yang, Qiuhong Lu, Xiangyu Hu, Dongwei Qi, Yehan Zhou, Yin Xiao, Li Cao, Fuhua Tian, Qi Pan

  Keywords: ferroptosis, hepatocellular carcinoma, CEP290, Nrf2 signaling pathway

  Published in Aging on March 10, 2022

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  Ferroptosis is an iron-dependent form of cell death. In spite of its significance in pathogenesis and disease progression, ferroptotic signal transduction in HBV-HCC has not been fully explained. Here, four HCC open-source datasets were downloaded from the GEO repository. Cox regression and LASSO models were established to prioritize novel prognostic candidate biomarkers, and the results were verified in vitro and in vivo. We identified 633 common DEGs in both of the bulk RNA-Seq expression profiles. Next, based upon the TCGA-LIHC cohort, a prognostic signature consisting of nine genes was extracted from 633 shared DEGs, and the specificity and sensitivity of the signature were evaluated in both training and validation datasets. This signature showed that the high-risk group had a worse prognosis than the low-risk group. CEP290 was discovered among the prognostic signature genes, and its expression notably correlated with survival, AFP level, TNM stage and vascular invasion. We confirmed expression of CEP290 in eight pairs of HCC tissues and diverse liver cancer cell lines. CEP290 knockdown reduced proliferation, migration and invasion in Hep3B liver cancer cells while Fe2+ and malondialdehyde levels were elevated. Mechanically, co-immunoprecipitation showed an interaction between CEP290 and Nrf2 proteins, and biological phenotypes of Hep3B cells under CEP290 interference were rescued by Nrf2 activator. Furthermore, CEP290 silencing considerably blocked protein expression of Nrf2 pathway members. Finally, suppression of CEP290 effectively inhibited tumor growth in vivo. The above results shed light on the important role of CEP290 in ferroptosis and present an important implication for HCC progression.

• Research Paper Volume 14, Issue 4 pp 1743-1766

  THRSP identified as a potential hepatocellular carcinoma marker by integrated bioinformatics analysis and experimental validation

  Relevance score: 6.912206

  Yuxi Ding, Xiaoling Liu, Yue Yuan, Yunjian Sheng, Decheng Li, Suvash Chandra Ojha, Changfeng Sun, Cunliang Deng

  Keywords: THRSP, hepatocellular carcinoma, prognosis, invasion, migration

  Published in Aging on February 23, 2022

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  Hepatocellular carcinoma (HCC) is the most common malignant liver tumor with high mortality and poor prognosis worldwide. This study aimed to identify hub genes and investigate the underlying molecular mechanisms in HCC progression by integrated bioinformatics analysis and experimental validation. Based on the Gene Expression Omnibus (GEO) databases and The Cancer Genome Atlas (TCGA), 12 critical differential co-expression genes were identified between tumor and normal tissues. Via survival analysis, we found higher expression of LCAT, ACSM3, IGF1, SRD5A2, THRSP and ACADS was associated with better prognoses in HCC patients. Among which, THRSP was selected for the next investigations. We found that THRSP mRNA expression was negatively correlated with its methylation and closely associated with clinical characteristics in HCC patients. Moreover, THRSP expression had a negative correlation with the infiltration levels of several immune cells (e.g., B cells and CD4+ T cells). qRT-PCR verified that THRSP was lower expressed in HCC tissues and cell lines compared with control. Silencing of THRSP promoted the migration, invasion, proliferation, and inhibited cell apoptosis of HCCLM and Huh7 cell lines. Decreased expression of THRSP promoted HCC progression by NF-κB, ERK1/2, and p38 MAPK signaling pathways. In conclusion, THRSP might serve as a novel biomarker and therapeutic target of HCC.

• Research Paper Volume 14, Issue 2 pp 961-974

  Integrative bioinformatics and experimental analysis revealed TEAD as novel prognostic target for hepatocellular carcinoma and its roles in ferroptosis regulation

  Relevance score: 5.7029395

  Xinxin Ren, Xiang Wang, Yuanliang Yan, Xi Chen, Yuan Cai, Qiuju Liang, Bi Peng, Zhijie Xu, Qingchun He, Fanhua Kang, Jianbo Li, Wenqin Zhang, Qianhui Hong, Jinwu Peng, Muzhang Xiao

  Keywords: TEAD family, hippo pathway, hepatocellular carcinoma, ferroptosis, immune infiltration

  Published in Aging on January 25, 2022

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  Objective: Transcriptional enhanced associate domain (TEAD) family consists of four members TEAD1/2/3/4 that regulate cell growth, stem cell functions and organ development. As the downstream of Hippo signaling pathway, TEAD family is involved in the progression of several cancers. However, the precise biology functions of TEAD family in hepatocellular carcinoma (HCC) have not been reported yet.

