scholarly journals A Pan-cancer Analysis of Molecular Characteristics and Oncogenic Role of Gasdermins

2021 ◽  
Author(s):  
mingchao Mu ◽  
Qiaoling Yu ◽  
Qin Zhang ◽  
Jing Guo ◽  
Xingjie Wang ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Cell Migration ◽  
Immunohistochemical Analysis ◽  
Effector Proteins ◽  
Molecular Characteristics ◽  
Cancer Heterogeneity ◽  
Cell Membrane Permeabilization ◽  
Pan Cancer

Abstract BackgroundThe gasdermins (GSDMs) family is proposed to be pore-forming effector proteins that cause cell membrane permeabilization and pyroptosis. Despite our increasing knowledge of GSDMD, GSDME and GSDMB, the biological functions and the regulation of GSDM expression and activation remain elusive for most GSDMs. In this study, we analyzed the molecular characteristics and oncogenic role of GSDM family genes systematically. MethodsTCGA, CCLE, cBioPortal, GEPIA, CellMiner and BioGRID databases were utilized in this study. Immunohistochemical analysis and a series of in vitro experiments were conducted.ResultsWe found that, in cancer, GSDM genes and their expressions extensively changed, which were associated with patient survival. The expression of GSDMs was widely associated with cancer-related pathways, drug resistance, immune subtypes, tumor microenvironment and cancer cell stemness. However, an intra- and inter-cancer heterogeneity was discovered regarding the corresponding GSDM gene. We found that GSDMA and GSDMB regulated drug resistance to the opposite direction of GSDME. In colorectal cancer, GSDME might be a positive regulator in cell invasion and metastasis through cell migration and angiogenesis, while GSDMA, GSDMB and GSDMD might be a negatively regulator of cell migration. ConclusionsGSDM family genes might play important roles in cancer other than pyroptosis. We suggest more efforts be made to investigate the GSDM family and each GSDM gene be studied as an entity in each type of cancer.

scholarly journals Role of the V1G1 subunit of V-ATPase in breast cancer cell migration

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Maria De Luca ◽  
Roberta Romano ◽  
Cecilia Bucci
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Motility ◽  
Cancer Progression ◽  
Tumor Formation ◽  
Downstream Signaling ◽  
Late Endosomes ◽  
Intracellular Compartments

AbstractV-ATPase is a large multi-subunit complex that regulates acidity of intracellular compartments and of extracellular environment. V-ATPase consists of several subunits that drive specific regulatory mechanisms. The V1G1 subunit, a component of the peripheral stalk of the pump, controls localization and activation of the pump on late endosomes and lysosomes by interacting with RILP and RAB7. Deregulation of some subunits of the pump has been related to tumor invasion and metastasis formation in breast cancer. We observed a decrease of V1G1 and RAB7 in highly invasive breast cancer cells, suggesting a key role of these proteins in controlling cancer progression. Moreover, in MDA-MB-231 cells, modulation of V1G1 affected cell migration and matrix metalloproteinase activation in vitro, processes important for tumor formation and dissemination. In these cells, characterized by high expression of EGFR, we demonstrated that V1G1 modulates EGFR stability and the EGFR downstream signaling pathways that control several factors required for cell motility, among which RAC1 and cofilin. In addition, we showed a key role of V1G1 in the biogenesis of endosomes and lysosomes. Altogether, our data describe a new molecular mechanism, controlled by V1G1, required for cell motility and that promotes breast cancer tumorigenesis.

scholarly journals Low Intensity Shockwave Treatment Modulates Macrophage Functions Beneficial to Healing Chronic Wounds

2021 ◽  
Vol 22 (15) ◽  
pp. 7844
Author(s):  
Jason S. Holsapple ◽  
Ben Cooper ◽  
Susan H. Berry ◽  
Aleksandra Staniszewska ◽  
Bruce M. Dickson ◽  
...  
Keyword(s):  
Macrophage Activation ◽  
Molecular Mechanisms ◽  
Chronic Wounds ◽  
Immunohistochemical Analysis ◽  
Therapeutic Effects ◽  
Gene Expressions ◽  
Extracorporeal Shock Wave

