A Pan-Cancer Analysis of Cystatin E/M Reveals Its Dual Functional Effects and Positive Regulation of Epithelial Cell in Human Tumors

Cystatin E/M (CST6), a representative cysteine protease inhibitor, plays both tumor-promoting and tumor-suppressing functions and is pursued as an epigenetically therapeutic target in special cancer types. However, a comprehensive and systematic analysis for CST6 in pan-cancer level is still lacking. In the present study, we explored the expression pattern of CST6 in multiple cancer types across ∼10,000 samples from TCGA (The Cancer Genome Atlas) and ∼8,000 samples from MMDs (Merged Microarray-acquired Datasets). We found that the dynamic expression alteration of CST6 was consistent with dual function in different types of cancer. In addition, we observed that the expression of CST6 was globally regulated by the DNA methylation in its promoter region. CST6 expression was positively correlated with the epithelial cell infiltration involved in epithelial-to-mesenchymal transition (EMT) and proliferation. The relationship between CST6 and tumor microenvironment was also explored. In particular, we found that CST6 serves a protective function in the process of melanoma metastasis. Finally, the clinical association analysis further revealed the dual function of CST6 in cancer, and a combination of the epithelial cell infiltration and CST6 expression could predict the prognosis for SKCM patients. In summary, this first CST6 pan-cancer study improves the understanding of the dual functional effects on CST6 in different types of human cancer.

Download Full-text

Pan-Cancer Analysis Shows Enrichment of Macrophages, Overexpression of Checkpoint Molecules, Inhibitory Cytokines, and Immune Exhaustion Signatures in EMT-High Tumors

Frontiers in Oncology ◽

10.3389/fonc.2021.793881 ◽

2022 ◽

Vol 11 ◽

Author(s):

Jayesh Kumar Tiwari ◽

Shloka Negi ◽

Manju Kashyap ◽

Sheikh Nizamuddin ◽

Amar Singh ◽

...

Keyword(s):

Cancer Progression ◽

Immune Escape ◽

The Cancer Genome Atlas ◽

Mesenchymal Transition ◽

Gene Signatures ◽

Immune Exhaustion ◽

Cancer Types ◽

Tcga Dataset ◽

Pan Cancer

Epithelial–mesenchymal transition (EMT) is a highly dynamic process that occurs under normal circumstances; however, EMT is also known to play a central role in tumor progression and metastasis. Furthermore, role of tumor immune microenvironment (TIME) in shaping anticancer immunity and inducing the EMT is also well recognized. Understanding the key features of EMT is critical for the development of effective therapeutic interventions. Given the central role of EMT in immune escape and cancer progression and treatment, we have carried out a pan-cancer TIME analysis of The Cancer Genome Atlas (TCGA) dataset in context to EMT. We have analyzed infiltration of various immune cells, expression of multiple checkpoint molecules and cytokines, and inflammatory and immune exhaustion gene signatures in 22 cancer types from TCGA dataset. A total of 16 cancer types showed a significantly increased (p < 0.001) infiltration of macrophages in EMT-high tumors (mesenchymal samples). Furthermore, out of the 17 checkpoint molecules we analyzed, 11 showed a significant overexpression (p < 0.001) in EMT-high samples of at least 10 cancer types. Analysis of cytokines showed significant enrichment of immunosuppressive cytokines—TGFB1 and IL10—in the EMT-high group of almost all cancer types. Analysis of various gene signatures showed enrichment of inflammation, exhausted CD8+ T cells, and activated stroma signatures in EMT-high tumors. In summary, our pan-cancer EMT analysis of TCGA dataset shows that the TIME of EMT-high tumors is highly immunosuppressive compared to the EMT-low (epithelial) tumors. The distinctive features of EMT-high tumors are as follows: (i) the enrichment of tumor-associated macrophages, (ii) overexpression of immune checkpoint molecules, (iii) upregulation of immune inhibitory cytokines TGFB1 and IL10, and (iv) enrichment of inflammatory and exhausted CD8+ T-cell signatures. Our study shows that TIMEs of different EMT groups differ significantly, and this would pave the way for future studies analyzing and targeting the TIME regulators for anticancer immunotherapy.