  Methods: We apply bioinformatics analysis based on databases including UALCAN, Oncomine, GEPIA, Kaplan-Meier plotter, WebGestalt, cBioPortal, TIMER2.0, and in vitro experimental evidence to identify the exact roles of TEAD family in HCC.

  Results: The results indicated that TEAD2/4 were significantly upregulated in HCC compared with normal tissues. Downregulated of TEAD2 could promote the death of HCC cells through inducing ferroptosis by iron accumulation and subsequent oxidative damage. According to the Kaplan-Meier plotter database, we found that the high expression of TEAD2 was significantly associated with poor disease-specific survival, overall survival, progression-free survival and relapse-free survival. In aspect of cancer immunity, Tumor Immune Estimation Resource algorithm showed that the expression of TEAD family members was obviously related to multiple of infiltrating immune cells including macrophages, neutrophils, dendritic cells, B cells, CD8+ T cells and CD4+ T cells. Finally, we conducted the functional enrichment analysis including protein-protein interaction network, gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway based on the TEAD family-associated coexpression genes.

  Conclusion: The study provided deep insight information of TEAD family in the diagnostic and prognostic evaluation of HCC patients.

• Research Paper

  LINC02362 attenuates hepatocellular carcinoma progression through the miR-516b-5p/SOSC2 axis

  Relevance score: 5.9714417

  Dezhi Li, Tao Zhou, Yaqin Li, Yanwei Xu, Xianyi Cheng, Junhui Chen, Wei V. Zheng

  Keywords: LINC02362, hepatocellular carcinoma, miR-516b-5p, SOSC2, ceRNA

  Published in Aging on January 6, 2022

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  Hepatocellular carcinoma (HCC) is one of the most death-related cancers worldwide. Identifying cancer-associated genes and uncovering the vital molecular mechanisms of HCC progression contribute greatly to the prognosis and novel therapeutic strategies for HCC patients. Although lncRNAs have been proved to be critical modulators of various cellular processes, the functions of lncRNAs in HCC progression are just emerging. Here, we found that a long non-coding RNA (lncRNA) named LINC02362, whose biological effects have yet been unveiled in cancers, was associated with a better prognosis in patients with HCC. Gain-of-function analyses showed that LINC02362 inhibited the survival, migration, invasion and epithelial-to-mesenchymal transition (EMT) of HCC cells. Moreover, miR-516b-5p was enriched as a target of LINC02362, which functioned as a sponge to regulate the endogenous levels of miR-516b-5p. Furthermore, we confirmed that SOSC2 served as a downstream target gene which was negatively controlled by miR-516b-5p. Importantly, a series of rescue experiments indicated that the tumor-suppressive effects of LINC02362 were achieved through the modulation of the miR-516b-5p/SOSC2 axis. In summary, we identified LINC02362 as a candidate tumor-inhibitory lncRNA that might serve as a biomarker for the prognosis of HCC and a promising therapeutic agent for patients with HCC.

• Research Paper Volume 13, Issue 22 pp 24866-24881

  A scoring model based on ferroptosis genes for prognosis and immunotherapy response prediction and tumor microenvironment evaluation in liver hepatocellular carcinoma

  Relevance score: 6.5690866

  Lei Gao, Juan Xue, Xiaomin Liu, Lei Cao, Ruifang Wang, Liangliang Lei

  Keywords: liver hepatocellular carcinoma, ferroptosis, model, prognosis, immunotherapy

