The Role of Ras-Associated Protein 1 (Rap1) in Cancer: Bad Actor or Good Player?

Metastasis is known as the most life-threatening event in cancer patients. In principle, the immune system can prevent tumor development. However, dysfunctional T cells may fail to eliminate the tumor cells effectively and provide additional survival advantages for tumor proliferation and metastasis. Constitutive activation of Ras-associated protein1 (Rap1) has not only led to T cell anergy, but also inhibited autophagy and supported cancer progression through various oncogenic events. Inhibition of Rap1 activity with its negative regulator, Rap1GAP, impairs tumor progression. However, active Rap1 reduces tumor invasion in some cancers, indicating that the pleiotropic effects of Rap1 signaling in cancers could be cancer-specific. All in all, targeting Rap1 signaling and its regulators could potentially control carcinogenesis, metastasis, chemoresistance and immune evasion. Rap1GAP could be a promising therapeutic target in combating cancer.

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Molecular Basis for CCRL2 Regulation of Leukocyte Migration

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.615031 ◽

2020 ◽

Vol 8 ◽

Author(s):

Tiziana Schioppa ◽

Francesca Sozio ◽

Ilaria Barbazza ◽

Sara Scutera ◽

Daniela Bosisio ◽

...

Keyword(s):

Cancer Progression ◽

Chemokine Receptors ◽

Transmembrane Domain ◽

Nk Cell ◽

Structural Features ◽

Negative Regulator ◽

Leukocyte Migration ◽

Genetic Ablation

CCRL2 is a seven-transmembrane domain receptor that belongs to the chemokine receptor family. At difference from other members of this family, CCRL2 does not promote chemotaxis and shares structural features with atypical chemokine receptors (ACKRs). However, CCRL2 also differs from ACKRs since it does not bind chemokines and is devoid of scavenging functions. The only commonly recognized CCRL2 ligand is chemerin, a non-chemokine chemotactic protein. CCRL2 is expressed both by leukocytes and non-hematopoietic cells. The genetic ablation of CCRL2 has been instrumental to elucidate the role of this receptor as positive or negative regulator of inflammation. CCRL2 modulates leukocyte migration by two main mechanisms. First, when CCRL2 is expressed by barrier cells, such endothelial, and epithelial cells, it acts as a presenting molecule, contributing to the formation of a non-soluble chemotactic gradient for leukocytes expressing CMKLR1, the functional chemerin receptor. This mechanism was shown to be crucial in the induction of NK cell-dependent immune surveillance in lung cancer progression and metastasis. Second, by forming heterocomplexes with other chemokine receptors. For instance, CCRL2/CXCR2 heterodimers were shown to regulate the activation of β2-integrins in mouse neutrophils. This mini-review summarizes the current understanding of CCRL2 biology, based on experimental evidence obtained by the genetic deletion of this receptor in in vivo experimental models. Further studies are required to highlight the complex functional role of CCRL2 in different organs and pathological conditions.

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HOXB4 promotes the malignant progression of ovarian cancer via DHDDS

10.21203/rs.2.18907/v1 ◽

2019 ◽

Author(s):

Na Li ◽

Jiao Xiong ◽

Zhengyu Li

Keyword(s):