Download Full-text

Integrated Genomic Analysis of Hypoxia Genes across Cancer Types Identifies Significant Associations with Cancer Hallmarks

10.1101/403717 ◽

2018 ◽

Author(s):

Lingjian Yang ◽

Laura Forker ◽

Christina S. Fjeldbo ◽

Robert G. Bristow ◽

Heidi Lyng ◽

...

Keyword(s):

Environmental Factor ◽

Epithelial Mesenchymal Transition ◽

Tumour Progression ◽

The Cancer Genome Atlas ◽

Silent Mutation ◽

Multiple Cancer ◽

Mesenchymal Transition ◽

Cancer Types ◽

Pan Cancer

ABSTRACTHypoxia is a generic micro-environmental factor in most solid tumours. While most published literature focused on in vitro or single tumour type investigations, we carried out the first multi-omics pan cancer analysis of hypoxia with the aim of gaining a comprehensive understanding of its implication in tumour biology. A core set of 52 mRNAs were curated based on experimentally validated hypoxia gene sets from multiple cancer types. The 52 mRNAs collectively stratified high- and low-hypoxia tumours from The Cancer Genome Atlas (TCGA) database (9698 primary tumours) in each of the 32 cancer types available. High- hypoxia tumours had high expression of not only mRNA but also protein and microRNA markers of hypoxia. In a pan cancer transcriptomic analysis, ≥70% of the known cancer hallmark pathways were enriched in high-hypoxia tumours, most notably epithelial mesenchymal transition potential, proliferation (G2M checkpoint, E2F targets, MYC targets) and immunology response. In a multi-omics analysis, gene expression-determined high- hypoxia tumours had a higher non-silent mutation rate, DNA damage repair deficiency and leukocyte infiltration. The associations largely remained significant after correcting for confounding factors, showing a profound impact of hypoxia in tumour evolution across cancer types. High-hypoxia tumours determined using the core gene set had a poor prognosis in 16/32 cancer types, with statistical significances remaining in five after adjusting for tumour stage and omics biomarkers. In summary, this first comprehensive in vivo map of hypoxia in cancers highlights the importance of this micro-environmental factor in driving tumour progression.

Download Full-text

Prognostic and Immunological Characterization of NSD3 Evaluated through an Integrative Pan-Cancer Analysis

10.21203/rs.3.rs-591803/v1 ◽

2021 ◽

Author(s):

Sha Li ◽

Yaqiong Liu ◽

Chaoling Yao ◽

Anji Xu ◽

Xiaoling Zeng ◽

...

Keyword(s):

Immune Cell ◽

Human Cancer ◽

The Cancer Genome Atlas ◽

Functional Enrichment ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Multiple Cancer ◽

Cancer Dataset ◽

Cancer Types ◽

Pan Cancer

Abstract Background: Nuclear receptor binding SET domain protein-3 (NSD3) has been reported to be a crucial regulator of carcinogenesis as a histone lysine methyltransferase in multiple cancer types. However, the underlying mechanisms have not been clearly delineated. Therefore, we aimed to investigate the expression pattern, prognostic value, and potential function of NSD3 in 33 types of human cancer. Methods: The potential roles of NSD3 were explored using datasets from The Cancer Genome Atlas (TCGA) pan-cancer dataset and an array of bioinformatics methods, including analyses of the relationship between NSD3 expression and prognosis, tumor mutational burden (TMB), microsatellite instability (MSI), DNA amplification, and immune cell inﬁltration across 33 cancer types. Results: Many types of cancers are characterized according to the dysregulation of NSD3, which is associated with the pathological stage of cancer. Patients in our study with higher NDS3 levels, which were attributed to NSD3 copy number amplification, always experienced shorter survival periods. Additionally, NSD3 expression was associated with TMB and MSI in 10 different cancer types. The top five cancers whose NSD3 expression correlated with immune scores were further analyzed. The levels of immune-cell infiltration differed significantly between high and low NSD3-expressing samples in each of the five cancer types. Functional enrichment of the NSD3 co-expressed genes indicated a role for NSD3 in the regulation of immune responses and tumorigenesis. Conclusions: Our study revealed that NSD3 can function as a prognostic marker in various cancers due to its role in tumorigenesis and tumor immunity.

