scholarly journals INTS8 is a therapeutic target for intrahepatic cholangiocarcinoma via the integration of bioinformatics analysis and experimental validation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Qi Zhou ◽  
Li Ji ◽  
Xueying Shi ◽  
Dawei Deng ◽  
Fangyue Guo ◽  
...  
Keyword(s):  
Cell Lines ◽  
Intrahepatic Cholangiocarcinoma ◽  
Therapeutic Target ◽  
Primary Liver Cancer ◽  
Univariate Analysis ◽  
Dna Methyltransferases ◽  
The Cancer Genome Atlas ◽  
Mmr Genes ◽  
Pan Cancer

AbstractIntrahepatic cholangiocarcinoma (CHOL) remains a rare malignancy, ranking as the leading lethal primary liver cancer worldwide. However, the biological functions of integrator complex subunit 8 (INTS8) in CHOL remain unknown. Thus, this research aimed to explore the potential role of INTS8 as a novel diagnostic or therapeutic target in CHOL. Differentially expressed genes (DEGs) in two Gene Expression Omnibus (GEO) datasets were obtained by the “RRA” package in R software. The “maftools” package was used to visualize the CHOL mutation data from The Cancer Genome Atlas (TCGA) database. The expression of INTS8 was detected by performing quantitative reverse transcription-PCR (qRT-PCR) and immunohistochemistry in cell lines and human samples. The association between subtypes of tumour-infiltrating immune cells (TIICs) and INTS8 expression in CHOL was determined by using CIBERSORT tools. We evaluated the correlations between INTS8 expression and mismatch repair (MMR) genes and DNA methyltransferases (DNMTs) in pan-cancer analysis. Finally, the pan-cancer prognostic signature of INTS8 was identified by univariate analysis. We obtained the mutation landscapes of an RRA gene set in CHOL. The expression of INTS8 was upregulated in CHOL cell lines and human CHOL samples. Furthermore, INTS8 expression was closely associated with a distinct landscape of TIICs, MMR genes, and DNMTs in CHOL. In addition, the high INTS8 expression group presented significantly poor outcomes, including overall survival (OS), disease-specific survival (DSS) and disease-free interval (DFI) (p < 0.05) in pan-cancer. INTS8 contributes to the tumorigenesis and progression of CHOL. Our study highlights the significant role of INTS8 in CHOL and pan-cancers, providing a valuable molecular target for cancer research.

scholarly journals INTS8 Predicts a Therapeutic Target for Intrahepatic Cholangiocarcinoma via Integration of Bioinformation Analysis and Experimental Validation

2021 ◽  
Author(s):  
Qi Zhou ◽  
Li Ji ◽  
Xueying Shi ◽  
Dawei Deng ◽  
Fangyue Guo ◽  
...  
Keyword(s):  
Cell Lines ◽  
Intrahepatic Cholangiocarcinoma ◽  
Therapeutic Target ◽  
Primary Liver Cancer ◽  
Dna Methyltransferases ◽  
Reverse Transcription Pcr ◽  
Tumorigenesis And Progression ◽  
Rare Malignancy ◽  
Poor Outcomes ◽  
Pan Cancer

Abstract Background & Aims: Intrahepatic cholangiocarcinoma (ICC) remains a rare malignancy, ranking the leading lethal primary liver cancer worldwide. However, biological functions of integrator complex subunit 8 (INTS8) remain unknown in ICC. Thus, this research aimed to explore the potential role of INTS8, as well as develop a novel diagnosed or therapeutic target in ICC. Methods: Differently expressed genes in two GEO datasets were obtained by RRA package in R software. The “maftools” package was implemented to visualize the cholangiocarcinoma (CHOL) mutation data in TCGA database. The expression of INTS8 was detected by preforming quantitative reverse transcription-PCR (qRT-PCR) and immunohistochemistry in cell lines and human samples, respectively. The association between subtypes of tumor-infiltrating immune cells (TICs) and INTS8 expression in CHOL was performed by using CIBERSORT tools. We evaluated a correlation between INTS8 expression and mismatch repair genes (MMRs) and DNA methyltransferases in pan-cancer analyses. Finally, the pan-cancer prognostic signatures of INTS8 were identified by univariate analyses. Results: We obtained the mutation landscape of a RRA gene set in CHOL. The expression of INTS8 was actually upregulated in ICC cell lines and human ICC samples. Furthermore, INTS8 expression is tightly associated with distinct landscape of TICs, the MMRs, and DNA methyltransferases in CHOL. In addition, the high INTS8 expression group presented a significantly poor outcomes, including overall survival (OS), disease-specific survival (DSS) and disease-free interval (DFI) (P < 0.05) in multi-cancers. Conclusions: INTS8 contributes to the tumorigenesis and progression of ICC. Our study highlights the significant roles of INTS8 in ICC and pan-cancers, providing a valuable molecular target for cancer research.