Extracorporeal Shock Wave Therapy (ESWT) is used clinically in various disorders including chronic wounds for its pro-angiogenic, proliferative, and anti-inflammatory effects. However, the underlying cellular and molecular mechanisms driving therapeutic effects are not well characterized. Macrophages play a key role in all aspects of healing and their dysfunction results in failure to resolve chronic wounds. We investigated the role of ESWT on macrophage activity in chronic wound punch biopsies from patients with non-healing venous ulcers prior to, and two weeks post-ESWT, and in macrophage cultures treated with clinical shockwave intensities (150–500 impulses, 5 Hz, 0.1 mJ/mm2). Using wound area measurements and histological/immunohistochemical analysis of wound biopsies, we show ESWT enhanced healing of chronic ulcers associated with improved wound angiogenesis (CD31 staining), significantly decreased CD68-positive macrophages per biopsy area and generally increased macrophage activation. Shockwave treatment of macrophages in culture significantly boosted uptake of apoptotic cells, healing-associated cytokine and growth factor gene expressions and modulated macrophage morphology suggestive of macrophage activation, all of which contribute to wound resolution. Macrophage ERK activity was enhanced, suggesting one mechanotransduction pathway driving events. Collectively, these in vitro and in vivo findings reveal shockwaves as important regulators of macrophage functions linked with wound healing. This immunomodulation represents an underappreciated role of clinically applied shockwaves, which could be exploited for other macrophage-mediated disorders.

scholarly journals Pan-cancer analysis reveals tumor-associated macrophage communication in the tumor microenvironment

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Linbang Wang ◽  
Tao He ◽  
Jingkun Liu ◽  
Jiaojiao Tai ◽  
Bing Wang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cell ◽  
Hub Genes ◽  
Tumor Associated Macrophage ◽  
Molecular Features ◽  
Receptor Interactions ◽  
Tumor Types ◽  
Pan Cancer

Abstract Background Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment (TME). However, their contribution to the immunosuppressive status of the TME remains unclear. Methods We integrated single-cell sequencing and transcriptome data from different tumor types to uncover the molecular features of TAMs. In vitro experiments and prospective clinical tests confirmed the results of these analysis. Results We first detected intra- and inter-tumoral heterogeneities between TAM subpopulations and their functions, with CD86+ TAMs playing a crucial role in tumor progression. Next, we focused on the ligand-receptor interactions between TAMs and tumor cells in different TME phenotypes and discovered that aberrant expressions of six hub genes, including FLI1, are involved in this process. A TAM-tumor cell co-culture experiment proved that FLI1 was involved in tumor cell invasion, and FLI1 also showed a unique pattern in patients. Finally, TAMs were discovered to communicate with immune and stromal cells. Conclusion We determined the role of TAMs in the TME by focusing on their communication pattern with other TME components. Additionally, the screening of hub genes revealed potential therapeutic targets.

PEAK1 promotes invasion and metastasis and confers drug resistance in breast cancer

2021 ◽  
Author(s):  
xingang wang ◽  
YAN ZHENG ◽  
YU WANG
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cell Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Multi Drug Resistance ◽  
Cancer Tissues

Abstract Background and AimsPseudopodium-enriched atypical kinase 1 (PEAK1) has reported to be upregulated in human malignancies and related with poor prognosis. Enhanced PEAK1 expression facilitates tumor cell survival, invasion, metastasis and chemoresistance. However, the role of PEAK1 in breast cancer is not clear. Here, we investigated the PEAK1 expression in breast cancer and analyzed its relation with clinicopathological status and chemotherapy resistance to the neoadjuvant chemotherapy (NAC). We also investigated the role of PEAK1 on breast cancer cells in vitro and in vivo. MethodsImmunohistochemistry (IHC) was performed in 112 surgical resected breast cancer tissues. The associations between clinicopathological status, multi-drug resistance and PEAK1 expression were determined. Effect of PEAK1 overexpression or down-expression on proliferation, colony formation, invasion, migration, metastasis and Doxorubicin sensitivity in the MCF-7 cells in vitro and in vivo was detected. ResultsPEAK1 was overexpressed in breast cancer tissues and NAC -resistant breast cancer tissues. High PEAK1 expression was related with tumor size, high tumor grade, T stage, LN metastasis, recurrence, Ki-67 expression, Her-2 expression and multi-drug resistance. Targeting PEAK1 inhibited cell growth, invasion, metastasis and reversed chemoresistance to Doxorubicin in breast cancer cells in vitro and in vivo. ConclusionHigh PEAK1 expression was associated with invasion, metastasis and chemoresistance of breast cancers. Furthermore, targeting PEAK1 could inhibit cell growth and metastasis, and reverse chemoresistance in breast cancer cells, which provides an effective treatment strategies for breast cancer.

scholarly journals GPR40-Deficiency Is Associated with Hepatic FAT/CD36 Upregulation, Steatosis, Inflammation and Cell Injury in C57BL/6 Mice

2020 ◽  
Author(s):  
Zhongyang Lu ◽  
Yanchun Li ◽  
Wing-Kin Syn ◽  
Ai-Jun Li ◽  
S Ritter ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Injury ◽  
Immunohistochemical Analysis ◽  
Hepatic Metabolism ◽  
Nonalcoholic Fatty Liver ◽  
Low Fat Diet ◽  
Cd36 Expression ◽  
Glucose Stimulated Insulin Secretion