Download Full-text

Pan-Cancer Analysis of the Associations of TGFBI Expression With Prognosis and Immune Characteristics

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.745649 ◽

2021 ◽

Vol 8 ◽

Author(s):

Yun Chen ◽

Han Zhao ◽

Yao Feng ◽

Qin Ye ◽

Jing Hu ◽

...

Keyword(s):

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Immune Cell ◽

Cell Infiltration ◽

Immune Cell Infiltration ◽

Tumor Mutational Burden ◽

Mrna And Protein Expression ◽

Cancer Types ◽

Growth Factor Beta ◽

Pan Cancer

Transforming growth factor-beta-induced (TGFBI) protein has important roles in tumor growth, metastasis, and immunity. However, there is currently no pan-cancer evidence regarding TGFBI. In this study, we conducted a pan-cancer analysis of TGFBI mRNA and protein expression and prognoses of various cancer types using public databases. We also investigated the associations of TGFBI expression with tumor microenvironment (TME) components, immune cell infiltration, tumor mutational burden (TMB), and microsatellite instability (MSI), along with the TGFBI genetic alteration types. The results showed that TGFBI expression varied among different cancer types, and it was positively or negatively related to prognosis in various cancers. TGFBI expression was also significantly correlated with TME components, TMB, MSI, immune cell infiltration, and immunoinhibitory and immunostimulatory gene subsets. These findings indicate that TGFBI participates in various immune responses and it may function as a prognostic marker in various cancers. The findings may be useful for developing immunotherapies that target TGFBI.

Download Full-text

Prognostic Value and Immune Characteristics of RUNX Family in Human Cancers: A Pan-cancer Analysis

10.21203/rs.3.rs-659794/v1 ◽

2021 ◽

Author(s):

Han Zhao ◽

Yun Chen ◽

Peijun Shen ◽

Lan Gong

Keyword(s):

Gene Expression ◽

Gene Family ◽

Immune Cell ◽

Malignant Tumors ◽

Genetic Alterations ◽

Genetic Mutation ◽

The Cancer Genome Atlas ◽

Different Types ◽

Cancer Types ◽

Pan Cancer

Abstract Background: Runt‑related transcription factors (RUNX) are involved in numerous fundamental biological processes and play crucial parts in tumorigenesis and metastasis both directly and indirectly. However, the pan-cancer evidence of RUNX gene family is no available. Methods: In this study, we analyzed the potential association between RUNX gene family expression and patient’s prognosis, immune cell infiltration, drug response, and genetic mutation data across different types of tumors using based on The Cancer Genome Atlas, Gene Expression Omnibus, and Oncomine database. Results: The results showed that the expression of the RUNX family varied among different cancer types, revealing its heterogeneity in cancers, and that expression of RUNX2 was lower than that of RUNX1 and RUNX3 across all cancer types. RUNX family gene expression was related to prognosis in several cancers. Furthermore, our study revealed a clear association between RUNX family expression and ESTIMATE score, RNA stemness, and DNA stemness scores. Compared with RUNX1 and RUNX2, RUNX3 showed relatively low levels of genetic alterations. RUNX family genes had clear associations with immune infiltrate subtypes, and their expression was positively related to immune checkpoint genes and drug sensitivity in most cases. Conclusions: These findings will help to elucidate the potential oncogenic roles of RUNX family genes in different types of cancer and it can function as a prognostic marker in various malignant tumors.

Download Full-text

Pan-cancer analysis of N4-acetylcytidine adaptor THUMPD1 as a predictor for prognosis and immunotherapy

Bioscience Reports ◽

10.1042/bsr20212300 ◽

2021 ◽

Author(s):

Kuangxun Li ◽

Junzhe Liu ◽

Xinyu Yang ◽

Zewei Tu ◽

Kai Huang ◽

...

