TRIP13 promotes lung cancer cell growth and metastasis through AKT/mTORC1/c-Myc signaling

BACKGROUNDS: Lung adenocarcinoma (LUAD) is a primary cause of cancer-patient mortality throughout the world. Thyroid hormone receptor interactor 13 (TRIP13) is a gene that expresses a protein involved in cell division, including tumorigenesis. Its expression is high in various human tumors; however, its role in LUAD cells remains undetermined. OBJECTIVE: To investigate the TRIP13’s role in the development of LUAD. METHODS: Bioinformation analysis was used to analyze the expression of TRIP13 in LUAD tissues and the impact on the prognosis of LUAD; CRISPR/Cas9 was used to construct the cell lines; CCK-8 was used to explore the cell proliferation; Transwell assays was applied to exam the cell migration and cell invasion abilities; Western blot and immunoprecipitation was used to explore the relation between TRIP13 and AKT/mTORC1/c-Myc signaling pathway. RESULTS: By analyzing LUAD data from The Cancer Genome Atlas and the Gene Expression Omnibus databases, we determined that TRIP13 is highly expressed in LUAD tissues and that this expression level has a negative impact on the patient mortality. TRIP13 has also proved to promote LUAD cell proliferation, migration, and invasion. In this study, we demonstrated that TRIP13 activates AKT/mTORC1/c-Myc signaling in these cells. CONCLUSION: Our results have identified the role and potential mechanism by which TRIP13 affects LUAD cells, which may provide a useful marker for helping to diagnose this disease and create new therapies against it.

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Clinical and Molecular Correlates of NLRC5 Expression in Patients With Melanoma

Frontiers in Bioengineering and Biotechnology ◽

10.3389/fbioe.2021.690186 ◽

2021 ◽

Vol 9 ◽

Author(s):

Lei Lv ◽

Qinqin Wei ◽

Zhiwen Wang ◽

Yujia Zhao ◽

Ni Chen ◽

...

Keyword(s):

Immune Cells ◽

Cancer Cell Line ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Missense Mutations ◽

Cancer Genome Atlas ◽

Important Regulator ◽

Public Datasets ◽

Splice Mutations ◽

The Impact

NLRC5 is an important regulator in antigen presentation and inflammation, and its dysregulation promotes tumor progression. In melanoma, the impact of NLRC5 expression on molecular phenotype, clinical characteristics, and tumor features is largely unknown. In the present study, public datasets from the Cancer Cell Line Encyclopedia (CCLE), Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), and cBioPortal were used to address these issues. We identify that NLRC5 is expressed in both immune cells and melanoma cells in melanoma samples and its expression is regulated by SPI1 and DNA methylation. NLRC5 expression is closely associated with Breslow thickness, Clark level, recurrence, pathologic T stage, and ulceration status in melanoma. Truncating/splice mutations rather than missense mutations in NLRC5 could compromise the expression of downstream genes. Low expression of NLRC5 is associated with poor prognosis, low activity of immune-related signatures, low infiltrating level of immune cells, and low cytotoxic score in melanoma. Additionally, NLRC5 expression correlates with immunotherapy efficacy in melanoma. In summary, these findings suggest that NLRC5 acts as a tumor suppressor in melanoma via modulating the tumor immune microenvironment. Targeting the NLRC5 related pathway might improve efficacy of immunotherapy for melanoma patients.

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Multiscale-omic assessment of EWSR1-NFATc2 fusion positive sarcomas identifies the mTOR pathway as a potential therapeutic target

npj Precision Oncology ◽

10.1038/s41698-021-00177-0 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Nathan D. Seligson ◽

Richard D. Maradiaga ◽

Colin M. Stets ◽

Howard M. Katzenstein ◽

Sherri Z. Millis ◽

...

Keyword(s):