scholarly journals STAT3 Is Activated By DYRK1A and Is a Potential Therapeutic Target in B-ALL

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3898-3898
Author(s):  
Malini Rammohan ◽  
Rahul S. Bhansali ◽  
Yi-Chien Tsai ◽  
Alexander Dong ◽  
Sebastien Malinge ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Lines ◽  
Therapeutic Target ◽  
Research Funding ◽  
Ex Vivo ◽  
Lymphoblastic Leukemia ◽  
Cell Types ◽  
Activating Mutations ◽  
Transcription 3

Abstract Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that mediates signal transduction from the extracellular surface to the nucleus. Canonically, STAT3 is phosphorylated at Tyrosine 705 (Y705) by JAK family kinases, which promotes its dimerization and subsequent localization to the nucleus. However, the role of Serine 727 (S727) phosphorylation in regulating STAT3 activity varies across cell types and remains unclear in hematopoietic tissues particularly. Several studies indicate that phosphorylation at S727 is critical for optimal STAT3 function. For example, astrogliogenesis is regulated by enhancing STAT3 activity by phosphorylation of S727 by DYRK1A. Of note, DYRK1A is overexpressed in Down syndrome-acute lymphoblastic leukemia (DS-ALL), and has previously been found to phosphorylate substrates in order to prime them for downstream phosphorylation events. Given these findings, we hypothesized that the DYRK1A phosphorylation of STAT3 at S727 is critical for promoting DS-ALL. Furthermore, certain subtypes of ALL have high rates of JAK2 activation, namely DS-ALL and Philadelphia-like ALL (Ph-like ALL); we propose that STAT3 can effectively be targeted specifically in these subtypes. In order to elucidate the role of DYRK1A phosphorylation of STAT3, we treated cytokine-deprived murine pre-B cells with EHT1610, a selective DYRK1 inhibitor, or vehicle and then pulsed the cells with JAK-STAT activating cytokines. EHT1610-treated cells had diminished S727 phosphorylation compared to vehicle, regardless of cytokine pulse; however, only vehicle-treated cells regained Y705 phosphorylation after cytokine pulse. This suggests that S727 phosphorylation is cytokine-independent and is critical for maintenance of Y705 phosphorylation. We then generated flag-tagged STAT3 S727 phospho-mimetic (S727D/E) and phospho-deficient (S727A) alleles and transduced them into pre-B cells. We observed that the degree of Y705 phosphorylation is dependent on S727, as cells expressing S727A have reduced Y705 phosphorylation compared to wild-type STAT3. Additionally, overexpression of the phospho-deficient allele conferred a significant proliferative impairment compared to the phospho-mimetic alleles. As DS-ALL and Ph-like ALL often have JAK2-activating mutations, we next aimed to determine if loss of S727 phosphorylation would decrease ALL cell growth. Indeed, two human Ph-like ALL cell lines, MHH-CALL4 and MUTZ5, displayed decreased proliferation when overexpressing the S727A mutant. These cell lines were also sensitive to treatment with C188-9, a small molecule STAT3 inhibitor that is in clinical trials for various solid tumors. Additionally, we treated primary patient ALL samples with amplification of HSA21 segments ex vivo and found that DS-ALL samples were preferentially sensitive to STAT3 inhibition compared to HD-ALL or iAMP-ALL, suggesting that STAT3 is specifically a target in JAK2-activated ALL. Our study provides new and significant insights into the regulation of STAT3 by DYRK1A, and presents a new therapeutic target for ALL cells with JAK2 activating mutations. Disclosures Bourquin: Amgen: Other: Travel Support. Crispino:Scholar Rock: Research Funding; Forma Therapeutics: Research Funding.

scholarly journals Pan-cancer analysis of the oncogenic role of discs large homolog associated protein 5 (DLGAP5) in human tumors

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Neng Tang ◽  
Xiaolin Dou ◽  
Xing You ◽  
Qiman Shi ◽  
Mujing Ke ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Carcinoma ◽  
Cell Lines ◽  
Cellular Proliferation ◽  
Germ Cell Tumors ◽  
Enrichment Analysis ◽  
Human Tumors ◽  
Testicular Germ Cell ◽  
Pan Cancer