Keyword(s):

Immune Cell ◽

Expression Profiles ◽

Immune Therapy ◽

Gene Expression Pattern ◽

Expression Level ◽

Cell Infiltration ◽

Clinical Samples ◽

Immune Cell Infiltration ◽

Cancer Types ◽

Pan Cancer

Background: THUMPD1 is a specific RNA adaptor that assists acetylation of mRNA and production of N4-acetylcytidine (ac4C). However, it remains unclear whether THUMPD1 plays a part in tumorigenesis and therapeutic efficacy. Here, we analyzed the expression profiles and prognostic value of THUMPD1 in pan-cancer and gained insights into the correlation between THUMPD1 expression level and immunotherapy efficacy. Methods: Gene expression pattern and its correlation with prognosis, immune cell infiltration in pan-cancer were obtained from GTEx, CCLE and TCGA databases, with Kaplan-Meier method and Spearman correlation analysis used. Western blotting and immunofluorescence on clinical samples was performed to validate our database-derived results. Correlation between THUMPD1 expression level and immunotherapy responses was also explored, based on clinical cohorts receiving PD-L1 antibody therapy. Finally, GSEA was performed to show the possible tumorigenic mechanism. Results: THUMPD1 was highly expressed in most cancer types, and this elevated expression indicated poor or improved prognosis for different cancers. In kidney renal clear cell carcinoma (KIRC) and rectum adenocarcinoma (READ), patients with higher THUMPD1 expression exhibited a better prognosis, while liver hepatocellular carcinoma (LIHC) patients had worse prognosis. Besides, THUMPD1 was significantly associated with immune cell infiltration, tumor mutation burden (TMB), microsatellite instability (MSI)，immune checkpoints and neoantigen in many cancer types. Further, more clinical advantages and therapeutic responses were observed in patients with high THUMPD1 expression. Conclusions: THUMPD1 may serve as a novel predictor to evaluate cancer prognosis and immune therapy efficacy in diverse cancer types.

Download Full-text

METTL7B is a novel prognostic biomarker of lower-grade glioma based on pan-cancer analysis

Cancer Cell International ◽

10.1186/s12935-021-02087-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Zhipeng Jiang ◽

Wen Yin ◽

Hecheng Zhu ◽

Jun Tan ◽

Youwei Guo ◽

...

Keyword(s):

Immune Cell ◽

Epithelial Mesenchymal Transition ◽

Prognostic Biomarker ◽

Disease Free Survival ◽

Cell Infiltration ◽

Lower Grade ◽

Immune Cell Infiltration ◽

Mesenchymal Transition ◽

Lower Grade Glioma ◽

Cancer Types

AbstractMethyltransferase-like 7B (METTL7B) is a member of the methyltransferase-like protein family that plays an important role in the development and progression of tumors. However, its prognostic value and the correlation of METTL7B expression and tumor immunity in some cancers remain unclear. By analyzing online data, we found that METTL7B is abnormally overexpressed in multiple human tumors and plays an important role in the overall survival (OS) of patients with 8 cancer types and disease-free survival (DFS) of patients with 5 cancer types. Remarkably, METTL7B expression was positively correlated with the OS and DFS of patients with lower-grade glioma (LGG). In addition, a positive correlation between METTL7B expression and immune cell infiltration in LGG was observed. Moreover, we identified a strong correlation between METTL7B expression and immune checkpoint gene expression in kidney chromophobe (KICH), LGG and pheochromocytoma and paraganglioma (PCPG). Furthermore, METTL7B was involved in the extracellular matrix (ECM) and immune-related pathways in LGGs. Finally, in vitro experiments showed that knockdown of METTL7B inhibited the growth, migration, invasion and the epithelial–mesenchymal transition (EMT) of LGG cells. METTL7B expression potentially represents a novel prognostic biomarker due to its significant association with immune cell infiltration in LGG.

Download Full-text

Dual-Function, Light Switchable Cobalt Catalysis via Active Site Metamorphosis

10.26434/chemrxiv.11353106.v1 ◽

2019 ◽

Author(s):

Enrico Bergamaschi ◽

Frédéric Beltran ◽

Christopher Teskey

Keyword(s):

Visible Light ◽

Active Site ◽

Catalytic Site ◽

Dual Function ◽

Catalytic Systems ◽

Hydride Complex ◽

Dual Functional ◽

Multiple Processes ◽

Olefin Migration

Switchable catalysis offers opportunities to control the rate or selectivity of a reaction via a stimulus such as pH or light. However, few examples of switchable catalytic systems that can facilitate multiple processes exist. Here we report a rare example of such dual-functional, switchable catalysis. Featuring an easily prepared, bench-stable cobalt(I) hydride complex in conjunction with pinacolborane, we can completely alter the reaction outcome between two widely employed transformations – olefin migration and hydroboration – with visible light as the sole trigger. This dichotomy arises from ligand photodissociation which leads to metamorphosis of the active catalytic site, resulting in divergent mechanistic pathways.