  Published in Aging on November 28, 2021

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  Ferroptosis is a type of iron-dependent programmed cell death. Ferroptosis inducers have been shown to have a great potential for cancer therapy. We aimed to generate a risk scoring model based on ferroptosis-related genes (FRGs) and validate its predictive performances in overall survival (OS) prediction and immunotherapy efficacy evaluation in liver hepatocellular carcinoma (LIHC). Differential and Univariate Cox regression analyses were applied to analyze RNA-seq data of LIHC samples from TCGA and GEO databases to identify prognosis-related ferroptosis genes. Patients were assigned to three clusters (Ferrclusters A, B, and C) based on the cluster analysis of prognostic ferroptosis genes. The principal component analysis (PCA) was performed to build a risk scoring model based on differentially expressed FRGs. Survival analysis revealed that Ferrcluster B LIHC patients had a lower OS rate alongside more severe immune cell infiltration versus Ferrcluster A and C patients; moreover, the LIHC patients in high-ferrscore group had significantly lower survival than the low-ferrscore group. Compared to low-ferrscore patients, Programmed cell death 1 (PD-1) mRNA expression significantly increased, and either PD-1 or PD-1 plus CTLA4 (cytotoxic T-lymphocyte associated protein 4) inhibitors showed unsatisfactory efficacy in high-ferrscore patients. Our study demonstrates the implication of FRGs in prognosis prediction and evaluation of immunotherapy efficacy in LIHC patients.

• Research Paper Volume 13, Issue 22 pp 24621-24639

  Construction of a genome instability-derived lncRNA-based risk scoring system for the prognosis of hepatocellular carcinoma

  Relevance score: 4.774667

  Dan-Ping Huang, Mian-Mian Liao, Jing-Jing Tong, Wei-Qu Yuan, De-Ti Peng, Jian-Ping Lai, Yi-Hao Zeng, Yi-Jun Qiu, Guang-Dong Tong

  Keywords: long non-coding RNAs, genomic instability, prognosis prediction, hepatocellular carcinoma, The Cancer Genome Atlas

  Published in Aging on November 18, 2021

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  Emerging evidence revealed the critical roles of long non-coding RNAs (lncRNAs) in maintaining genomic instability. However, genome instability-associated lncRNAs (GILncRNAs) and their performance in clinical prognostic significance in hepatocellular carcinoma (HCC) are rarely reported. Our study constructed a computational framework integrating somatic mutation information and lncRNA expression profiles of HCC genome and we identified 88 GILncRNAs of HCC. Function enrichment analysis revealed that GILncRNAs were involved in various metabolism processes and genome instability of cancer. A genome instability-derived lncRNA-based gene signature (GILncSig) was constructed using training set data. The performance of GILncSig for outcome prediction was validated in testing set and The Cancer Genome Atlas (TCGA) set. The multivariate cox regression analysis and stratification analysis demonstrated GILncSig could serve as an independent prognostic factor for the overall survival of HCC patients. The time-dependent Receiver Operating Characteristic (ROC) curve illustrated GILncSig outperformed two recently published lncRNA signatures for overall survival prediction. The combination of GILncSig and tumor protein p53 (TP53) mutation status exhibited better prognostic performance in survival evaluation compared to TP53 mutation status alone. AC145343.1 was further validated to be a risk factor for HCC in vitro among GILncSig. Overall, our study provided a novel approach for identification of genome instability-associated lncRNAs and established an independent risk score system for outcome prediction of HCC patients, which provided a new insight for exploring in-depth mechanism and potential therapy strategy.

• Research Paper Volume 13, Issue 21 pp 24205-24218

  YTH domain family: potential prognostic targets and immune-associated biomarkers in hepatocellular carcinoma

  Relevance score: 5.889749

  Miaomiao Liu, Zijin Zhao, Yuan Cai, Peng Bi, Qiuju Liang, Yuanliang Yan, Zhijie Xu

  Keywords: hepatocellular carcinoma, YTH domain family, expression profiles, infiltrating immune cells, methylation

  Published in Aging on November 8, 2021

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  Hepatocellular carcinoma (HCC) is the most common high malignancy with insidious onset, invasive fast-growing, high recurrence rate and fatality. YTH domain family plays essential roles in development of HCC. However, the biological function of YTH domain family in HCC have not been clarified. Here, through evaluating the expression profiles of YTH domain family, we found that upregulated YTHDF1 might be more significant and valuable in development and progression of HCC. There was a strong correlation between YTHDC1, YTHDF1 and YTHDF2 and pathological stage of HCC patients. Kaplan-Meier plotter revealed that HCC patients with high level of YTHDF1 and YTHDF2 were highly related to a shorter overall survival time, and low level of YTHDF1 (p = 0.0017) has an important association with a longer progression-free survival time. Genetic alterations using cBioPortal revealed that the alteration rates of YTHDF3 were the highest. We also found that the functions of YTH domain family were linked to several cancer-associated pathways, including peptidyl-serine modification, peptidyl-tyrosine modification and negative regulation of cellular component movement. TIMER database indicated that the YTH domain family had a strong relationship with the infiltration of six types of immune cells (macrophages, neutrophils, CD8+ T-cells, B-cells, CD4+ T-cells and dendritic cells). Next, Ualcan databases revealed that the global methylation levels of YTHDC1 was higher in HCC patients, while YTHDF2 was lower in HCC patients. In conclusion, our findings will enhance the understanding of YTH domain family in HCC pathology, and provide novel insights into YTH-targeted therapy for HCC patients.