Abstract Background In recent years, there have been many studies on the relationship between DLGAP5 and different types of cancers, yet there is no pan-cancer analysis of DLGAP5. Therefore, this study aims to analyze the roles of DLGAP5 in human tumors. Methods Firstly, we evaluated the expression level of DLGAP5 in 33 types of tumors throughout the datasets of TCGA (Cancer Genome Atlas) and GEO (Gene Expression Synthesis). Secondly, we used the GEPIA2 and Kaplan-Meier plotter to conduct Survival prognosis analysis. Additionally, cBioPortal web was utilized to analyze the genetic alteration of DLGAP5, after which we selected hepatocellular carcinoma (HCC) cell lines to define the function of DLGAP5. Last but not least, we performed immune infiltration analysis and DLGAP5-related gene enrichment analysis. Results DLGAP5 is highly expressed in most type of cancers, and there is a significant correlation between the expression of DLGAP5 and the prognosis of cancer patients. We have observed that DLGAP5 promotes the proliferation and invasion of hepatocellular carcinoma (HCC) cell lines. We also found that DLGAP5 expression was related with the CD8+ T-cell infiltration status in kidney renal clear cell carcinoma, uveal melanoma, and thymoma, and cancer-associated fibroblast infiltration was observed in breast invasive carcinoma, kidney renal papillary cell carcinoma and testicular germ cell tumors. In addition, enrichment analysis revealed that cell cycle- and oocyte meiosis-associated functions were involved in the functional mechanism of DLGAP5. Conclusions Taken together, our unpresented pan-cancer analysis of DLGAP5 provides a relatively integrative understanding of the oncogenic role of DLGAP5 in various tumors. DLGAP5 may prompt HCC cellular proliferation, invasion and metastasis. All of these provides solid basement and will promote more advanced understanding the role of DLGAP5 in tumorigenesis and development from the perspective of clinical tumor samples and cells.

scholarly journals Aggresome–Autophagy Associated Gene HDAC6 Is a Potential Biomarker in Pan-Cancer, Especially in Colon Adenocarcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhiyong Zhang ◽  
Xin Zhang ◽  
Aimin Huang
Keyword(s):  
Expression Profiles ◽  
Cancer Cell Line ◽  
Tumor Metabolism ◽  
The Cancer Genome Atlas ◽  
Differentially Expressed ◽  
Immune Checkpoints ◽  
Histone Deacetylase 6 ◽  
Potential Biomarker ◽  
Pan Cancer

BackgroundHistone deacetylase 6 (HDAC6) regulates cytoplasmic signaling networks through the deacetylation of various cytoplasmic substrates. Recent studies have identified the role of HDAC6 in tumor development and immune metabolism, but its specific function remains unclear.MethodsThe current study determined the role of HDAC6 in tumor metabolism and tumor immunity through a multi-database pan-cancer analysis. The Cancer Genome Atlas (TCGA), Genotype-Tissue Expression (GTEx), and Cancer Cell Line Encyclopedia (CCLE) datasets were used to determine the expression levels, prognosis, tumor progression, immune checkpoints, and immune metabolism of HDAC6 in 33 tumors. Pathways, immune checkpoints, immune neoantigens, immune microenvironment, tumor mutational burden (TMB), microsatellite instability (MSI), DNA mismatch repair (MMR), and the value of methyltransferases. The R package was used for quantitative analysis and panoramic description.ResultsIn the present study, we determined that HDAC6 is differentially expressed in pan carcinomas, and by survival, we found that HDAC6 was generally associated with the prognosis of pancreatic adenocarcinoma, Thymoma, and uveal melanoma, where low expression of HDAC6 had a significantly worse prognosis. Secondly, through this experiment, we confirmed that HDAC6 expression level was associated with tumor immune infiltration and tumor microenvironment, especially in PAAD. Finally, HDAC6 was associated with immune neoantigen and immune checkpoint gene expression profiles in all cancers in addition to TMB and MSI in pan-cancers.ConclusionHDAC6 is differentially expressed in pan-cancers and plays an essential role in tumor metabolism and immunity. HDAC6 holds promise as a tumor potential prognostic marker, especially in colon cancer.

scholarly journals PS2 - 167 CIC Deficiency is Associated with Dysregulation of Genes Involved in Cell Adhesion and Developmental Processes

2016 ◽  
Vol 43 (S4) ◽  
pp. S13-S13
Author(s):  
V.G. LeBlanc ◽  
S. Chittaranjan ◽  
M. Firme ◽  
S.Y. Chan ◽  
J. Song ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Cell Lines ◽  
Somatic Mutations ◽  
Control Cell ◽  
The Cancer Genome Atlas ◽  
Mitogen Activated Protein Kinase ◽  
Low Grade ◽  
Type I ◽  
Developmental Processes