Download Full-text

Characterization of the Survival Influential Genes in Carcinogenesis

International Journal of Molecular Sciences ◽

10.3390/ijms22094384 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4384

Author(s):

Divya Sahu ◽

Yu-Lin Chang ◽

Yin-Chen Lin ◽

Chen-Ching Lin

Keyword(s):

Cell Cycle ◽

Cox Regression ◽

Monte Carlo Algorithm ◽

Functional Modules ◽

Protective Genes ◽

Cancer Types ◽

Underlying Mechanisms ◽

Patient Prognosis ◽

Pan Cancer

The genes influencing cancer patient mortality have been studied by survival analysis for many years. However, most studies utilized them only to support their findings associated with patient prognosis: their roles in carcinogenesis have not yet been revealed. Herein, we applied an in silico approach, integrating the Cox regression model with effect size estimated by the Monte Carlo algorithm, to screen survival-influential genes in more than 6000 tumor samples across 16 cancer types. We observed that the survival-influential genes had cancer-dependent properties. Moreover, the functional modules formed by the harmful genes were consistently associated with cell cycle in 12 out of the 16 cancer types and pan-cancer, showing that dysregulation of the cell cycle could harm patient prognosis in cancer. The functional modules formed by the protective genes are more diverse in cancers; the most prevalent functions are relevant for immune response, implying that patients with different cancer types might develop different mechanisms against carcinogenesis. We also identified a harmful set of 10 genes, with potential as prognostic biomarkers in pan-cancer. Briefly, our results demonstrated that the survival-influential genes could reveal underlying mechanisms in carcinogenesis and might provide clues for developing therapeutic targets for cancers.

Download Full-text

Oncology Clinicians’ Challenges to Providing Palliative Cancer Care—A Theoretical Domains Framework, Pan-Cancer System Survey

Current Oncology ◽

10.3390/curroncol28020140 ◽

2021 ◽

Vol 28 (2) ◽

pp. 1483-1494

Author(s):

Sharlette Dunn ◽

Madelene A. Earp ◽

Patricia Biondo ◽

Winson Y. Cheung ◽

Marc Kerba ◽

...

Keyword(s):

Online Survey ◽

Social Issues ◽

Theoretical Domains Framework ◽

Advanced Cancer Patients ◽

Behaviour Change Wheel ◽

Negative Perceptions ◽

Cancer Types ◽

Multifaceted Interventions ◽

Competing Priorities ◽

Pan Cancer

Despite the known benefits, healthcare systems struggle to provide early, integrated palliative care (PC) for advanced cancer patients. Understanding the barriers to providing PC from the perspective of oncology clinicians is an important first step in improving care. A 33-item online survey was emailed to all oncology clinicians working with all cancer types in Alberta, Canada, from November 2017 to January 2018. Questions were informed by Michie’s Theoretical Domains Framework and Behaviour Change Wheel (BCW) and queried (a) PC provision in oncology clinics, (b) specialist PC consultation referrals, and (c) working with PC consultants and home care. Respondents (n = 263) were nurses (41%), physicians (25%), and allied healthcare professionals (18%). Barriers most frequently identified were “clinicians’ limited time/competing priorities” (64%), “patients’ negative perceptions of PC” (63%), and clinicians’ capability to manage patients’ social issues (63%). These factors mapped to all three BCW domains: motivation, opportunity, and capability. In contrast, the least frequently identified barriers were clinician motivation and perceived PC benefits. Oncology clinicians’ perceptions of barriers to early PC were comparable across tumour types and specialties but varied by professional role. The main challenges to early integrated PC include all three BCW domains. Notably, motivation is not a barrier for oncology clinicians; however, opportunity and capability barriers were identified. Multifaceted interventions using these findings have been developed, such as tip sheets to enhance capability, reframing PC with patients, and earlier specialist PC nursing access, to enhance clinicians’ use of and patients’ benefits from an early PC approach.

Download Full-text