scholarly journals Identification of Mutation Landscape and Immune Cell Component for Liver Hepatocellular Carcinoma Highlights Potential Therapeutic Targets and Prognostic Markers

2021 ◽  
Vol 12 ◽  
Author(s):  
Hengzhen Wang ◽  
Wenjing Jiang ◽  
Haijun Wang ◽  
Zheng Wei ◽  
Hali Li ◽  
...  

Liver hepatocellular carcinoma (LIHC) is a primary malignancy, and there is a lack of effective treatment for advanced patients. Although numerous studies exist to reveal the carcinogenic mechanism of LIHC, few studies have integrated multi-omics data to systematically analyze pathogenesis and reveal potential therapeutic targets. Here, we integrated genomic variation data and RNA-seq profiles obtained by high-throughput sequencing to define high- and low-genomic instability samples. The mutational landscape was reported, and the advanced patients of LIHC were characterized by high-genomic instability. We found that the tumor microenvironment underwent metabolic reprograming driven by mutations accumulate to satisfy tumor proliferation and invasion. Further, the co-expression network identifies three mutant long non-coding RNAs as potential therapeutic targets, which can promote tumor progression by participating in specific carcinogenic mechanisms. Then, five potential prognostic markers (RP11-502I4.3, SPINK5, CHRM3, SLC5A12, and RP11-467L13.7) were identified by examining the association of genes and patient survival. By characterizing the immune landscape of LIHC, loss of immunogenicity was revealed as a key factor of immune checkpoint suppression. Macrophages were found to be significantly associated with patient risk scores, and high levels of macrophages accelerated patient mortality. In summary, the mutation-driven mechanism and immune landscape of LIHC revealed by this study will serve precision medicine.

2021 ◽  
Vol 12 ◽  
Author(s):  
Jinfeng Ning ◽  
Fengjiao Wang ◽  
Kaibin Zhu ◽  
Binxi Li ◽  
Qing Shu ◽  
...  

Lung squamous cell carcinoma (LUSC) has a poor clinical prognosis and a lack of available targeted therapies. Therefore, there is an urgent need to identify novel prognostic markers and therapeutic targets to assist in the diagnosis and treatment of LUSC. With the development of high-throughput sequencing technology, integrated analysis of multi-omics data will provide annotation of pathogenic non-coding variants and the role of non-coding sequence variants in cancers. Here, we integrated RNA-seq profiles and copy number variation (CNV) data to study the effects of non-coding variations on gene regulatory network. Furthermore, the 372 long non-coding RNAs (lncRNA) regulated by CNV were used as candidate genes, which could be used as biomarkers for clinical application. Nine lncRNAs including LINC00896, MCM8-AS1, LINC01251, LNX1-AS1, GPRC5D-AS1, CTD-2350J17.1, LINC01133, LINC01121, and AC073130.1 were recognized as prognostic markers for LUSC. By exploring the association of the prognosis-related lncRNAs (pr-lncRNAs) with immune cell infiltration, GPRC5D-AS1 and LINC01133 were highlighted as markers of the immunosuppressive microenvironment. Additionally, the cascade response of pr-lncRNA-CNV-mRNA-physiological functions was revealed. Taken together, the identification of prognostic markers and carcinogenic regulatory mechanisms will contribute to the individualized treatment for LUSC and promote the development of precision medicine.


2021 ◽  
Vol 11 ◽  
Author(s):  
Mu Song ◽  
Mulati Kuerban ◽  
Lu Zhao ◽  
Xiaolin Peng ◽  
Youqin Xu

BackgroundThe DNA-binding protein RFX6 was overexpressed in hepatocellular carcinoma, and its expression level was correlated with the prognosis and immune cell infiltration in liver hepatocellular carcinoma. However, the mechanism of the abnormal expression and the biological effects of RFX6 in liver cancer remains unknown.MethodsTo understand the specific expression mechanism of RFX6 in liver cancer, we performed bioinformatic prediction, CHIP-qPCR assay, co-IP, and dual-luciferase assay to assess the regulating mechanism of RFX6. In the meantime, a series of biological experiments in vivo and in vitro were conducted to analyze the biological significance of RFX6 in hepatocellular carcinoma.ResultsWe demonstrated that knockdown of RFX6 in liver cancer cells significantly suppressed the proliferation, migration, and invasion of cancer cells. Moreover, inhibition of RFX6 could affect the immune response of T cells. Among a number of interacting proteins, we revealed that RFX6 directly binds to DTX2, a regulator of the Notch signaling pathway by targeting NOTCH1, and helps in its transcription stability. Furthermore, we discovered that miRNA-542-3p, the expression of which was decreased in hepatocellular carcinoma, was directly involved in the negative regulation of the expression of RFX6.ConclusionIn summary, we discovered that the miRNA-542-3p–RFX6–DTX2–NOTCH1 regulatory pathway played significant roles in the tumor progression of liver hepatocellular carcinoma.