• Research Paper Volume 13, Issue 21 pp 24117-24135

  Integrated analysis of expression, prognostic value and immune infiltration of GSDMs in hepatocellular carcinoma

  Relevance score: 5.863786

  Kuan Hu, Zhijie Xu, Lei Yao, Yuanliang Yan, Lei Zhou, Juanni Li

  Keywords: GSDM family, hepatocellular carcinoma, expression profiles, prognosis, immune infiltration

  Published in Aging on November 3, 2021

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  Six Gasdermins (GSDM) family members participate in various biological processes especially pyroptosis, as well as in the initiation and development of many types of cancer. However, the systematic analysis of the GSDM family in hepatocellular carcinoma (HCC) is lacking. In this study, several bioinformatics databases were recruited to analyze the roles of the GSDMs in differential expression, prognostic correlation, functional enrichment exploration, immune modulation, genetic alterations, and methylated modification in patients with HCC. Consequently, the mRNA expression of all the six GSDMs was accordantly increased in HCC, while only the protein expressions of GSDMB, GSDMD, and GSDME were apparently increased in HCC tissue. The expression of all the GSDMs (except GSDMA) was significantly higher in tumor stage 1–3 subgroups, compared with that in normal subgroups. Higher GSDME expression was significantly associated with shorter overall survival (OS) and disease specific survival (DSS) in patients with HCC. GSDMD had the highest genetic alteration rate among the GSDMs. The three signal pathways which were most likely related to GSDMs-associated molecules were the cell adhesion, growth regulation, and hormone metabolic process. The majority of GSDMs members were positively correlated with the infiltration of B cells, neutrophils, and dendritic cells, however negatively correlated with macrophage. All of the six GSDM members showed remarkably decreased methylation levels in HCC tissues. In conclusion, the GSDM family (especially GSDME) had the potential to become essential biomarkers to better improve the diagnosis and prognosis of HCC, as well as provided insight for the development of therapeutic targets.

• Research Paper Volume 13, Issue 19 pp 23020-23035

  DCP1A is an unfavorable prognostic-related enhancer RNA in hepatocellular carcinoma

  Relevance score: 6.452524

  Hao Wu, Jinrui Zhang, Yi Bai, Sai Zhang, Zhixin Zhang, Wen Tong, Pinsheng Han, Bing Fu, Yamin Zhang, Zhongyang Shen

  Keywords: hepatocellular carcinoma, enhancer RNA, DCP1A, prognosis, bioinformatics

  Published in Aging on October 4, 2021

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  Long non-coding RNAs (lncRNAs) are associated with occurrence and development of tumors. Enhancer RNA (eRNA) is a special type of lncRNAs produced from transcription of enhancer elements. The function of eRNAs in tumors have elicited significant attention recently. However, the clinical significance and role of eRNAs in hepatocellular carcinoma (HCC) has not been fully explored. The current study sought to explore the expression level and prognostic value of key eRNAs in HCC. Bioinformatics analyses were used to explore expression levels of key prognostic eRNAs in HCC and their correlation with target genes. A total of 1580 enhancer RNAs (eRNAs) and 1791 target genes were initially retrieved from TCGA-LIHC gene expression database. Further analysis through survival and correlation analysis led to identification of 12 eRNAs and 13 target genes. The findings showed that DCP1A was the most prognosis-related eRNA. This eRNA showed the highest correlation with the target gene, PRKCD. Analysis showed that poor overall survival (OS) in HCC patients was correlated with high expression level of DCP1A (eRNA) and PRKCD (target gene). The up-regulation of DCP1A was associated with advanced tumor stage, larger tumor size and higher histological grade. The results of pan-cancer analysis showed that the expression of DCP1A was differentially expressed in 13 other types of tumor tissues and their corresponding normal tissues. This eRNA was highly expressed in digestive system tumors. Functional analysis showed that high expression level of DCP1A was implicated in multiple tumor-related signaling pathways. The findings of the current study indicated DCP1A is a novel biomarker that can be used as a potential therapeutic target for HCC patients.