Ewing Sarcoma ◽

Additional Data ◽

Gene Expression Omnibus ◽

Mtor Pathway ◽

The Cancer Genome Atlas ◽

Molecular Characteristics ◽

Potential Therapeutic Target ◽

Disease Stabilization ◽

Cancer Genome Atlas ◽

Ewing Family Of Tumors

AbstractSarcomas harboring EWSR1-NFATc2 fusions have historically been categorized and treated as Ewing sarcoma. Emerging evidence suggests unique molecular characteristics and chemotherapy sensitivities in EWSR1-NFATc2 fusion positive sarcomas. Comprehensive genomic profiles of 1024 EWSR1 fusion positive sarcomas, including 14 EWSR1-NFATc2 fusions, were identified in the FoundationCore® database. Additional data from the Gene Expression Omnibus, the Genomics of Drug Sensitivity in Cancer and The Cancer Genome Atlas datasets were included for analysis. EWSR1-NFATc2 fusion positive sarcomas were genomically distinct from traditional Ewing sarcoma and demonstrated upregulation of the mTOR pathway. We also present a case of a 58-year-old male patient with metastatic EWSR1-NFATc2 fusion positive sarcoma who achieved 47 months of disease stabilization when treated with combination mTOR and VEGF inhibition. EWSR1-NFATc2 fusion positive sarcomas are molecularly distinct entities with overactive mTOR signaling; which may be therapeutically targetable. These findings support the use of precision medicine in the Ewing family of tumors.

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Heme Biosynthesis mRNA Expression Signature: Towards a Novel Prognostic Biomarker in Patients with Diffusely Infiltrating Gliomas

Cancers ◽

10.3390/cancers13040662 ◽

2021 ◽

Vol 13 (4) ◽

pp. 662

Author(s):

Mario Mischkulnig ◽

Barbara Kiesel ◽

Daniela Lötsch ◽

Thomas Roetzer ◽

Martin Borkovec ◽

...

Keyword(s):

Overall Survival ◽

Mrna Expression ◽

Postoperative Management ◽

Heme Biosynthesis ◽

The Cancer Genome Atlas ◽

Sequencing Data ◽

Who Grade ◽

Expression Signature ◽

Cancer Genome Atlas ◽

The Impact

Diffusely infiltrating gliomas are characterized by a variable clinical course, and thus novel prognostic biomarkers are needed. The heme biosynthesis cycle constitutes a fundamental metabolic pathway and might play a crucial role in glioma biology. The aim of this study was thus to investigate the role of the heme biosynthesis mRNA expression signature on prognosis in a large glioma patient cohort. Glioma patients with available sequencing data on heme biosynthesis expression were retrieved from The Cancer Genome Atlas (TCGA). In each patient, the heme biosynthesis mRNA expression signature was calculated and categorized into low, medium, and high expression subgroups. Differences in progression-free and overall survival between these subgroups were investigated including a multivariate analysis correcting for WHO grade, tumor subtype, and patient age and sex. In a total of 693 patients, progression-free and overall survival showed a strictly monotonical decrease with increasing mRNA expression signature subgroups. In detail, median overall survival was 134.2 months in the low, 79.9 months in the intermediate, and 16.5 months in the high mRNA expression signature subgroups, respectively. The impact of mRNA expression signature on progression-free and overall survival was independent of the other analyzed prognostic factors. Our data indicate that the heme biosynthesis mRNA expression signature might serve as an additional novel prognostic marker in patients with diffusely infiltrating gliomas to optimize postoperative management.

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Carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) in Pancreatic Ductal Adenocarcinoma (PDA): An integrative analysis of a novel therapeutic target

Scientific Reports ◽

10.1038/s41598-019-54545-9 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 2

Author(s):

Ritu Pandey ◽

Muhan Zhou ◽

Shariful Islam ◽

Baowei Chen ◽

Natalie K Barker ◽

...

Keyword(s):

Cell Adhesion ◽

Pancreatic Ductal Adenocarcinoma ◽

Therapeutic Target ◽

Cell Activity ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Ductal Adenocarcinoma ◽

Wild Type ◽

Cancer Genome Atlas ◽

Novel Therapeutic

AbstractWe investigated biomarker CEACAM6, a highly abundant cell surface adhesion receptor that modulates the extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDA). The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) RNA-Seq data from PDA patients were analyzed for CEACAM6 expression and evaluated for overall survival, association, enrichment and correlations. A CRISPR/Cas9 Knockout (KO) of CEACAM6 in PDA cell line for quantitative proteomics, mitochondrial bioenergetics and tumor growth in mice were conducted. We found CEACAM6 is over-expressed in primary and metastatic basal and classical PDA subtypes. Highest levels are in classical activated stroma subtype. CEACAM6 over-expression is universally a poor prognostic marker in KRAS mutant and wild type PDA. High CEACAM6 expression is associated with low cytolytic T-cell activity in both basal and classical PDA subtypes and correlates with low levels of T-REG markers. In HPAF-II cells knockout of CEACAM6 alters ECM-cell adhesion, catabolism, immune environment, transmembrane transport and autophagy. CEACAM6 loss increases mitochondrial basal and maximal respiratory capacity. HPAF-II CEACAM6−/− cells are growth suppressed by >65% vs. wild type in mice bearing tumors. CEACAM6, a key regulator affects several hallmarks of PDA including the fibrotic reaction, immune regulation, energy metabolism and is a novel therapeutic target in PDA.