Ovarian Cancer ◽

Poor Prognosis ◽

Malignant Progression ◽

Stem Cell Markers ◽

Tumor Proliferation ◽

The Poor ◽

Proliferation And Metastasis ◽

Proliferation And Invasion ◽

Tumor Proliferation And Metastasis

Abstract Background: Homeobox B4 (HOXB4) is associated with the poor prognosis of various cancer types. However, how HOXB4 promotes ovarian cancer (OV) progression remains to be determined. Methods：The Cancer Genome Atlas (TCGA) database indicated that high level of HOXB4 in OV was correlated with poor prognosis. The biological functions of HOXB4 were confirmed through a colony formation, migration, and invasion assay. The effect of HOXB4 on the expression of EMT and cancer stem cell markers was detected. The transcriptional target of HOXB4 was DHDDS, which was detected by a ChIP assay. A xenograft tumor model was performed in nude mice to detect the role of HOXB4 in tumor proliferation and metastasis. Results：Results showed that the expression of HOXB4 was higher in OV tissues than in normal tissues and correlated with the poor prognosis of OV. HOXB4 knockdown suppressed the proliferation and invasion ability of OV cells in vitro. Conversely, these effects were enhanced by the up-regulation of HOXB4 in OV cells. The binding of two DNA motifs through HOXB4 regulated DHDDS expression and contributed to the malignant progression of OV. The role of HOXB4 in promoting tumor proliferation and metastasis was verified in mice. Further investigation revealed that HOXB4 triggered Snail and Zeb1 expression. Conclusion: Overall, HOXB4 overexpression was remarkably correlated with the poor prognosis of OV. HOXB4 up-regulated DHDDS, which co-contributed to the enhancer proliferation and invasion of OV cells, thus accelerating the malignant progression of OV.

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Pharmacologic Depletion of Microglia Increases Viral Load in the Brain and Enhances Mortality in Murine Models of Flavivirus-Induced Encephalitis

Journal of Virology ◽

10.1128/jvi.00525-18 ◽

2018 ◽

Vol 92 (16) ◽

Cited By ~ 22

Author(s):

Scott Seitz ◽

Penny Clarke ◽

Kenneth L. Tyler

Keyword(s):

Immune Cells ◽

Mrna Level ◽

Cns Injury ◽

Cytokines And Chemokines ◽

Life Threatening ◽

The Central Nervous System ◽

The Brain ◽

Stimulating Factor ◽

Life Threatening Event

ABSTRACT Flaviviruses account for most arthropod-borne cases of human encephalitis in the world. However, the exact mechanisms of injury to the central nervous system (CNS) during flavivirus infections remain poorly understood. Microglia are the resident immune cells of the CNS and are important for multiple functions, including control of viral pathogenesis. Utilizing a pharmacologic method of microglia depletion (PLX5622 [Plexxikon Inc.], an inhibitor of colony-stimulating factor 1 receptor), we sought to determine the role of microglia in flaviviral pathogenesis. Depletion of microglia resulted in increased mortality and viral titer in the brain following infection with either West Nile virus (WNV) or Japanese encephalitis virus (JEV). Interestingly, microglial depletion did not prevent virus-induced increases in the expression of relevant cytokines and chemokines at the mRNA level. In fact, the expression of several proinflammatory genes was increased in virus-infected, microglia-depleted mice compared to virus-infected, untreated controls. In contrast, and as expected, expression of the macrophage marker triggering receptor expressed on myeloid cells 2 (TREM2) was decreased in virus-infected, PLX5622-treated mice compared to virus-infected controls. IMPORTANCE As CNS invasion by flaviviruses is a rare but life-threatening event, it is critical to understand how brain-resident immune cells elicit protection or injury during disease progression. Microglia have been shown to be important in viral clearance but may also contribute to CNS injury as part of the neuroinflammatory process. By utilizing a microglial depletion model, we can begin to parse out the exact roles of microglia during flaviviral pathogenesis with hopes of understanding specific mechanisms as potential targets for therapeutics.

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Biological mechanisms linked to inflammation in cancer: Discovery of tumor microenvironment-related biomarkers and their clinical application in solid tumors

The International Journal of Biological Markers ◽

10.1177/1724600820906155 ◽

2020 ◽

Vol 35 (1_suppl) ◽

pp. 8-11 ◽

Cited By ~ 3

Author(s):

Paola Nisticò ◽

Gennaro Ciliberto

Keyword(s):