• Research Paper Volume 13, Issue 19 pp 22802-22829

  Highly expressed centromere protein L indicates adverse survival and associates with immune infiltration in hepatocellular carcinoma

  Relevance score: 5.975813

  Zhili Zeng, Xiao Jiang, Zhibin Pan, Ruisheng Zhou, Zhuangteng Lin, Ying Tang, Ying Cui, Enxin Zhang, Zebiao Cao

  Keywords: centromere protein L, hepatocellular carcinoma, tumor immunity, prognosis, biomarker

  Published in Aging on October 4, 2021

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  Background: Hepatocellular carcinoma (HCC) is characterized by rapid progression, high recurrence rate and poor prognosis. Early prediction for the prognosis and immunotherapy efficacy is of great significance to improve the survival of HCC patients. However, there is still no reliable predictor at present. This study is aimed to explore the role of centromere protein L (CENPL) in predicting prognosis and its association with immune infiltration in HCC.

  Methods: The expression of CENPL was identified through analyzing the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) data. The association between CENPL expression and clinicopathological features was investigated by the Wilcoxon signed-rank test or Kruskal Wallis test and logistic regression. The role of CENPL in prognosis was examined via Kaplan-Meier method and Log-rank test as well as univariate and multivariate Cox regression analysis. Besides, in TIMER and GEPIA database, we investigated the correlation between CENPL level and immunocyte and immunocyte markers, and the prognostic-related methylation sites in CENPL were identified by MethSurv.

  Results: CENPL had a high expression in HCC samples. Increased CENPL was prominently associated with unfavorable survival, and maybe an independent prognostic factor of worse overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), progression-free interval (PFI). Additionally, CENPL expression was significantly correlated with immune cell infiltration and some markers. CENPL also contained a methylation site that was notably related to poor prognosis.

  Conclusions: Elevated CENPL may be a promising prognostic marker and associate with immune infiltration in HCC.

• Research Paper Volume 13, Issue 18 pp 22120-22133

  Metformin inhibits hepatocellular carcinoma development by inducing apoptosis and pyroptosis through regulating FOXO3

  Relevance score: 6.5921803

  Zetian Shen, Han Zhou, Aomei Li, Tiancong Wu, Xiaoqin Ji, Lei Guo, Xixu Zhu, Dagan Zhang, Xia He

  Keywords: metformin, hepatocellular carcinoma, FOXO3, pyroptosis, NLRP3

  Published in Aging on September 21, 2021

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  This study aimed to expand our understanding of metformin (Met) in inhibiting hepatocellular carcinoma (HCC) progression and to investigate its underlying mechanism. Met was administrated to HCC cells at 5, 10, and 20 μM, after which the cell phenotype was evaluated. RNA-seq cluster analysis was used to screen for target genes modulated by Met. Luciferase activity and ChIP assays were performed to detect the effect of FOXO3 on the transcriptional activation of NLRP3. We evaluated the effect of Met and FOXO3 and on the growth of HCC cells in vivo. Met inhibited HCC cell proliferation and promoted apoptosis. Met also induced pyroptosis of HCC cells. FOXO3 was significantly upregulated by Met treatment, and FOXO3 activated transcription of NLRP3. Cells after Met treatment together with FOXO3 knockdown have a stronger colony formation and migration ability but a lower apoptosis rate compared to the Met treatment alone group. In vivo, Met inhibited HCC tumor growth. The tumors in Met treatment and FOXO3 knockdown group grew faster than in Met treatment group. Thus, Met attenuates HCC cell development by inducing apoptosis and pyroptosis. This effect of metformin is partially dependent on FOXO3 which can activate the transcription of NLRP3.

• Research Paper Volume 13, Issue 18 pp 22256-22275

  Nucleotide variants in hepatitis B virus preS region predict the recurrence of hepatocellular carcinoma

  Relevance score: 5.8813925

  Xi Chen, Minfeng Zhang, Nan Li, Rui Pu, Ting Wu, Yibo Ding, Peng Cai, Hongwei Zhang, Jun Zhao, Jianhua Yin, Guangwen Cao

  Keywords: hepatitis B virus, viral variant, prediction model, hepatocellular carcinoma, prognosis

  Published in Aging on September 17, 2021

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  Background: Hepatitis B virus (HBV) variants in the preS region have been associated with hepatocellular carcinoma (HCC). However, the effect of the preS variants on HCC prognosis remains largely unknown. We aimed to identify the preS variants that reliably predict postoperative prognosis in HCC.