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Data mining of immune-related prognostic genes in metastatic melanoma microenvironment

Bioscience Reports ◽

10.1042/bsr20201704 ◽

2020 ◽

Vol 40 (11) ◽

Author(s):

Wei Han ◽

Biao Huang ◽

Xiao-Yu Zhao ◽

Guo-Liang Shen

Keyword(s):

Gene Expression ◽

Tumor Microenvironment ◽

Metastatic Melanoma ◽

Interaction Network ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Protein Protein Interaction ◽

Subtype Identification ◽

Cancer Genome Atlas ◽

Immune Related Genes

Abstract Skin cutaneous melanoma (SKCM) is one of the most deadly malignancies. Although immunotherapies showed the potential to improve the prognosis for metastatic melanoma patients, only a small group of patients can benefit from it. Therefore, it is urgent to investigate the tumor microenvironment in melanoma as well as to identify efficient biomarkers in the diagnosis and treatments of SKCM patients. A comprehensive analysis was performed based on metastatic melanoma samples from the Cancer Genome Atlas (TCGA) database and ESTIMATE algorithm, including gene expression, immune and stromal scores, prognostic immune-related genes, infiltrating immune cells analysis and immune subtype identification. Then, the differentially expressed genes (DEGs) were obtained based on the immune and stromal scores, and a list of prognostic immune-related genes was identified. Functional analysis and the protein–protein interaction network revealed that these genes enriched in multiple immune-related biological processes. Furthermore, prognostic genes were verified in the Gene Expression Omnibus (GEO) databases and used to predict immune infiltrating cells component. Our study revealed seven immune subtypes with different risk values and identified T cells as the most abundant cells in the immune microenvironment and closely associated with prognostic outcomes. In conclusion, the present study thoroughly analyzed the tumor microenvironment and identified prognostic immune-related biomarkers for metastatic melanoma.

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B7-H6 Is Associated with Poor Prognosis and a Potential Therapeutic Target of T-Lymphoblastic Lymphoma

Blood ◽

10.1182/blood-2020-139146 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 33-33

Author(s):

Lei Yuan ◽

Lu Sun ◽

Yu Zhao ◽

Hongmei Jing ◽

Xiaoyan Ke

Keyword(s):

Cell Proliferation ◽

Therapeutic Target ◽

Poor Prognosis ◽

Elevated Serum ◽

Lymphoblastic Lymphoma ◽

Jurkat Cells ◽

Migration And Invasion ◽

Serum Lactate Dehydrogenase ◽

Nuclear Localization Sequence ◽

The Impact

Background:B7-H6 is a novel co-stimulatory protein that is exclusively expressed on a variety of cancer cells and associated with poor prognosis. T cell lymphoblastic lymphoma (T-LBL) is a highly aggressive hematological malignancy whose treatment requires reliable prognostic biomarkers and therapeutic targets. The rare nature and delayed progression of T-LBL has limited its clinical management. Methods:B7-H6 expression was analyzed by immunohistochemistry (IHC) in 65 T-LBL samples, and its association with clinicopathological characteristics and prognosis was analyzed. Jurkat cell with B7-H6 depletion was constructed to investigate the impact of B7-H6 on cell proliferation, migration, and invasion ability. RNA sequencing was used to explore aberrantly expressing genes. Results:In this study, we used immunohistochemistry to show the expression of B7-H6 in 61.5% (40/65) of the cohort, including 38.5% (25/65) patients with membrane/cytoplasmic expression of B7-H6. Although B7-H6 expression varied across samples and did not correlate with patient survival, it was significantly associated with B symptoms, higher ECOG score (3-4), elevated serum lactate dehydrogenase, and reduced complete remission at interim evaluation. B7-H6 underwent translocation into the nucleus of T-LBL cells and had a specific nuclear localization sequence in the C-terminus. Depleting Jurkat cells of B7-H6 impaired cell proliferation, migration, and invasion. RNAseq showed the differential expression of RAG-1 that could be involved in the tumorigenesis of T-LBL. Conclusions:B7-H6 may serve as a novel prognostic biomarker and therapeutic target of T-LBL. Disclosures Ke: Peking University Third Hospital:Current Employment.

