scholarly journals Identification of Therapeutic Targets and Prognostic Biomarkers Among Chemokine (C-C Motif) Ligands in the Liver Hepatocellular Carcinoma Microenvironment

Author(s):  
Zhongyi Jiang ◽  
Changchang Xing ◽  
Pusen Wang ◽  
Xueni Liu ◽  
Lin Zhong

Background: Liver hepatocellular carcinoma (LIHC) is the third leading cause of cancer-related death and the sixth most common solid tumor worldwide. In the tumor microenvironment, the cross-talk between cancer cells, immune cells, and stromal cells exerts significant effects on neoplasia and tumor development and is modulated in part by chemokines. Chemokine (C-C motif) ligands (CCL) can directly target tumor cells and stromal cells, and they have been shown to regulate tumor cell proliferation, cancer stem-like cell properties, cancer invasiveness and metastasis, which directly and indirectly affect tumor immunity and influence cancer progression, therapy and patient outcomes. However, the prognostic values of chemokines CCL in LIHC have not been clarified.Methods: In this study, we comprehensively analyzed the relationship between transcriptional chemokines CCL and disease progression of LIHC using the ONCOMINE dataset, GEPIA, UALCAN, STRING, WebGestalt, GeneMANIA, TRRUST, DAVID 6.8, LinkedOmics, TIMER, GSCALite, and Open Targets. We validated the protein levels of chemokines CCL through western blot and immunohistochemistry.Results: The transcriptional levels of CCL5/8/11/13/15/18/20/21/25/26/27/28 in LIHC tissues were significantly elevated while CCL2/3/4/14/23/24 were significantly reduced. A significant correlation was found between the expression of CCL14/25 and the pathological stage of LIHC patients. LIHC patients with low transcriptional levels of CCL14/21 were associated with a significantly poor prognosis. The functions of differentially expressed chemokines CCL were primarily related to the chemokine signaling pathway, cytokine–cytokine receptor interactions, and TNF-α signaling pathway. Our data suggested that RELA/REL, NFKB1, STAT1/3/6, IRF3, SPI1, and JUN were key transcription factors for chemokines CCL. We found significant correlations among the expression of chemokines CCL and the infiltration of six types of immune cells (B cells, CD8+ T cells, CD4+ T cells, macrophages, neutrophils, and dendritic cells) and immune checkpoints (PD-1. PD-L1, and CTLA-4). The western blot and immunohistochemistry results showed that protein expression levels of CCL5 and CCL20 were upregulated in LIHC. CCL5 and CCL20 were significantly correlated with the clinical outcome of patients with LIHC, and could be negatively regulated by some drugs or small molecules.Conclusions: Our results may provide novel insights for the potential suitable targets of immunological therapy and prognostic biomarkers for LIHC.

2020 ◽  
Author(s):  
Hui Li ◽  
Qun Li ◽  
Hong Jing ◽  
Jianghai Zhao ◽  
Hui Zhang ◽  
...  

Abstract BackgroundJumonjiC (JmjC) domain-containing protein 5 (JMJD5) plays an important role in cancer metabolism. However, the prognostic value of JMJD5 in most human cancers is still unknown. In this study, we aim to investigate the expression and prognostic value of JMJD5, immune cells infiltration, and the correlations among them. MethodsWe performed a detailed cancer vs. normal analysis of JMJD5 mRNA expression via online Tumor Immune Estimation Resource (TIMER). The protein expressions of JMJD5 in various cancers vs. adjacent normal tissues were examined by immunohistochemistry (IHC) of tissue microarray sections (TMAs). Moreover, the Kaplan-Meier Plotter databases were used to evaluate the prognostic values in above cancers. The correlations between JMJD5 expression level and abundances of six immune infiltrating cells (B cells, CD4+ T cells, CD8+ T cells, macrophages, neutrophils and dendritic cells) were explored by TIMER database in breast cancer (BRCA), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC) and stomach adenocarcinoma (STAD). The prognostic values of tumor- infiltrating immune cells were also investigated by TIMER in above four cancers. Finally, the COX proportional hazards model was used to investigate the correlations among clinical outcome, the abundance of immune cell infiltrates and the expression of JMJD5 in above four cancer types.ResultsThe expression of JMJD5 was significantly lower in human breast carcinoma (BRCA), cholangiocarcinoma (CHOL), liver hepatocellular carcinoma (LIHC) and lung cancer (LUC) but higher in prostate adenocarcinoma (PRAD) and stomach adenocarcinoma (STAD) comparing to their respective normal tissues. And high expression of JMJD5 has better prognosis only in BRCA, LIHC, LUC but the opposite effect in STAD. JMJD5 expression is significant correlation with the abundance of six immune cells infiltration in above four cancers. Both the BRCA or lung adenocarcinoma (LUAD) patients with abundance of B cell and the STAD patients with low level of macrophage have a better cumulative survival. ConclusionsWe provided novel evidence of JMJD5 as an essential prognostic biomarker in cancers through analyses the correlation of the JMJD5 expression, tumor-infiltrating B cells and macrophages and prognostic value. This study offers new perspectives therapeutic target in BRCA, LUAD and STAD.