Tumor Microenvironment ◽

Tumor Cells ◽

Cancer Progression ◽

Cancer Biology ◽

Tumor Development ◽

Short Paper ◽

Great Relevance ◽

Cellular Components ◽

The Relationship

Our view of cancer biology radically shifted from a “cancer-cell-centric” vision to a view of cancer as an organ disease. The concept that genetic and/or epigenetic alterations, at the basis of cancerogenesis, are the main if not the exclusive drivers of cancer development and the principal targets of therapy, has now evolved to include the tumor microenvironment in which tumor cells can grow, proliferate, survive, and metastasize only within a favorable environment. The interplay between cancer cells and the non-cellular and cellular components of the tumor microenvironment plays a fundamental role in tumor development and evolution both at the primary site and at the level of metastasis. The shape of the tumor cells and tumor mass is the resultant of several contrasting forces either pro-tumoral or anti-tumoral which have at the level of the tumor microenvironment their battle field. This crucial role of tumor microenvironment composition in cancer progression also dictates whether immunotherapy with immune checkpoint inhibitor antibodies is going to be efficacious. Hence, tumor microenvironment deconvolution has become of great relevance in order to identify biomarkers predictive of efficacy of immunotherapy. In this short paper we will briefly review the relationship between inflammation and cancer, and will summarize in 10 short points the key concepts learned so far and the open challenges to be solved.

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An Overview of the Role of Mechanical Stretching in the Progression of Lung Cancer

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.781828 ◽

2021 ◽

Vol 9 ◽

Author(s):

Fengying Gong ◽

Yuchao Yang ◽

Liangtao Wen ◽

Congrong Wang ◽

Jingjun Li ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Progression ◽

Mechanical Load ◽

Tumor Development ◽

Physical Factors ◽

Mechanical Factors ◽

Tissue Characteristics ◽

The Relationship ◽

Mechanical Stretching

Cells and tissues in the human body are subjected to mechanical forces of varying degrees, such as tension or pressure. During tumorigenesis, physical factors, especially mechanical factors, are involved in tumor development. As lung tissue is influenced by movements associated with breathing, it is constantly subjected to cyclical stretching and retraction; therefore, lung cancer cells and lung cancer-associated fibroblasts (CAFs) are constantly exposed to mechanical load. Thus, to better explore the mechanisms involved in lung cancer progression, it is necessary to consider factors involved in cell mechanics, which may provide a more comprehensive analysis of tumorigenesis. The purpose of this review is: 1) to provide an overview of the anatomy and tissue characteristics of the lung and the presence of mechanical stimulation; 2) to summarize the role of mechanical stretching in the progression of lung cancer; and 3) to describe the relationship between mechanical stretching and the lung cancer microenvironment, especially CAFs.

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The Expanding Role of MT1-MMP in Cancer Progression

Pharmaceuticals ◽

10.3390/ph12020077 ◽

2019 ◽

Vol 12 (2) ◽

pp. 77 ◽

Cited By ~ 8

Author(s):

Anna M. Knapinska ◽

Gregg B. Fields

Keyword(s):

Transcription Factor ◽

Immune Responses ◽

Cancer Progression ◽

Negative Regulator ◽

Fibrillar Collagen ◽

Biological Functions ◽

Complete Mapping ◽

Membrane Type

For over 20 years, membrane type 1 matrix metalloproteinase (MT1-MMP) has been recognized as a key component in cancer progression. Initially, the primary roles assigned to MT1-MMP were the activation of proMMP-2 and degradation of fibrillar collagen. Proteomics has revealed a great array of MT1-MMP substrates, and MT1-MMP selective inhibitors have allowed for a more complete mapping of MT1-MMP biological functions. MT1-MMP has extensive sheddase activities, is both a positive and negative regulator of angiogenesis, can act intracellularly and as a transcription factor, and modulates immune responses. We presently examine the multi-faceted role of MT1-MMP in cancer, with a consideration of how the diversity of MT1-MMP behaviors impacts the application of MT1-MMP inhibitors.

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CircPLK1 sponges miR-296-5p to facilitate triple-negative breast cancer progression

Epigenomics ◽

10.2217/epi-2019-0093 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1163-1176 ◽

Cited By ~ 16

Author(s):

Yanan Kong ◽

Lu Yang ◽

Weidong Wei ◽

Ning Lyu ◽

Yutian Zou ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Expression Profiles ◽

Proliferation And Metastasis ◽

Underlying Mechanisms

Aim: To investigate the role of circRNAs in triple-negative breast cancer (TNBC) and the underlying mechanisms. Materials & methods: We performed circRNA microarrays to explore the expression profiles of TNBC cell lines. Experiments in vitro and in vivo were conducted to explore the effects of circPLK1 on tumor proliferation and metastasis as well as the interaction between circPLK1, miR-296-5p and PLK1 in TNBC. Results & conclusion: CircPLK1 was significantly upregulated in TNBC and associated with poor survivals. CircPLK1 knockdown inhibited cell growth and invasion in vitro as well as tumor occurrence and metastasis in vivo. CircPLK1-miR-296-5p- PLK1 axis regulates tumor progression by ceRNA mechanism in TNBC, indicating that circPLK1 may serve as a prognostic factor and novel therapeutic target for TNBC.