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Clinical Significance of miR-210 and its Prospective Signaling Pathways in Non-Small Cell Lung Cancer: Evidence from Gene Expression Omnibus and the Cancer Genome Atlas Data Mining with 2763 Samples and Validation via Real-Time Quantitative PCR

Cellular Physiology and Biochemistry ◽

10.1159/000488823 ◽

2018 ◽

Vol 46 (3) ◽

pp. 925-952 ◽

Cited By ~ 12

Author(s):

Rong-quan He ◽

Wei-luan Cen ◽

Jie-mei Cen ◽

Wei-ning Cen ◽

Jia-yi Li ◽

...

Keyword(s):

Clinical Significance ◽

Meta Analysis ◽

Gene Expression Omnibus ◽

Small Cell ◽

The Cancer Genome Atlas ◽

Small Cell Lung ◽

Free Survival ◽

Real Time Quantitative Pcr ◽

Cancer Genome Atlas ◽

Genome Atlas

Background/Aims: Since the function of microRNA (miR)-210 in non-small cell lung cancer (NSCLC) remains unclear, we aimed to explore the clinical significance of miR-210 in NSCLC. Methods: NSCLC-related data from 1673 samples on Gene Expression Omnibus and 1090 samples on The Cancer Genome Atlas were obtained and analyzed. The expression level of miR-210 was validated via real-time quantitative PCR analysis with 125 paired clinical samples. A meta-analysis was performed to generate a comprehensive understanding of miR-210 expression and its clinical significance in NSCLC. In addition, bioinformatics analysis was also conducted to reveal the potential underlying mechanism of miR-210 action in NSCLC. Results: miR-210 expression was consistently elevated in NSCLC solid tissue samples. However, its expression was controversial in easily obtained body fluids (i.e., blood, plasma, and serum). Moreover, an overall pooled meta-analysis implied a comparatively higher level of miR-210 expression in NSCLC cancerous tissue than in normal control tissue (P < 0.001). In addition, a meta-analysis of outcome revealed a significant diagnostic capacity of miR-210 in NSCLC by detecting its expression in serum and sputum (area under the summary receiver operating characteristic curve 0.82 and 0.81, respectively). miR-210 overexpression was associated with poor progression-free survival (PFS) in NSCLC and was negatively related to overall survival and disease-free survival. Bioinformatic gene enrichment and annotation analyses showed that the target genes of miR-210 were greatly enriched in cell adhesion and plasma membrane, and three pathways were considered to be the main functional circuits of miR-210: renin secretion, the cGMP-PKG signaling pathway, and cell adhesion molecules. Conclusion: In NSCLC, miR-210 expression was elevated and overexpression indicated poor PFS. Expression level of miR-210 in serum and sputum showed significant diagnostic value for NSCLC.

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LncRNA NCRNA00173 is down-regulated in pediatric osteosarcoma and suppresses cell metastasis of osteosarcoma cells through regulating PI3k/Akt pathway

10.21203/rs.2.19195/v1 ◽

2019 ◽

Author(s):

Zhongquan Zhao ◽

Jiechao Chen ◽

Dezhi Xia

Keyword(s):

Cell Proliferation ◽

Protein Expression ◽

Tumor Growth ◽

Nude Mice ◽

Akt Pathway ◽

Migration And Invasion ◽

Kaplan Meier ◽

Disability Rate ◽

Cell Metastasis ◽

The Impact

Abstract Background: Osteosarcoma (OS) is a primary malignant tumor with high mortality and disability rate in childhood and adolescent, whereas the influence of LncRNA00173 (NCRNA00173) on pediatric OS progression is not obvious yet. Therefore, this study aimed to investigate the expression of NCRNA00173 in pediatric OS and its effect on OS progression. Methods: In our study, qRT-PCR was adopted to test the NCRNA00173 expression in 40 pairs of pediatric OS tissues and OS cell lines. Kaplan-Meier method and Cox proportional hazard model were performed to analyze the prognosis of pediatric OS patients. The cell proliferation, apoptosis, migration and invasion of U2OS and HOS cells were test by MTT assay, flow cytometry, wound-healing, and transwell assay, respectively. The protein expression levels of PI3K/Akt pathway were measured by western blot. In addition, tumor growth in nude mice was also detected. Results: The expression of NCRNA00173 was down-regulated and relevant with poor prognosis in pediatric OS. Overexpression of NCRNA00713 inhibited cell proliferation, migration and invasion, as well as accelerated cell apoptosis in U2OS and HOS cells. Overexpression of NCRNA00713 suppressed tumor growth in nude mice. The protein expression of p-PI3K and p-Akt were remarkedly decreased in U2OS and HOS cells after transfection with NCRNA00173. In addition, 740 Y-P (PI3K/Akt pathway activator) eliminated the impact of NCRNA00173 in HOS. Conclusions: NCRNA00173 was down-regulated in pediatric OS and suppressed metastasis of OS cells by regulating PI3k/Akt pathway.

