scholarly journals The Role of TRPC1 in Modulating Cancer Progression

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 388 ◽  
Author(s):  
Osama M Elzamzamy ◽  
Reinhold Penner ◽  
Lori A Hazlehurst
Keyword(s):  
Cancer Progression ◽  
Calcium Ions ◽  
Functional Role ◽  
Second Messengers ◽  
Metastatic Tumor ◽  
Unique Role ◽  
Promising Target ◽  
Tumor Growth And Metastasis ◽  
Cancer Multiple

Calcium ions (Ca2+) play an important role as second messengers in regulating a plethora of physiological and pathological processes, including the progression of cancer. Several selective and non-selective Ca2+-permeable ion channels are implicated in mediating Ca2+ signaling in cancer cells. In this review, we are focusing on TRPC1, a member of the TRP protein superfamily and a potential modulator of store-operated Ca2+ entry (SOCE) pathways. While TRPC1 is ubiquitously expressed in most tissues, its dysregulated activity may contribute to the hallmarks of various types of cancers, including breast cancer, pancreatic cancer, glioblastoma multiforme, lung cancer, hepatic cancer, multiple myeloma, and thyroid cancer. A range of pharmacological and genetic tools have been developed to address the functional role of TRPC1 in cancer. Interestingly, the unique role of TRPC1 has elevated this channel as a promising target for modulation both in terms of pharmacological inhibition leading to suppression of tumor growth and metastasis, as well as for agonistic strategies eliciting Ca2+ overload and cell death in aggressive metastatic tumor cells.

scholarly journals Is the C-C Motif Ligand 2–C-C Chemokine Receptor 2 Axis a Promising Target for Cancer Therapy and Diagnosis?

2020 ◽  
Vol 21 (23) ◽  
pp. 9328
Author(s):  
Hiroaki Iwamoto ◽  
Kouji Izumi ◽  
Atsushi Mizokami
Keyword(s):  
Cancer Progression ◽  
Chemokine Receptor ◽  
Anticancer Agents ◽  
Mononuclear Cells ◽  
Chemical Mediator ◽  
Cancer Models ◽  
Promising Target ◽  
Therapy And Diagnosis ◽  
Inflammatory Tissue

C-C motif ligand 2 (CCL2) was originally reported as a chemical mediator attracting mononuclear cells to inflammatory tissue. Many studies have reported that CCL2 can directly activate cancer cells through a variety of mechanisms. CCL2 can also promote cancer progression indirectly through increasing the recruitment of tumor-associated macrophages into the tumor microenvironment. The role of CCL2 in cancer progression has gradually been understood, and various preclinical cancer models elucidate that CCL2 and its receptor C-C chemokine receptor 2 (CCR2) are attractive targets for intervention in cancer development. However, clinically available drugs that regulate the CCL2–CCR2 axis as anticancer agents are not available at this time. The complete elucidation of not only the oncological but also the physiological functions of the CCL2–CCR2 axis is required for achieving a satisfactory effect of the CCL2–CCR2 axis-targeted therapy.

scholarly journals Treatment with the Recombinant SLIT2 Protein Delays AML Leukemogenesis In Vivo

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2368-2368
Author(s):  
Luise A de Albuquerque Simoes ◽  
Isabel Weinhäuser ◽  
Diego A Pereira-Martins ◽  
César Alexander Ortiz Rojas ◽  
Thiago Mantello Bianco ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Lines ◽  
Cancer Progression ◽  
Functional Role ◽  
Conflicts Of Interest ◽  
Therapeutic Potential ◽  
Leukemic Cells ◽  
Control Group