Somatic mutations in the Capicua (CIC) gene were first identified in Type I low-grade gliomas (LGGs), which are characterized by 1p/19q co-deletions and IDH mutations. They are found at frequencies of ~50-70% in this glioma subtype, and have since been identified in ~40% of stomach adenocarcinomas (STADs) of the microsatellite instability (MSI) subtype; however, the role of these somatic mutations in malignancy has yet to be established. In Drosophila, CIC functions as a transcriptional repressor whose activity is inhibited upon activation of the mitogen-activated protein kinase (MAPK) signalling pathway. Though mammalian CIC appears to retain these functions, only three of its target genes have been established in human cells: ETV1, ETV4, and ETV5 (ETV1/4/5). To further probe CIC’s transcriptional network, we developed CIC knockout cell lines and performed transcriptomic and proteiomic analyses in these and in control cell lines expressing wild type CIC, identifying a total of 582 differentially expressed genes. We also used RNA-seq data from The Cancer Genome Atlas (TCGA) for Type I LGGs and STADs to perform additional differential expression analyses between CIC-deficient and CIC-expressing samples. Though gene-level overlap was limited between the three contexts, we found that CIC appears to regulate the expression of genes involved in cell-cell adhesion, metabolism, and developmental processes in all three contexts. These results shed light on the pathological role of CIC mutations and may help explain why these have been associated with poorer outcome within Type I LGGs.

A pan-cancer analysis based on weighted gene co-expression network analysis identifies the biomarker utility of lamin B1 in human tumors

2021 ◽  
pp. 1-17
Author(s):  
Youwei Hua ◽  
Zhihui He ◽  
Xu Zhang
Keyword(s):  
Network Analysis ◽  
Disease Free Survival ◽  
The Cancer Genome Atlas ◽  
Free Survival ◽  
Lamin B1 ◽  
Cancer Genome Atlas ◽  
Mrna Binding ◽  
Functional Mechanisms ◽  
Pan Cancer

Emerging evidence has revealed a relationship between lamin B1 (LMNB1) and several cancers such as cervical cancer, liver cancer, and prostate cancer. But no systematic pan-cancer analysis is available. Little is known about the clinical significance and biomarker utility of LMNB1. In this study, we first revealed the key role of LMNB1 in esophageal carcinoma (ESCA) through weighted gene co-expression network analysis (WGCNA) and disease-free survival (DFS) analysis. Based on this result and the datasets of the cancer genome atlas (TCGA), we explored the biomarker utility of LMNB1 across thirty-three tumors. We found that LMNB1 was highly expressed in most of the cancers and significant associations existed between LMNB1 expression and prognosis of cases of nearly half of the cancers. We also found that LMNB1 expression was associated with the infiltration level of Macrophages M1 and T cells CD4 memory activated in some cancers. Moreover, LMNB1 was mainly involved in the functional mechanisms of MRNA binding, olfactory transduction, and gene silencing. Our study first provides a pan-cancer study of LMNB1, thereby offering a relatively comprehensive understanding of the biomarker utility of LMNB1 across thirty-three tumors.

scholarly journals An Integrated Pan-Cancer Analysis and Structure-Based Virtual Screening of GPR15

2019 ◽  
Vol 20 (24) ◽  
pp. 6226 ◽  
Author(s):  
Yanjing Wang ◽  
Xiangeng Wang ◽  
Yi Xiong ◽  
Cheng-Dong Li ◽  
Qin Xu ◽  
...  
Keyword(s):  
Virtual Screening ◽  
G Protein ◽  
Large Scale ◽  
3D Structure ◽  
Rectal Adenocarcinoma ◽  
Squamous Carcinoma ◽  
The Cancer Genome Atlas ◽  
G Protein Coupled ◽  
Pan Cancer

G protein-coupled receptor 15 (GPR15, also known as BOB) is an extensively studied orphan G protein-coupled receptors (GPCRs) involving human immunodeficiency virus (HIV) infection, colonic inflammation, and smoking-related diseases. Recently, GPR15 was deorphanized and its corresponding natural ligand demonstrated an ability to inhibit cancer cell growth. However, no study reported the potential role of GPR15 in a pan-cancer manner. Using large-scale publicly available data from the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) databases, we found that GPR15 expression is significantly lower in colon adenocarcinoma (COAD) and rectal adenocarcinoma (READ) than in normal tissues. Among 33 cancer types, GPR15 expression was significantly positively correlated with the prognoses of COAD, neck squamous carcinoma (HNSC), and lung adenocarcinoma (LUAD) and significantly negatively correlated with stomach adenocarcinoma (STAD). This study also revealed that commonly upregulated gene sets in the high GPR15 expression group (stratified via median) of COAD, HNSC, LUAD, and STAD are enriched in immune systems, indicating that GPR15 might be considered as a potential target for cancer immunotherapy. Furthermore, we modelled the 3D structure of GPR15 and conducted structure-based virtual screening. The top eight hit compounds were screened and then subjected to molecular dynamics (MD) simulation for stability analysis. Our study provides novel insights into the role of GPR15 in a pan-cancer manner and discovered a potential hit compound for GPR15 antagonists.