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miR-940 potentially promotes proliferation and metastasis of endometrial carcinoma through regulation of MRVI1

Bioscience Reports ◽

10.1042/bsr20190077 ◽

2019 ◽

Vol 39 (6) ◽

Cited By ~ 4

Author(s):

Zhan Zhou ◽

Ya-Ping Xu ◽

Li-Juan Wang ◽

Yan Kong

Keyword(s):

Cell Proliferation ◽

Endometrial Carcinoma ◽

Cell Lines ◽

In Silico Analysis ◽

Good Prognosis ◽

The Cancer Genome Atlas ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Proliferation Ability ◽

And Migration

AbstractThe specific functions and clinical significance of miR-940 in endometrial carcinoma (EC) have not been studied. First, we assessed the expression of miR-940 and MRVI1 in EC tissues collected from The Cancer Genome Atlas (TCGA) database and EC cell lines. miR-940 was significantly overexpressed in EC tissues and cell lines, particularly in RL95-2 cells. Correlation analysis showed that miR-940 expression level was remarkably associated with age, grade, and death. Moreover, the overall survival (OS) rate in the miR-940 low expression group was higher, compared with miR-940 high expression group. Univariate and multivariate models demonstrated that miR-940 expression, stage, and age were predictive indicators of OS. Moreover, there was no significance of the proliferation ability among the three EC cell lines (RL95-2, ISK, and KLE). To reveal the biological roles of miR-940, we respectively transfected RL95-2 cells with miR-940 mimics, miR-940 inhibitors, and control to further investigate the cell proliferation ability, and migration as well as invasion potential of RL95-2 cells. The transfection of miR-940 mimics significantly increased the proliferation and migration/invasion ability of RL95-2 cells. MRVI1 was predicted to be a potential target of miR-940 by means of in silico analysis followed by validation using luciferase reporter assays. MRVI1 was correlated with good prognosis. Moreover, forced expression of MRVI1 in miR-940 mimic transfected cells abolished the facilitation of miR-940 on cell proliferation, migration, and invasion of RL95-2 and KLE cells. In conclusion, our study demonstrates that miR-940 might function as a reliable diagnostic and prognostic signature in EC.

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Identification of novel mRNA-miRNA-lncRNA competing endogenous RNA network associated with prognosis of breast cancer

Epigenomics ◽

10.2217/epi-2019-0209 ◽

2019 ◽

Vol 11 (13) ◽

pp. 1501-1518 ◽

Cited By ~ 6

Author(s):

Guansheng Zhong ◽

Weiyang Lou ◽

Minya Yao ◽

Chengyong Du ◽

Haiyan Wei ◽

...

Keyword(s):

Breast Cancer ◽

Gene Expression Omnibus ◽

The Cancer Genome Atlas ◽

Cancer Prognosis ◽

Competing Endogenous Rna ◽

Hub Genes ◽

Cerna Network ◽

Competing Endogenous Rna Network ◽

Cancer Genome Atlas ◽

Genome Atlas

Aim: To identify novel competing endogenous RNA (ceRNA) network related to patients prognosis in breast cancer. Materials & methods: Dysregulated mRNA based on intersection of three Gene Expression Omnibus and The Cancer Genome Atlas datasets were analyzed by bioinformatics. Results: In total 72 upregulated and 208 downregulated genes were identified. Functional analysis showed that some pathways related to cancer were significantly enriched. By means of stepwise reverse prediction and validation from mRNA to lncRNA, 19 hub genes, nine key miRNA and four key lncRNAs were identified by expression and survival analysis. Ultimately, the coexpression analysis identified RRM2-let-7a-5p- SNHG16/ MAL2 as key ceRNA subnetwork associated with prognosis of breast cancer. Conclusion: We successfully constructed a novel ceRNA network, among which each component was significantly associated with breast cancer prognosis.

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