2019 ◽  
Author(s):  
Yucheng Ji ◽  
Guang-xiang Gu

Abstract Background Liver hepatocellular carcinoma (LIHC), as the main type of liver cancer, has become a main health issue as the third-most common cause of mortality in cancer patients. However, conventional chemo- or radio- therapies shows little improvement in survival, which calls for novel therapies. Because of the immunotolerance mechanism existing naturally in liver, immunotherapy provides significant effect in treatment of LIHC patients. Up to now, various immunotherapies have been proposed, but due to the complex pathways from which LIHC cancerous cell escape immunosurveillance, combined therapies are often needed, which are still under development. Methods In the current study, with data downloaded from TCGA database, CIBERSORT was performed for identifying the composition of infiltrating immune cells and further statistical analyses using R 3.5.3 were carried out, aiming at connecting specific immune cells with clinical survival. Results With data of immune and stromal scores downloaded from the website of MD Anderson Cancer Centre, both showed significance in survival time. Further analyses based on the result of CIBERSORT demonstrated that the number of macrophages M0 and T cells CD8 infiltration between para-carcinoma and tumour tissues are markedly different. With combination of clinical data, we were able to identify that a higher amount of activated NK cells (p=0.008) and a lower amount of resting NK cells (p=0.047) presented a longer survival time. Conclusion With the help of the TCGA database and multiple techniques, statistical analyses of transcriptome profiling data and clinical data were successfully carried out. The results in this study may pave the way for a new therapeutic strategy which could be combined with current treatments to further improve the clinical outcome of LIHC patients. Further and deeper investigation of other available data, however, were needed in order to verify the results of current study.


2021 ◽  
Vol 12 ◽  
Author(s):  
Yingxi Du ◽  
Yarui Ma ◽  
Qing Zhu ◽  
Tongzheng Liu ◽  
Yuchen Jiao ◽  
...  

Background: N6-methyladenosine (m6A) is related to the progression of multiple cancers. However, the underlying influences of m6A-associated genes on the tumor immune microenvironment in hepatocellular carcinoma (HCC) remain poorly understood. Therefore, we sought to construct a survival prediction model using m6A-associated genes to clarify the molecular and immune characteristics of HCC.Methods: HCC case data were downloaded from The Cancer Genome Atlas (TCGA). Then, by applying consensus clustering, we identified two distinct HCC clusters. Next, four m6A-related genes were identified to construct a prognostic model, which we validated with Gene Expression Omnibus (GEO) and International Cancer Genome Consortium (ICGC) datasets. Additionally, the molecular and immune characteristics in different subgroups were analyzed.Results: m6A RNA methylation regulators were differentially expressed between HCC and normal samples and linked with immune checkpoint expression. Using consensus clustering, we divided HCC samples into two subtypes with distinct clinical features. Cluster 2 was associated with unfavorable prognosis, higher immune checkpoint expression and immune cell infiltration levels. In addition, the immune and carcinogenic signaling pathways were enriched in cluster 2. Furthermore, we constructed a risk model using four m6A-associated genes. Patients with different risk scores had distinct survival times, expression levels of immunotherapy biomarkers, TP53 mutation rates, and sensitivities to chemotherapy and targeted therapy. Similarly, the model exhibited an identical impact on overall survival in the validation cohorts.Conclusion: The constructed m6A-based signature may be promising as a biomarker for prognostics and to distinguish immune characteristics in HCC.


2021 ◽  
Author(s):  
Wentao Qin ◽  
Mingyang Jiang ◽  
Yang Hu ◽  
Mingjing Xie ◽  
Yiji Jike ◽  
...  

Abstract Background Osteosarcoma (OS) is the most common primary malignancy in children and adolescents, with a high mortality and disability rate. Autophagy plays an important role in the regulation of apoptosis, invasion and metastasis of tumor cells. Hence, construction of a risk score model of autophagy related genes (ARGs) of OS would benefit the treatment and prognosis evaluation. Methods We downloaded a dataset of OS from The Cancer Genome Atlas (TCGA) database, and found the OS-related ARGs through Human Autophagy Database (HADb). Five hub ARGs (CCL2, AMBRA1, VEGFA, MYC and EGFR) were obtained by using multivariate Cox regression model. Then we calculated the risk scores and constructed a prediction model. Another two datasets downloaded from GEO were combined to verify the accuracy and validity of the model. The role of immune cell infiltration was systematically explored, and prediction of response to targeted drugs was assessed. Immunohistochemistry was carried out to verify the expression of the key ARGs. Results Based on these five hub ARGs, we constructed a risk score model related to OS. High accuracy and validity were demonstrated by datasets downloaded from GEO. These five ARGs played a role in cancer-related biological processes, such as MAPK pathway and PI3K pathway. The results of targeted drug sensitivity analyses coincided with the pathway analysis. Immunohistochemistry showed that the expression of 5 ARGs in OS group was more obvious than that in paracancerous group. Conclusion This study constructs a risk score model related to autophagy of OS, explores the prognostic value of autophagy related genes, and finds possible therapeutic targets.