Abstract Accumulating evidence suggest that the axon guidance molecules SLIT and ROBO are not only implicated in physiological process but also in cancer progression. Depending on the type of cancer the SLIT-ROBO axis can either act as a tumor suppressor gene, in which case the SLIT2 promoter site is frequently hypermethylated or as an oncogene, whereby high expression is often associated with poor prognosis. In the context of acute myeloid leukemia (AML), low expression of SLIT2 has been associated with low overall survival (OS) (Golos et al., 2019), while the functional role of SLIT2 remains largely unknown. Recently, we showed that the knockdown of SLIT2 increased cell proliferation of acute promyelocytic leukemia (APL) cells resulting in a more aggressive course of disease progression in vivo using the murine transgenic APL model (Weinhäuser et al., 2020). Here, we aimed to study the functional role of SLIT2 in a more heterogeneous disease, such as AML. Using different publicly available datasets. (GSE58477, normal karyotype blasts: 62, healthy CD34 +: 10; GSE63409, LSC: 14, HSC: 5) we detected increased methylation at the SLIT2 promoter site of AML leukemic cells compared to healthy CD34 + cells suggesting SLIT2 tumor suppressive functions. In addition, we measured decreased levels of SLIT2 in the bone marrow (BM) plasma of AML patients compared to healthy donors. To assess the biological role of SLIT2, we treated AML cell lines (KASUMI1, MV411, and MOLM13) with recombinant SLIT2 (50 ng/mL) in vitro. Administration of SLIT2 reduced AML cell growth, colony formation and induced cell cycle arrest in the G1 phase for all AML cell lines. Conversely, the knockdown of SLIT2 promoted increased THP-1 and OCI-AML3 cell proliferation. Next, we determined whether the treatment with SLIT2 could delay leukemogenesis in vivo using the AML cell line MV4-11. Engraftment was monitored by luciferase bioluminescent signal and NSGS mice were either treated with recombinant SLIT2 using a dose of 25 ng/g of body weight or vehicle (control group). SLIT2 therapy resulted in a lower disease burden, decreased leukemic infiltration in the BM and spleen, reduced spleen size, and increased OS compared to the control group (p<0.05). In conclusion, we showed that SLIT2 methylation is recurrent in AML patients and that the level of SLIT2 in the plasma of AML patients is reduced. Moreover, SLIT2 treatment appears to have a cytostatic effect on different AML cell lines delaying leukemogenesis in vivo. Overall, our study reveals the therapeutic potential of SLIT2 in hematological malignancies, which could be used as an adjuvant in the clinic. Disclosures No relevant conflicts of interest to declare.

CD81 as a tumor target

2017 ◽  
Vol 45 (2) ◽  
pp. 531-535 ◽  
Author(s):  
Felipe Vences-Catalán ◽  
Caroline Duault ◽  
Chiung-Chi Kuo ◽  
Ranjani Rajapaksa ◽  
Ronald Levy ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Protein Trafficking ◽  
Migration And Invasion ◽  
Tumor Target ◽  
Immune Synapse ◽  
Cellular Processes ◽  
Tumor Growth And Metastasis ◽  
Listeria Infection ◽  
Partner Proteins

CD81 participates in a variety of important cellular processes such as membrane organization, protein trafficking, cellular fusion and cell–cell interactions. In the immune system, CD81 regulates immune synapse, receptor clustering and signaling; it also mediates adaptive and innate immune suppression. CD81 is a gateway in hepatocytes for pathogens such as hepatitis C virus and Plasmodium; it also confers susceptibility to Listeria infection. These diverse biological roles are due to the tendency of CD81 to associate with other tetraspanins and with cell-specific partner proteins, which provide the cells with a signaling platform. CD81 has also been shown to regulate cell migration and invasion, and has therefore been implicated in cancer progression. Indeed, we have recently shown that CD81 contributes to tumor growth and metastasis. CD81 is expressed in most types of cancer, including breast, lung, prostate, melanoma, brain cancer and lymphoma, and the overexpression or down-regulation of this molecule has been correlated with either good or bad prognosis. Here, we discuss the role of CD81 in cancer and its potential therapeutic use as a tumor target.

scholarly journals CT45A1 promotes the metastasis of osteosarcoma cells in vitro and in vivo through β-catenin

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Mingxin Wen ◽  
Hui Ren ◽  
Shouqiang Zhang ◽  
Tao Li ◽  
Jiefeng Zhang ◽  
...  
Keyword(s):  
Functional Role ◽  
Migration And Invasion ◽  
Osteosarcoma Cells ◽  
Unique Role ◽  
Cancer Testis Antigens ◽  
Elevated Expression ◽  
Cancer Testis