2021 ◽  
Author(s):  
Yin-Hai Dai ◽  
Fuping Li ◽  
Wei-Jie Kong ◽  
Xue-Qin Zhang ◽  
Mao Wang ◽  
...  

Abstract Background: Previous studies have proved that the aberrant expressions of PFDNs (Prefoldin) family proteins were correlated with several human cancer. However, the specific functions of PFDNs in liver hepatocellular carcinoma(LIHC) remain unknown. The study aimed to identify the prognostic biomarkers and independent indicators among PFDN1/2/3/4/5/6 in liver hepatocellular carcinoma.Methods: We used these databases including Oncomine, Ualcan, GEPIA2, Human Protein Atlas, The Cancer Genome Atlas, Kaplan-Meier plotter, cBioPortal, STRI-NG and TIMER and the software of Cytoscape in our study.Results: PFDN1/2/3/4/5/6 were highly expressed in LIHC tissues. The mRNA expression levels of PFDN1/2/3/4/5/6 were relevant to tumor grades.PFDN1/3/4/5 expressions significantly changed in different cancer stages. The protein expression levels of PFDNs were higher in LIHC tissue than normal liver tissue. Moreover, High mRNA expressions of PFDN1/2/3/4 were associated with shorter OS of LIHC patients. In multivariate analysis,high expressions of PFDN1/2/4 were independently correlated with poorer OS of LIHC patients. In our findings,55% of patients with LIHC had genetic mutations on PFDNs. Besides, there were significant associations between the expressions of PFDN1/2/3/4/5 and six types of infiltrated immune cells(B cells, CD4+T cells, CD8+T cells, neutrophil, macrophage, and dendritic cells).Conclusions:PFDN1/2/3/4 were potential prognostic markers to suggest poor OS of LIHC patients. In addition, high PFDN1/2/4 expressions were independent prognostic factors in OS for LIHC patients.


2021 ◽  
Author(s):  
Meihai Deng ◽  
Hao Liang ◽  
Kunpeng Hu ◽  
Zhaozhong Zhong ◽  
Zhiyong Xiong ◽  
...  

Abstract Background: Liver hepatocellular carcinoma (LIHC) is one of the most common malignant cancers worldwide, the overall prognosis of LIHC remains unsatisfactory. Valuable prognostic biomarkers are still urgently needed for LIHC. This study aimed to explore hub genes associated with the prognosis of LIHC and tumor microenvironmental immune infiltration, providing potential prognostic biomarker and therapeutic target for LIHC. Methods: RNA-seq counts data for LIHC samples were obtained from TCGA database. RNA-seq counts data for normal liver samples were obtained from GTEx database. Weighted gene co-expression network analysis (WGCNA) was used to cluster differentially expressed genes with similar expression profiles to form modules and significant modules and key genes were screened. Next, these genes was verified by cox analyses and overall survival analysis. Further, CIBERSORT was used to explore the relationship between these genes and tumor infiltrating immune cells. Results: A total number of 2661 significant DEGs were included for consensus WGCNA analysis, which identified 6 modules. Blue module (r=0.85, p<0.0001) showed high relationship with LIHC, which included 400 genes. After the overall survival analyses of hub genes, CDC20, CDCA5, CDCA8, KIF2C and KIFC1 were identified as five potential marker genes, which would result in an unfavorable prognosis in LIHC. Further CIBERSORT analysis showed these novel biomarkers expression levels in LIHC were positively correlated with activated memory CD4+ T cells, follicular helper T cells, regulatory T cells and macrophages M0. While, resting memory CD4+ T cells, monocytes, macrophages M2, resting mast cells showed a negative correlation with the 5 novel biomarkers expression levels. Conclusions: The study screened 5 genes with marked prognostic capability for LIHC and found these genes were correlated with the infiltration of immune cells in LIHC tumor microenvironment. The findings might provide a more detailed molecular mechanism underlying LIHC occurrence and progression, holding promise for acting as potential biomarkers and therapeutic targets.