  Methods: RNA-seq data of 203 HCC patients retrieved from public database were screened for the preS variants related to HCC prognosis. The variants in the sera and tumors were then validated in our prospective cohort enrolling 103 HBV-associated HCC patients.

  Results: By analyzing prognosis-related gene sets in the RNA-seq data, 12 HBV preS variants were associated with HCC recurrence. Of those, G40C and C147T in the sera predicted an unfavorable recurrence-free survival in our cohort (hazard ratio [HR]=2.18, 95% confidence interval [CI]=1.37-3.47, p=0.001 for G40C; HR=1.84, 95% CI=1.15-2.92, p=0.012 for C147T). G40C and C147T were significantly associated with microscopic vascular invasion, larger tumor size, and abnormal liver function. Multivariate Cox regression analysis showed that G40C significantly increased the risk of HCC recurrence in patients with postoperative antiviral treatment. The HCC prognosis-prediction model consisting of α-fetoprotein and G40C in the sera achieved the best performance (sensitivity=0.80, specificity=0.70, and area under the curve=0.79). Functional analysis indicated that these two variants were associated with cell proliferation, chromosome instability, carcinogenesis, metastasis, and anticancer drug resistance.

  Conclusions: G40C and C147T are serological biomarkers for HCC prognosis and the prognostic model consisting of serological α-fetoprotein and G40C achieved the best performance in predicting postoperative prognosis.

• Research Paper Volume 13, Issue 17 pp 21155-21190

  Liver-specific over-expression of Cripto-1 in transgenic mice promotes hepatocyte proliferation and deregulated expression of hepatocarcinogenesis-related genes and signaling pathways

  Relevance score: 5.7176247

  Yu Liu, Yan-Qing Li, Shi-Hao Huang, Yong-Long Li, Jia-Wei Xia, Jun-Shuang Jia, Fang Wei, Jia-Hong Wang, Guan-Qi Dai, Yu-Cai Wang, Xiao-Yan Li, Liu-Xin Han, Xiao-Ling Zhang, Xu-Dong Xiang, Wen-Tao Zhao, Dong Xiao, Xiao-Lin Lin

  Keywords: Cripto-1 (CR-1), hepatocellular carcinoma (HCC), transgenic mice, hepatocarcinogenesis

  Published in Aging on September 13, 2021

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  In this study, we investigated the role of embryonic gene Cripto-1 (CR-1) in hepatocellular carcinoma (HCC) using hepatocyte-specific CR-1-overexpressing transgenic mice. The expression of truncated 1.7-kb CR-1 transcript (SF-CR-1) was significantly higher than the full-length 2.0-kb CR-1 transcript (FL-CR-1) in a majority of HCC tissues and cell lines. Moreover, CR-1 mRNA and protein levels were significantly higher in HCC tissues than adjacent normal liver tissues. Hepatocyte-specific over-expression of CR-1 in transgenic mice enhanced hepatocyte proliferation after 2/3 partial hepatectomy (2/3 PHx). CR-1 over-expression significantly increased in vivo xenograft tumor growth of HCC cells in nude mice and in vitro HCC cell proliferation, migration, and invasion. CR-1 over-expression in the transgenic mouse livers deregulated HCC-related signaling pathways such as AKT, Wnt/β-catenin, Stat3, MAPK/ERK, JNK, TGF-β and Notch, as well as expression of HCC-related genes such as CD5L, S100A8, S100A9, Timd4, Orm2, Orm3, PDK4, DMBT1, G0S2, Plk2, Plk3, Gsta1 and Gsta2. However, histological signs of precancerous lesions, hepatocyte dysplasia or HCC formation were not observed in the livers of 3-, 6- or 8-month-old hepatocyte-specific CR-1-overexpressing transgenic mice. These findings demonstrate that liver-specific CR-1 overexpression in transgenic mice deregulates signaling pathways and genes associated with HCC.