GPR40 is highly expressed in pancreatic islets and its activation increases glucose-stimulated insulin secretion from pancreas. Therefore, GPR40 is considered as a target for type 2 diabetes mellitus (T2DM). Since nonalcoholic fatty liver disease (NAFLD) is associated with T2DM and GPR40 is also expressed by hepatocytes and macrophages, it is important to understand the role of GPR40 in NAFLD. However, the role of GPR40 in NAFLD in animal models has not been well defined. In this study, we fed wild-type or GPR40 knockout C57BL/6 mice high-fat diet (HFD) for 20 weeks and then assessed the effect of GPR40-deficiency on HFD-induced NAFLD. Assays on metabolic parameters showed that HFD increased bodyweight, glucose, insulin, insulin resistance, cholesterol and alanine aminotransferase (ALT), and GPR40-deficiency did not mitigate the HFD-induced metabolic abnormalities. In contrast, we found that GPR40-deficiency was associated with increased bodyweight, insulin, insulin resistance, cholesterol and ALT in control mice fed low fat diet (LFD). Surprisingly, histology and Oil Red O staining showed that GPR40-deficiency in LFD-fed mice was associated with steatosis. Immunohistochemical analysis showed that GPR40-deficiency also increased F4/80, a macrophage biomarker, in LFD-fed mice. Furthermore, results showed that GPR40-deficiency led to a robust upregulation of hepatic fatty acid translocase (FAT)/CD36 expression. Finally, our in vitro studies showed that GPR40 knockdown by siRNA or GPR40 antagonist increased palmitic acid-induced FAT/CD36 mRNA in hepatocytes. Taken together, this study indicates that GPR40 plays an important role in homeostasis of hepatic metabolism and inflammation and inhibits nonalcoholic steatohepatitis by possible modulation of FAT/CD36 expression.

scholarly journals Pre-Clinical Drug Testing in 2D and 3D Human In Vitro Models of Glioblastoma Incorporating Non-Neoplastic Astrocytes: Tunneling Nano Tubules and Mitochondrial Transfer Modulates Cell Behavior and Therapeutic Response

2019 ◽  
Vol 20 (23) ◽  
pp. 6017 ◽  
Author(s):  
Prospero Civita ◽  
Diana M. Leite ◽  
Geoffrey Pilkington
Keyword(s):  
Drug Resistance ◽  
Hyaluronic Acid ◽  
Drug Testing ◽  
Tunneling Nanotubes ◽  
Mitochondrial Transfer ◽  
Culture Models ◽  
And Migration ◽  
2D And 3D

The role of astrocytes in the glioblastoma (GBM) microenvironment is poorly understood; particularly with regard to cell invasion and drug resistance. To assess this role of astrocytes in GBMs we established an all human 2D co-culture model and a 3D hyaluronic acid-gelatin based hydrogel model (HyStem™-HP) with different ratios of GBM cells to astrocytes. A contact co-culture of fluorescently labelled GBM cells and astrocytes showed that the latter promotes tumour growth and migration of GBM cells. Notably, the presence of non-neoplastic astrocytes in direct contact, even in low amounts in co-culture, elicited drug resistance in GBM. Recent studies showed that non-neoplastic cells can transfer mitochondria along tunneling nanotubes (TNT) and rescue damaged target cancer cells. In these studies, we explored TNT formation and mitochondrial transfer using 2D and 3D in vitro co-culture models of GBM and astrocytes. TNT formation occurs in glial fibrillary acidic protein (GFAP) positive “reactive” astrocytes after 48 h co-culture and the increase of TNT formations was greater in 3D hyaluronic acid-gelatin based hydrogel models. This study shows that human astrocytes in the tumour microenvironment, both in 2D and 3D in vitro co-culture models, could form TNT connections with GBM cells. We postulate that the association on TNT delivery non-neoplastic mitochondria via a TNT connection may be related to GBM drug response as well as proliferation and migration.

scholarly journals 2, 3-Dihydro-3β-methoxy Withaferin-A Lacks Anti-Metastasis Potency: Bioinformatics and Experimental Evidences

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Anupama Chaudhary ◽  
Rajkumar S. Kalra ◽  
Vidhi Malik ◽  
Shashank P. Katiyar ◽  
Durai Sundar ◽  
...  
Keyword(s):  
Cell Migration ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Human Cancer ◽  
Effector Proteins ◽  
Withaferin A ◽  
Migration And Invasion ◽  
Cell Metastasis