2018 ◽  
Vol 1 (1) ◽  
pp. 28-32
Author(s):  
Piyawat Komolmit

การรักษามะเร็งด้วยแนวความคิดของการกระตุ้นให้ภูมิต้านทานของร่างกายไปทำลายเซลล์มะเร็งนั้น ปัจจุบันได้รับการพิสูจน์ชัดว่าวิธีการนี้สามารถหยุดยั้งการแพร่กระจายของเซลล์มะเร็ง โดยไม่ก่อให้เกิดภาวะแทรกซ้อนทางปฏิกิริยาภูมิต้านทานต่ออวัยวะส่วนอื่นที่รุนแรง สามารถนำมาใช้ทางคลินิกได้ ยุคของการรักษามะเร็งกำลังเปลี่ยนจากยุคของยาเคมีบำบัดเข้าสู่การรักษาด้วยภูมิต้านทาน หรือ immunotherapy ยากลุ่ม Immune checkpoint inhibitors โดยเฉพาะ PD-1 กับ CTLA-4 inhibitors จะเข้ามามีบทบาทในการรักษามะเร็งตับในระยะเวลาอันใกล้ จำเป็นแพทย์จะต้องมีความรู้ความเข้าใจในพื้นฐานของ immune checkpoints และยาที่ไปยับยั้งโมเลกุลเหล่านี้ Figure 1 เมื่อ T cells รับรู้แอนทิเจนผ่านทาง TCR/MHC จะมีปฏิกิริยาระหว่าง co-receptors หรือ immune checkpoints กับ ligands บน APCs หรือ เซลล์มะเร็ง ทั้งแบบกระตุ้น (co-stimulation) หรือยับยั้ง (co-inhibition) TCR = T cell receptor, MHC = major histocompatibility complex


2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Xiao-hua Li ◽  
Fu-ling Chen ◽  
Hong-lin Shen

Abstract Background Bone disease causes short-term or long-term physical pain and disability. It is necessary to explore new drug for bone-related disease. This study aimed to explore the role and mechanism of Salidroside in promoting osteogenic differentiation of adipose-derived stromal cells (ADSCs). Methods ADSCs were isolated and treated with different dose of Salidroside. Cell count kit-8 (CCK-8) assay was performed to assess the cell viability of ADSCs. Then, ALP and ARS staining were conducted to assess the early and late osteogenic capacity of ADSCs, respectively. Then, differentially expressed genes were obtained by R software. Then, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of the differentially expressed genes were further analyzed. The expression of OCN, COL1A1, RUNX2, WNT3A, and β-catenin were measured by real-time PCR and Western blot analysis. Last, β-catenin was silenced by small interfering RNA. Results Salidroside significantly increased the ADSCs viability at a dose-response manner. Moreover, Salidroside enhanced osteogenic capacity of ADSCs, which are identified by enhanced ALP activity and calcium deposition. A total of 543 differentially expressed genes were identified between normal and Salidroside-treated ADSCs. Among these differentially expressed genes, 345 genes were upregulated and 198 genes were downregulated. Differentially expressed genes enriched in the Wnt/β-catenin signaling pathway. Western blot assay indicated that Salidroside enhanced the WNT3A and β-catenin expression. Silencing β-catenin partially reversed the promotion effects of Salidroside. PCR and Western blot results further confirmed these results. Conclusion Salidroside promoted osteogenic differentiation of ADSCs through Wnt/β-catenin signaling pathway.