• Research Paper Volume 13, Issue 17 pp 21283-21293

  RUFY3 promotes the progression of hepatocellular carcinoma through activating NF-κB-mediated epithelial-mesenchymal transition

  Relevance score: 5.863786

  Yang Zhang, Weixing Ni, Lei Qin

  Keywords: RUFY3, epithelial-mesenchymal transition, hepatocellular carcinoma, NF-κB

  Published in Aging on September 12, 2021

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  RUFY3 (RUN and FYVE domain-containing protein 3) has been demonstrated to exhibit carcinogenic effect in multiple malignancies. However, the exact role of RUFY3 in hepatocellular carcinoma (HCC) progression remains elusive. Herein, we aimed to identify the role and the underlying mechanism of RUFY3 in HCC progression. The RUFY3 levels in HCC specimens were detected by qRT-PCR, western blot, and immunohistochemistry, and its clinical significance in HCC patients was assessed. The effect of RUFY3 on HCC cell growth, migration, and invasion was explored by CCK-8 assay, wound healing assay, and transwell migration and invasion assays in vitro. The effect of RUFY3 on HCC cell growth and metastasis was also conducted in vivo through establishing xenograft tumor and lung metastatic mice model. The underlying mechanism responsible for RUFY3-induced HCC cell behavior was also investigated. Our results indicated that high levels of RUFY3 significantly correlated with tumor size, microvascular invasion, clinical stage, and poor prognosis for HCC patients. In addition, RUFY3 facilitated HCC cell growth, invasion, and metastasis both in vitro and in vivo through activating nuclear factor-κ-gene binding (NF-κB)-mediated epithelial-mesenchymal transition (EMT). Taken together, our results revealed that RUFY3 accelerated HCC progression via driving NF-κB-mediated EMT, suggesting a novel target for HCC treatment.

• Research Paper Volume 13, Issue 17 pp 21294-21308

  PPM1D is a potential prognostic biomarker and correlates with immune cell infiltration in hepatocellular carcinoma

  Relevance score: 6.4400496

  Zhangtao Yu, Yinghui Song, Mengting Cai, Bo Jiang, Zhihua Zhang, Le Wang, Yu Jiang, Lianhong Zou, Xiehong Liu, Nanhui Yu, Xianhai Mao, Chuang Peng, Sulai Liu

  Keywords: PPM1D, Wip1, prognostic biomarker, immune infiltrates, hepatocellular carcinoma

  Published in Aging on September 1, 2021

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  Background: Protein phosphatase magnesium-dependent 1 delta (PPM1D), also referred to as wild-type p53-induced phosphatase 1 (Wip1) or protein phosphatase 2C delta (PP2Cδ), is an oncogenic nuclear serine/threonine phosphatase belonging to the PP2C family. However, the knowledge regarding PPM1D mRNA expression, tumor immunity, and the prognosis in hepatocellular carcinoma (HCC) is scanty.

  Methods: We analyzed PPM1D, including its expression in both the normal and tumor tissue using the Sangerbox database and Tumor Immune Estimation Resource (TIMER). We evaluated its correlation with prognosis in different tumor types by the Kaplan-Meier plotter and Gene Expression Profiling Interactive Analysis (GEPIA). The correlations between PPM1D and the cancer immune infiltrates were determined using TIMER. The correlations between PPM1D expression and gene marker sets of the immune infiltrates were established by both the TIMER and GEPIA. Immunohistochemistry was performed to detect the expression of Wip1 protein encoded by PPM1D in HCC, and the relationship between Wip1 expression and the prognosis of HCC were analyzed.

  Results: We found out that PPM1D mRNA expression was significantly higher in several human cancers, including HCC, than in the corresponding normal human tissues. The PPM1D mRNA high expression in HCC was significantly correlated with poor prognosis. The expression was associated with progression-free survival (PFS) in multiple HCC patients’ cohorts (PFS HR = 1.5, P = 0.0066). This was especially in early stage (stage 1) and AJCC_T 1 of HCC. Besides, PPM1D mRNA expression indicated a positive correlation with tumor-infiltrating Monocytes, tumor-associated macrophages (TAMs), M1 Macrophage, M2 Macrophage, dendritic cells (DCs), T-helper (Th) and Treg. Wip1 was higher in HCC than paracancerous tissue. High expression of Wip1 was associated with poor prognosis of HCC.

  Conclusion: Our findings suggested that PPM1D mRNA is critical in activating tumor immunity. Besides, they implied that PPM1D could be a potential prognostic biomarker for cancer progression. Moreover, it correlated with tumor immune cell infiltration in HCC.