scholarly journals Essential role of TAK1 in regulating mantle cell lymphoma survival

Blood ◽  
2012 ◽  
Vol 120 (2) ◽  
pp. 347-355 ◽  
Author(s):  
Daniela Buglio ◽  
Sangeetha Palakurthi ◽  
Kate Byth ◽  
Francisco Vega ◽  
Dorin Toader ◽  
...  
Keyword(s):  
Cell Lines ◽  
Therapeutic Target ◽  
Essential Role ◽  
Large Cell ◽  
Lymphoma Cell ◽  
Primary Lymphoma ◽  
Molecular Events ◽  
Mantle Cell ◽  
Induced Apoptosis

Abstract TGF-β–activated kinase 1 (TAK1), a member of the MAPK kinase family, plays a key role in B-cell growth and development. In the present study, we examined the potential role of TAK1 as a therapeutic target for lymphoma. Here, we show that the active phosphorylated form of TAK1 is abundantly expressed in a panel of lymphoma cell lines, including mantle cell, anaplastic large cell, and Hodgkin lymphoma cell lines. Silencing TAK1 expression via the use of siRNA inhibited the activation of NF-κB and p38 and induced apoptosis in lymphoma cell lines. Moreover, submicromolar concentrations of AZ-TAK1, a novel ATP-competitive small molecule inhibitor of TAK1, dephosphorylated TAK1, p38, and IκB-α in lymphoma cell lines. These molecular events were associated with the release of cytochrome c into the cytosol, down-regulation of X-linked inhibitor of apoptosis, activation of caspase 9, and induction of apoptosis. We also demonstrate that primary lymphoma cells express TAK1 and pTAK1 and were sensitive to AZ-TAK1–mediated cell death. Collectively, our data demonstrate an essential role for TAK1 in regulating critical survival mechanisms in lymphoma and suggest that it may serve as a therapeutic target.

scholarly journals SPOCD1 regulated by miR-133a-3p promotes hepatocellular carcinoma invasion and metastasis

2022 ◽  
Vol 50 (1) ◽  
pp. 030006052110537
Author(s):  
Tianying Zheng ◽  
Xin Zhang ◽  
Yonggang Wang ◽  
Aijun Wang
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Colony Formation ◽  
Quantitative Polymerase Chain Reaction ◽  
The Cancer Genome Atlas ◽  
Luciferase Assay ◽  
Luciferase Reporter ◽  
Downstream Target

Objective To investigate the tumorigenic role of spen paralogue and orthologue C-terminal domain-containing 1 (SPOCD1) in hepatocellular carcinoma (HCC) and identify the upstream regulatory mechanism. Methods We analyzed SPOCD1 and miR-133-3p expression in normal and HCC tissues from the Cancer Genome Atlas and UALCAN databases, and in normal hepatocytes and HCC cell lines by real-time quantitative polymerase chain reaction and western blot. We identified the miR-133a-3p-binding site on the SPOCD1 3ʹ-untranslated region using TargetScan. Hierarchical regulation was confirmed by luciferase assay and miR-133a-3p overexpression/silencing. Cell proliferation, migration, invasion, and colony formation were assessed by MTT, scratch, transwell, and clonogenic assays, respectively. Results SPOCD1 was highly expressed in HCC tissues and cell lines, while miR-133a-3p expression was significantly downregulated. Kaplan–Meier analysis indicated that high SPOCD1 expression was significantly associated with poor survival. TargetScan and luciferase reporter assay revealed that SPOCD1 was the downstream target of miR-133a-3p. Overexpression of miR-133a-3p significantly inhibited the expression of SPOCD1, while miR-133a-3p knockdown significantly increased SPOCD1 expression. Conclusion SPOCD1, regulated by miR-133a-3p, promotes HCC cell proliferation, migration, invasion, and colony formation. This study provides the first evidence for the role of the miR-133a-3p/SPOCD1 axis in HCC tumorigenesis.

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