2010 ◽  
Vol 31 (2) ◽  
pp. 179-193 ◽  
Author(s):  
Maddalena Frau ◽  
Fiorella Biasi ◽  
Francesco Feo ◽  
Rosa M. Pascale

Author(s):  
Xiao-Wei Fu ◽  
Chun-Qing Song

Background: Hepatocellular carcinoma (HCC) is characterized by a poor prognosis and accounts for the fourth common cause of cancer-related deaths. Recently, pyroptosis has been revealed to be involved in the progression of multiple cancers. However, the role of pyroptosis in the HCC prognosis remains elusive.Methods: The clinical information and RNA-seq data of the HCC patients were collected from the TCGA-LIHC datasets, and the differential pyroptosis-related genes (PRG) were firstly explored. The univariate Cox regression and consensus clustering were applied to recognize the HCC subtypes. The prognostic PRGs were then submitted to the LASSO regression analysis to build a prognostic model in the TCGA training cohort. We further evaluated the predictive model in the TCGA test cohort and ICGC validation cohort (LIRI-JP). The accuracy of prediction was validated using the Kaplan—Meier (K-M) and receiver operating characteristic (ROC) analyses. The single-sample gene set enrichment analysis (ssGSEA) was used to determine the differential immune cell infiltrations and related pathways. Finally, the expression of the prognostic genes was validated by qRT-PCR in vivo and in vitro.Results: We identified a total of 26 differential PRGs, among which three PRGs comprising GSDME, GPX4, and SCAF11 were subsequently chosen for constructing a prognostic model. This model significantly distinguished the HCC patients with different survival years in the TCGA training, test, and ICGC validation cohorts. The risk score of this model was confirmed as an independent prognostic factor. A nomogram was generated indicating the survival years for each HCC patient. The ssGSEA demonstrated several tumor-infiltrating immune cells to be remarkably associated with the risk scores. The qRT-PCR results also showed the apparent dysregulation of PRGs in HCC. Finally, the drug sensitivity was analyzed, indicating that Lenvatinib might impact the progression of HCC via targeting GSDME, which was also validated in human Huh7 cells.Conclusion: The PRG signature comprised of GSDME, GPX4, and SCAF11 can serve as an independent prognostic factor for HCC patients, which would provide further evidence for more clinical and functional studies.


2018 ◽  
Vol 14 (1) ◽  
pp. 24-32 ◽  
Author(s):  
Chitra Jeyaram ◽  
Manuel Philip ◽  
Rajadurai Chinnasamy Perumal ◽  
Jubina Benny ◽  
Jayasankar Madusoodhanan Jayakumari ◽  
...  

Background:Recent advances in next-generation sequencing technology allow highthroughput RNA-Sequencing to be widely applied in studying coding and non-coding RNA profiling in cells. RNA-Seq data usually contains functional transcriptomic and other small and larger non-coding (nc) RNA sequences. </P><P> Objective: MicroRNAs (miRNAs), a small nc-RNA act as epigenetic markers and the expression of their target genes and pathways that regulate Hepatocellular Carcinoma (HCC), a primary malignancy of the liver. The unreported potential novel miRNAs targeting HCC pathways can be identified from the sequenced data.Methods:In this study, we performed a computational identification of novel putative miRNAs and their targets from publicly available high-throughput sequencing Fastq data of human HCC cells HepG2, NorHep and SKHep1, retrieved from NCBI-SRA.Results:Totally, 572 unique known precursor miRNAs and 1062 unique novel miRNAs were identified from HepG2, Nor and SKHep1 HCC cell lines. Interestingly, 140 novel miRNAs were predicted to be extensively involved in targeting genes of HCC related pathways such as apoptosis, cell signaling, cell division, cell-cycle arrest, GPCR, MAPK cascade, TOR signaling, TNFSF11 signaling and liver development.Conclusion:The predicted novel miRNAs reported in the paper might have a vital role in regulating the molecular mechanism of HCC and thus, further studies on these miRNAs will provide significant clues for researchers into the complex biological process of liver cancer.


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