2022 ◽  
Vol 2022 ◽  
pp. 1-16
Author(s):  
Dan Chen ◽  
Xiaoting Li ◽  
Hui Li ◽  
Kai Wang ◽  
Xianghua Tian

Background. As the most common hepatic malignancy, hepatocellular carcinoma (HCC) has a high incidence; therefore, in this paper, the immune-related genes were sought as biomarkers in liver cancer. Methods. In this study, a differential expression analysis of lncRNA and mRNA in The Cancer Genome Atlas (TCGA) dataset between the HCC group and the normal control group was performed. Enrichment analysis was used to screen immune-related differentially expressed genes. Cox regression analysis and survival analysis were used to determine prognostic genes of HCC, whose expression was detected by molecular experiments. Finally, important immune cells were identified by immune cell infiltration and detected by flow cytometry. Results. Compared with the normal group, 1613 differentially expressed mRNAs (DEmRs) and 1237 differentially expressed lncRNAs (DElncRs) were found in HCC. Among them, 143 immune-related DEmRs and 39 immune-related DElncRs were screened out. These genes were mainly related to MAPK cascade, PI3K-AKT signaling pathway, and TGF-beta. Through Cox regression analysis and survival analysis, MMP9, SPP1, HAGLR, LINC02202, and RP11-598F7.3 were finally determined as the potential diagnostic biomarkers for HCC. The gene expression was verified by RT-qPCR and western blot. In addition, CD4 + memory resting T cells and CD8 + T cells were identified as protective factors for overall survival of HCC, and they were found highly expressed in HCC through flow cytometry. Conclusion. The study explored the dysregulation mechanism and potential biomarkers of immune-related genes and further identified the influence of immune cells on the prognosis of HCC, providing a theoretical basis for the prognosis prediction and immunotherapy in HCC patients.


2021 ◽  
Vol 12 ◽  
Author(s):  
Shenglan Cai ◽  
Xingwang Hu ◽  
Ruochan Chen ◽  
Yiya Zhang

BackgroundEnhancer RNAs (eRNAs) are intergenic long non-coding RNAs (lncRNAs) that participate in the progression of malignancies by targeting tumor-related genes and immune checkpoints. However, the potential role of eRNAs in hepatocellular carcinoma (HCC) is unclear. In this study, we aimed to construct an immune-related eRNA prognostic model that could be used to prospectively assess the prognosis of patients with HCC.MethodsGene expression profiles of patients with HCC were downloaded from The Cancer Genome Atlas (TCGA). The eRNAs co-expressed from immune genes were identified as immune-related eRNAs. Cox regression analyses were applied in a training cohort to construct an immune-related eRNA signature (IReRS), that was subsequently used to analyze a testing cohort and combination of the two cohorts. Kaplan-Meier and receiver operating characteristic (ROC) curves were used to validate the predictive effect in the three cohorts. Gene Set Enrishment Analysis (GSEA) computation was used to identify an IReRS-related signaling pathway. A web-based cell type identification by estimating relative subsets of RNA transcripts (CIBERSORT) computation was used to evaluate the relationship between the IReRS and infiltrating immune cells.ResultsA total of sixty-four immune-related eRNAs (IReRNAs) was identified in HCC, and 14 IReRNAs were associated with overall survival (OS). Five IReRNAs were used for constructing an immune-related eRNA signature (IReRS), which was shown to correlate with poor survival and to be an independent prognostic biomarker for HCC. The GSEA results showed that the IReRS was correlated to cancer-related and immune-related pathways. Moreover, we found that IReRS was correlated to infiltrating immune cells, including CD8+ T cells and M0 macrophages. Finally, differential expressions of the five risk IReRNAs in tumor tissues vs. adjacent normal tissues and their prognostic values were verified, in which the AL445524.1 may function as an oncogene that affects prognosis partly by regulating CD4-CLTA4 related genes.ConclusionOur results suggest that the IReRS could serve as a biomarker for predicting prognosis in patients with HCC. Additionally, it may be correlated to the tumor immune microenvironment and could also be used as a biomarker in immunotherapy for HCC.