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Circ_0000218 plays a carcinogenic role in colorectal cancer progression by regulating miR-139-3p/RAB1A axis

The Journal of Biochemistry ◽

10.1093/jb/mvz078 ◽

2019 ◽

Vol 167 (1) ◽

pp. 55-65 ◽

Cited By ~ 13

Author(s):

Fu-Lai Pei ◽

Ming-Zheng Cao ◽

Yue-Feng Li

Keyword(s):

Colorectal Cancer ◽

Cancer Progression ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Rna Immunoprecipitation ◽

Proliferation And Metastasis ◽

Polymerase Chain ◽

Local Lymph Node ◽

Colorectal Cancer Progression

Abstract Accumulating researches have confirmed that circRNA abnormal expression plays a prominent role in the progression of colorectal cancer (CRC). The role of circ_0000218 in CRC and its potential mechanism are not clear. In this study, real-time polymerase chain reaction (RT-PCR) was employed to measure the circ_0000218, miR-139-3p and RAB1A mRNA expression in CRC tissues and cells. Immunohistochemistry and western blot were conducted to determine the RAB1A expression in CRC tissues and cells, respectively. Colony formation assay and BrdU method were employed to monitor the effect of circ_0000218 on cell proliferation. Transwell assay was adopted to detect cell migration and invasion. Dual luciferase reporter assay and RNA immunoprecipitation assay were adopted to confirm the targeting relationship between circ_0000218 and miR-139-3p, miR-139-3p and RAB1A. We demonstrated that circ_0000218 was notably upregulated in CRC tissues and cell lines, and its high expression level was markedly linked to the increase of T staging and local lymph node metastasis. Circ_0000218 overexpression enhanced the proliferation and metastasis of CRC cells while knocking down circ_0000218 caused the opposite effects. We also observed that miR-139-3p was negatively regulated by circ_0000218, while RAB1A was positively regulated by it. Collectively, this study suggested that circ_0000218 upregulated RAB1A and promoted CRC proliferation and metastasis via sponging miR-139-3p.

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Microbiome dysbiosis in lung cancer: from composition to therapy

npj Precision Oncology ◽

10.1038/s41698-020-00138-z ◽

2020 ◽

Vol 4 (1) ◽

Author(s):

Ning-Ning Liu ◽

Qiang Ma ◽

Yang Ge ◽

Cheng-Xiang Yi ◽

Lu-Qi Wei ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Progression ◽

Tumor Development ◽

Disease Status ◽

Specific Pattern ◽

Current Status ◽

Healthy Human ◽

Human Lungs ◽

Underlying Mechanisms

AbstractThe correlations between microbiota dysbiosis and cancer have gained extensive attention and been widely explored. As a leading cancer diagnosis worldwide, lung cancer poses a great threat to human health. The healthy human lungs are consistently exposed to external environment and harbor a specific pattern of microbiota, sharing many key pathological and physiological characteristics with the intestinal tract. Although previous findings uncovered the critical roles of microbiota in tumorigenesis and response to anticancer therapy, most of them were focused on the intestinal microbiota rather than lung microbiota. Notably, the considerable functions of microbiota in maintaining lung homeostasis should not be neglected as the microbiome dysbiosis may promote tumor development and progression through production of cytokines and toxins and multiple other pathways. Despite the fact that increasing studies have revealed the effect of microbiome on the induction of lung cancer and different disease status, the underlying mechanisms and potential therapeutic strategies remained unclear. Herein, we summarized the recent progresses about microbiome in lung cancer and further discussed the role of microbial communities in promoting lung cancer progression and the current status of therapeutic approaches targeting microbiome to alleviate and even cure lung cancer.

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