AbstractWithaferin-A is a withanolide, predominantly present in Ashwagandha (Withania somnifera). It has been shown to possess anticancer activity in a variety of human cancer cells in vitro and in vivo. Molecular mechanism of such cytotoxicity has not yet been completely understood. Withaferin-A and Withanone were earlier shown to activate p53 tumor suppressor and oxidative stress pathways in cancer cells. 2,3-dihydro-3β-methoxy analogue of Withaferin-A (3βmWi-A) was shown to lack cytotoxicity and well tolerated at higher concentrations. It, on the other hand, protected normal cells against oxidative, chemical and UV stresses through induction of anti-stress and pro-survival signaling. We, in the present study, investigated the effect of Wi-A and 3βmWi-A on cell migration and metastasis signaling. Whereas Wi-A binds to vimentin and heterogeneous nuclear ribonucleoprotein K (hnRNP-K) with high efficacy and downregulates its effector proteins, MMPs and VEGF, involved in cancer cell metastasis, 3βmWi-A was ineffective. Consistently, Wi-A, and not 3βmWi-A, caused reduction in cytoskeleton proteins (Vimentin, N-Cadherin) and active protease (u-PA) that are essential for three key steps of cancer cell metastasis (EMT, increase in cell migration and invasion).

scholarly journals Normoxic Tumour Extracellular Vesicles Modulate the Response of Hypoxic Cancer and Stromal Cells to Doxorubicin In Vitro

2020 ◽  
Vol 21 (17) ◽  
pp. 5951
Author(s):  
Laura Patras ◽  
Marcel H. A. M. Fens ◽  
Pieter Vader ◽  
Arjan Barendrecht ◽  
Alina Sesarman ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Extracellular Vesicles ◽  
Hypoxia Inducible Factor ◽  
B Cell Lymphoma ◽  
Tumour Microenvironment ◽  
Hypoxia Inducible Factor 1 ◽  
Apoptotic Protein ◽  
Donor Cells

Extracellular vesicles (EV) secreted in the tumour microenvironment (TME) are emerging as major antagonists of anticancer therapies by orchestrating the therapeutic outcome through altering the behaviour of recipient cells. Recent evidence suggested that chemotherapeutic drugs could be responsible for the EV-mediated tumour–stroma crosstalk associated with cancer cell drug resistance. Here, we investigated the capacity of tumour EV (TEV) secreted by normoxic and hypoxic (1% oxygen) C26 cancer cells after doxorubicin (DOX) treatment to alter the response of naïve C26 cells and RAW 264.7 macrophages to DOX. We observed that C26 cells were less responsive to DOX treatment under normoxia compared to hypoxia, and a minimally cytotoxic DOX concentration that mounted distinct effects on cell viability was selected for TEV harvesting. Homotypic and heterotypic pretreatment of naïve hypoxic cancer and macrophage-like cells with normoxic DOX-elicited TEV rendered these cells slightly less responsive to DOX treatment. The observed effects were associated with strong hypoxia-inducible factor 1-alpha (HIF-1α) induction and B-cell lymphoma–extra-large anti-apoptotic protein (Bcl-xL)-mediated anti-apoptotic response in normoxic DOX-treated TEV donor cells, being also tightly connected to the DOX-TEV-mediated HIF-1α induction, as well as Bcl-xL levels increasing in recipient cells. Altogether, our results could open new perspectives for investigating the role of chemotherapy-elicited TEV in the colorectal cancer TME and their modulatory actions on promoting drug resistance.

scholarly journals Role of Berry Anthocyanins and Phenolic Acids on Cell Migration and Angiogenesis: An Updated Overview

Nutrients ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 1075 ◽  
Author(s):  
Panagiotis Tsakiroglou ◽  
Natalie E. VandenAkker ◽  
Cristian Del Bo’ ◽  
Patrizia Riso ◽  
Dorothy Klimis-Zacas
Keyword(s):  
Wound Healing ◽  
Cell Migration ◽  
Phenolic Acids ◽  
Rho Gtpase ◽  
Small Gtpases ◽  
Endothelial Cell Migration ◽  
Berry Extracts

Cell migration is a critical process that is highly involved with normal and pathological conditions such as angiogenesis and wound healing. Important members of the RHO GTPase family are capable of controlling cytoskeleton conformation and altering motility characteristics of cells. There is a well-known relationship between small GTPases and the PI3K/AKT pathway. Endothelial cell migration can lead to angiogenesis, which is highly linked to wound healing processes. Phenolics, flavonoids, and anthocyanins are major groups of phytochemicals and are abundant in many natural products. Their antioxidant, antimicrobial, anti-inflammatory, antidiabetic, angiogenenic, neuroprotective, hepatoprotective, and cardioprotective properties have been extensively documented. This comprehensive review focuses on the in vitro and in vivo role of berry extracts and single anthocyanin and phenolic acid compounds on cell migration and angiogenesis. We aim to summarize the most recent published studies focusing on the experimental model, type of berry extract, source, dose/concentration and overall effect(s) of berry extracts, anthocyanins, and phenolic acids on the above processes.

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