AbstractIncreased expression of cancer/testis antigens (CTAs) is reported in various tumors. However, the unique role of CTAs in tumor genesis has not yet been verified. Here, we first report the functional role of CT45A1 in the carcinogenesis of osteosarcoma. RNA sequencing and immunohistochemistry confirmed that elevated expression of CT45A1 was detected in osteosarcoma, especially in metastatic tissues of osteosarcoma. Furthermore, osteosarcoma patients with poorer prognosis showed high expression of CT45A1. In cell tests, CT45A1 overexpression was shown to strengthen the proliferation, migration, and invasion abilities of osteosarcoma cells, while silencing CT45A1 markedly elicited the opposite effects in these tests by disrupting the activation of β-catenin. In summary, we identify a novel role of CT45A1 in osteosarcoma. Furthermore, our results suggested that CT45A1 may contribute to the development of osteosarcoma and could be a possible therapeutic target for osteosarcoma patients.

scholarly journals BTLA-HVEM Couple in Health and Diseases: Insights for Immunotherapy in Lung Cancer

2021 ◽  
Vol 11 ◽  
Author(s):  
Clemence Demerlé ◽  
Laurent Gorvel ◽  
Daniel Olive
Keyword(s):  
Lung Cancer ◽  
Cancer Progression ◽  
Immune Escape ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoints ◽  
Tumor Immune Escape ◽  
Promising Target ◽  
Tnf Receptor Family ◽  
Receptor Family

Lung cancer is the leading cause of cancer deaths worldwide. Immunotherapies (IT) have been rapidly approved for lung cancer treatment after the spectacular results in melanoma. Responses to the currently used checkpoint inhibitors are strikingly good especially in metastatic diseases. However, durable responses are observed in only 25% of cases. Consequently, there is an urgent need for new immunotherapy targets. Among the multiple checkpoints involved in the tumor immune escape, the BTLA-HVEM couple appears to be a promising target. BTLA (B- and T- Lymphocyte Attenuator) is a co-inhibitory receptor mainly expressed by B and T cells, repressing the activation signal transduction. BTLA shares similarities with other immune checkpoints such as PD-1 and CTLA-4 which are the targets of the currently used immunotherapies. Furthermore, BTLA expression points out terminally exhausted and dysfunctional lymphocytes, and correlates with lung cancer progression. The ligand of BTLA is HVEM (Herpes Virus Entry Mediator) which belongs to the TNF receptor family. Often described as a molecular switch, HVEM is constitutively expressed by many cells, including cells from tumor and healthy tissues. In addition, HVEM seems to be involved in tumor immuno-evasion, especially in lung tumors lacking PD-L1 expression. Here, we propose to review the role of BTLA-HVEM in immuno-escape in order to highlight its potential for designing new immunotherapies.

The Role of STAT3 Signaling in Different Types of Cancers: A Comprehensive Review

2020 ◽  
Vol 16 (3) ◽  
pp. 189-198
Author(s):  
Kaviarasan Lakshmanan ◽  
Gowramma Byran ◽  
Sravanthi Bandlamudi ◽  
Praveen Thaggikuppe Krishnamurthy
Keyword(s):  
Cancer Progression ◽  
Myeloid Leukemia ◽  
Inflammatory Responses ◽  
Vital Role ◽  
Signal Transducer ◽  
Stat3 Signaling ◽  
Solid Malignancies ◽  
Different Types ◽  
Tumor Growth And Metastasis

Signal transducer and activator of transcription (STAT3) is an important transcription factor capable of mediating or even driving cancer progression through hyperactivation or gain-offunction mutations. It plays a key role in regulating host immune and inflammatory responses and in the pathogenesis of many cancers. However, compelling evidence suggests that STAT3 is constitutively activated in many cancers and plays a vital role in tumor growth and metastasis. Hyperactive STAT3 is also implicated in various hematopoietic and solid malignancies, such as chronic and acute myeloid leukemia, melanoma or prostate cancer. The classical understanding of STAT functions is linked to their phosphorylated parallel dimer conformation, in which they induce gene transcription. In this review, we discuss the functions and the roles of STAT3 signal in various types of cancers.

scholarly journals MicroRNA Response Elements-Mediated miRNA-miRNA Interactions in Prostate Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Mohammed Alshalalfa
Keyword(s):  
Gene Expression ◽  
Prostate Cancer ◽  
Cancer Progression ◽  
Biological Networks ◽  
Functional Role ◽  
Systems Perspective ◽  
Mrna Gene ◽  
Mrna Gene Expression ◽  
Tumor Suppressor Mirnas