2020 ◽  
Vol 24 (19) ◽  
pp. 11243-11253 ◽  
Author(s):  
Li Li ◽  
Xiaowei Song ◽  
Yanju Lv ◽  
Qiuying Jiang ◽  
Chengjuan Fan ◽  
...  

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Guohe Song ◽  
Yang Shi ◽  
Meiying Zhang ◽  
Shyamal Goswami ◽  
Saifullah Afridi ◽  
...  

AbstractDiverse immune cells in the tumor microenvironment form a complex ecosystem, but our knowledge of their heterogeneity and dynamics within hepatocellular carcinoma (HCC) still remains limited. To assess the plasticity and phenotypes of immune cells within HBV/HCV-related HCC microenvironment at single-cell level, we performed single-cell RNA sequencing on 41,698 immune cells from seven pairs of HBV/HCV-related HCC tumors and non-tumor liver tissues. We combined bio-informatic analyses, flow cytometry, and multiplex immunohistochemistry to assess the heterogeneity of different immune cell subsets in functional characteristics, transcriptional regulation, phenotypic switching, and interactions. We identified 29 immune cell subsets of myeloid cells, NK cells, and lymphocytes with unique transcriptomic profiles in HCC. A highly complex immunological network was shaped by diverse immune cell subsets that can transit among different states and mutually interact. Notably, we identified a subset of M2 macrophage with high expression of CCL18 and transcription factor CREM that was enriched in advanced HCC patients, and potentially participated in tumor progression. We also detected a new subset of activated CD8+ T cells highly expressing XCL1 that correlated with better patient survival rates. Meanwhile, distinct transcriptomic signatures, cytotoxic phenotypes, and evolution trajectory of effector CD8+ T cells from early-stage to advanced HCC were also identified. Our study provides insight into the immune microenvironment in HBV/HCV-related HCC and highlights novel macrophage and T-cell subsets that could be further exploited in future immunotherapy.


2020 ◽  
Author(s):  
Lin Wang ◽  
Qian Wei ◽  
Ming Zhang ◽  
Lianze Chen ◽  
Zinan Li ◽  
...  

Abstract Background Esophageal cancer (ESCA) is one of the deadliest solid malignancies with worse survival in the world. The poor prognosis of ESCA is not only related to malignant cells, but also affected by the microenvironment. We aimed to establish prognostic signature consisting of immune genes to predict the survival outcome of patients and estimate the prognosis value of infiltrating immune cells in tumor microenvironment (TME). Methods Based on integrated analysis of gene expression profiling and immune gene database, differentially immune-related genes were filtered out. Then, stepwise Cox regression analysis was applied to identify survival related immune genes and construct prognosis signature. Functional enrichment analysis was performed to explore biology function. Kaplan-Meier (K-M) curves and receiver operating characteristic (ROC) curves were performed to validate the predictive effect of predictive signature. We also verified the clinical value of prognostic signature under the influence of different clinical parameters. For deeper analysis, we evaluated the correlation between prognosis signature and infiltrating immune cells by Tumor Immune Estimation Resource (TIMER) and CIBERSORT. Results Finally, we identified 303 differentially immune genes as candidate and constructed immune prognosis signature composed of six immune genes. Furthermore, we observed that the prognosis signature was enriched in cytokine-mediated signaling pathway, lymphocyte activation, immune effector process, cancer pathway, NF-kappa B signaling pathway. K-M survival curves showed that the prognosis signature indeed have good predictive ability in entire ESCA set ( P =0.003), validation set 1 ( P =0.008) and validation set 2 ( P =0.036). The area under the curve (AUC) of ROC curves validated the predictive accuracy of immune signature in three cohorts (AUC=0.757, 0.800 and 0.701), respectively. In addition, we identified the prognosis value of infiltrating-immune cells including activated memory CD4 T cells, T cells follicular helper cells and monocytes and provided a landscape of TME. Conclusions The results indicated that immune prognosis signature can be a novel biomarker to predict survival outcome, which can provide new targets for immunotherapy and individualized therapies in ESCA and open up a new prospect for improving the prognosis of ESCA patients in the era of immunotherapy.


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