The cell is a highly organized system of interacting molecules including proteins, mRNAs, and miRNAs. Analyzing the cell from a systems perspective by integrating different types of data helps revealing the complexity of diseases. Although there is emerging evidence that microRNAs have a functional role in cancer, the role of microRNAs in mediating cancer progression and metastasis remains not fully explored. As the amount of available miRNA and mRNA gene expression data grows, more systematic methods combining gene expression and biological networks become necessary to explore miRNA function. In this work I integrated functional miRNA-target interactions with mRNA and miRNA expression to infer mRNA-mediated miRNA-miRNA interactions. The inferred network represents miRNA modulation through common targets. The network is used to characterize the functional role of microRNA response element (MRE) to mediate interactions between miRNAs targeting the MRE. Results revealed that miRNA-1 is a key player in regulating prostate cancer progression. 11 miRNAs were identified as diagnostic and prognostic biomarkers that act as tumor suppressor miRNAs. This work demonstrates the utility of a network analysis as opposed to differential expression to find important miRNAs that regulate prostate cancer.

scholarly journals Functional Role of Dendritic Cell Subsets in Cancer Progression and Clinical Implications

2020 ◽  
Vol 21 (11) ◽  
pp. 3930
Author(s):  
Annalisa Del Prete ◽  
Francesca Sozio ◽  
Ilaria Barbazza ◽  
Valentina Salvi ◽  
Laura Tiberio ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Cancer Progression ◽  
Cell Response ◽  
Functional Role ◽  
T Cell Response ◽  
Cytotoxic T Cell ◽  
Dendritic Cell Subsets

Dendritic cells (DCs) constitute a complex network of cell subsets with common functions but also with many divergent aspects. All dendritic cell subsets share the ability to prime T cell response and to undergo a complex trafficking program related to their stage of maturation and function. For these reasons, dendritic cells are implicated in a large variety of both protective and detrimental immune responses, including a crucial role in promoting anti-tumor responses. Although cDC1s are the most potent subset in tumor antigen cross-presentation, they are not sufficient to induce full-strength anti-tumor cytotoxic T cell response and need close interaction and cooperativity with the other dendritic cell subsets, namely cDC2s and pDCs. This review will take into consideration different aspects of DC biology, including the functional role of dendritic cell subsets in both fostering and suppressing tumor growth, the mechanisms underlying their recruitment into the tumor microenvironment, as well as the prognostic value and the potentiality of dendritic cell therapeutic targeting. Understanding the specificity of dendritic cell subsets will allow to gain insights on role of these cells in pathological conditions and to design new selective promising therapeutic approaches.

Downregulation of IRAK3 by miR-33b-3p relieves chondrocyte inflammation and apoptosis in an in vitro osteoarthritis model

2020 ◽  
Vol 85 (3) ◽  
pp. 545-552
Author(s):  
Tao Tao ◽  
Yunkun Zhang ◽  
Hui Wei ◽  
Ke Heng
Keyword(s):  
Functional Role ◽  
Regulatory Mechanism ◽  
Interleukin 1 ◽  
Inverse Correlation ◽  
Promising Target ◽  
Tnf Α ◽  
Direct Target ◽  
Distinctive Role

ABSTRACT Interleukin-1 receptor-associated kinase-3 (IRAK3) has a distinctive role in regulating inflammation. However, the functional role of IRAK3 and regulatory mechanism underlying the pathogenesis of osteoarthritis (OA) remain unclear. Here, we first found that IRAK3 was upregulated, while miR-33b-3p was downregulated in the cartilage of OA patients and IL-1β-induced CHON-001 cells. IRAK3 was confirmed as the direct target of miR-33b-3p and negatively regulated by miR-33b-3p. There was an inverse correlation between IRAK3 mRNA expression and miR-33b-3p expression in OA cartilage tissues. The in vitro functional experiments showed that miR-33b-3p overexpression caused a remarkable increase in viability, a significant decrease in inflammatory mediators (IL-1β and TNF-α), and apoptosis in IL-1β-induced CHON-001 cells. Importantly, IRAK3 knockdown imitated, while overexpression reversed the effects of miR-33b-3p on IL-1β-induced inflammation and apoptosis in CHON-001 cells. Collectively, miR-33b-3p significantly alleviated IL-1β-induced inflammation and apoptosis by downregulating IRAK3, which may serve as a promising target for OA.

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