scholarly journals Nuclear PHGDH promotes neutrophil recruitment to drive liver cancer progression

2021 ◽  
Author(s):  
Hongwen Zhu ◽  
Hua Yu ◽  
Hu Zhou ◽  
Wencheng Zhu ◽  
Xiongjun Wang
Keyword(s):  
Liver Cancer ◽  
Cancer Progression ◽  
Malignant Tumors ◽  
Metabolic Dysregulation ◽  
Metabolic Role ◽  
Act Domain ◽  
Advanced Stages ◽  
Nuclear Location ◽  
Phosphoglycerate Dehydrogenase

Metabolic dysregulation and the communications between cancer and immune cells are emerging as two essential features of malignant tumors. In this study, we observed that nuclear localization of phosphoglycerate dehydrogenase (PHGDH) associates with poor prognosis of liver cancer patients, and Phgdh is required for liver cancer progression in a mouse model. Unexpectedly, the impairment of Phgdh enzyme activity exerts a slight effect on liver cancer model, indicating PHGDH contributes to liver cancer progression mainly depending on its non-metabolic roles with nuclear location. PHGDH uses its ACT domain to bind cMyc in nuclear and forms a transactivation axis PHGDH/p300/cMyc/AF9 which drives CXCL1/8 gene expression. Chemokines CXCL1/8 promotes neutrophils recruitment and then supports tumor associated macrophages (TAMs) filtration in liver, thereby urging liver cancer into advanced stages. Forced cytosolic location of PHGDH or destruction of the PHGDH/cMyc interaction abolishes the oncogenic function of nuclear PHGDH. Collectively, this study reveals a non-metabolic role of PHGDH with altered cellular location in liver cancer, and suggests a promising drug target for liver cancer therapy by targeting the interaction between PHGDH and undruggable cMyc.

scholarly journals Structure–Activity Relationships (SARs) of α-Ketothioamides as Inhibitors of Phosphoglycerate Dehydrogenase (PHGDH)

2020 ◽  
Vol 13 (2) ◽  
pp. 20
Author(s):  
Quentin Spillier ◽  
Séverine Ravez ◽  
Judith Unterlass ◽  
Cyril Corbet ◽  
Charline Degavre ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Structure Activity Relationship ◽  
Therapeutic Agents ◽  
Activity Relationship ◽  
Cancer Treatments ◽  
Promising Strategy ◽  
Structure Activity ◽  
Phosphoglycerate Dehydrogenase ◽  
Relationship Study

For many years now, targeting deregulation within cancer cells’ metabolism has appeared as a promising strategy for the development of more specific and efficient cancer treatments. Recently, numerous reports highlighted the crucial role of the serine synthetic pathway, and particularly of the phosphoglycerate dehydrogenase (PHGDH), the first enzyme of the pathway, to sustain cancer progression. Yet, because of very weak potencies usually in cell-based settings, the inhibitors reported so far failed to lay ground on the potential of this approach. In this paper, we report a structure–activity relationship study of a series of α-ketothioamides that we have recently identified. Interestingly, this study led to a deeper understanding of the structure–activity relationship (SAR) in this series and to the identification of new PHGDH inhibitors. The activity of the more potent compounds was confirmed by cellular thermal shift assays and in cell-based experiments. We hope that this research will eventually provide a new entry point, based on this promising chemical scaffold, for the development of therapeutic agents targeting PHGDH.

scholarly journals The role of HOMER3 in liver cancer progression.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 89-89
Author(s):  
Precious Takondwa Makondi
Keyword(s):  
Liver Cancer ◽  
Viral Hepatitis ◽  
Cancer Progression ◽  
Alcohol Intake ◽  
Clinical Stage ◽  
Gene Set Enrichment Analysis ◽  
High Expression ◽  
Obesity And Diabetes ◽  
Tumor Tissues

89 Background: Liver cancer (LC) is in the seventh most common cancer and the fourth largest cause of cancer deaths. Although significant progress has been made in the prevention and treatment of viral hepatitis; alcoholic liver disease, obesity and diabetes are now emerging as major causes for LC. Recently there has been increase in identification of biomarkers which can predict LC risk and disease progression, but the roles of HOMER3 gene in LC are not known. Methods: First the expression of HOMER3 between normal and tumor tissues was determined using The Cancer Genome Atlas (TCGA), Genetic Expression Omnibus (GEO) and protein atlas datasets. HOMER3 expression at different clinical stage and overall survival (OS) was also determined. The role of HOMER3 on OS in relation to cancer stage, hepatitis virus infection and alcohol intake was also determined. STRING database determined HOMER3 interaction network and TCGA was used to verify the correlation status, and the roles of the network genes on OS. The pathways enriched by HOMER3 were determined by Gene Set Enrichment Analysis (GSEA). Results: HOMER3 was significantly highly expressed in tumor tissues as compared to normal tissues. The expression of HOMER3 correlated positively with clinical stage, with highest expression in advanced stages (Stage 3 and 4), and high HOMER3 expression was associated with poor OS. HOMER3’ s high expression was associated with poor OS in advanced stage, alcohol intake, and in those negative of viral hepatitis infection. HOMER3 interacted with HOMER1, SHANK1, GRM5, GRM1, DLGAP1, SHANK2, DLG4, SHANK3, DLG2 and DLGAP4, with positive correlation to HOMER1, SHANK1, GRM5, GRM1, DLGAP1, DLG4 and DLGAP4 and negative correlation to SHANK2, SHANK3 and DLG2. HOMER1 and DLGAP4 high expression were associated with poor OS while SHANK2, SHANK3 and DLG2 high expression were associated with favorable OS. GRM5 and GRM1 high expression were associated with favorable OS despite being positively correlated with HOMER3. ECM receptor interaction and Notch signaling were the upregulated pathways while Metabolism of xenobiotics by cytochrome p450 and PPAR signaling were the downregulated pathways. Conclusions: HOMER3 may is have a role in liver cancer progression of which its targeting may improve LC outcome.

scholarly journals PATZ1 (MAZR) Co-occupies Genomic Sites With p53 and Inhibits Liver Cancer Cell Proliferation via Regulating p27

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhen Long Ng ◽  
Jiamin Siew ◽  
Jia Li ◽  
Guanxu Ji ◽  
Min Huang ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Liver Cancer ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Cellular Proliferation ◽  
Zinc Finger Protein ◽  
Kinase Inhibitor ◽  
Transcriptional Start Site ◽  
Cancer Cell Proliferation

Liver cancer is the third most common cause of cancer death in the world. POZ/BTB and AT-hook-containing zinc finger protein 1 (PATZ1/MAZR) is a transcription factor associated with various cancers. However, the role of PATZ1 in cancer progression remains controversial largely due to lack of genome-wide studies. Here we report that PATZ1 regulates cell proliferation by directly regulating CDKN1B (p27) in hepatocellular carcinoma cells. Our PATZ1 ChIP-seq and gene expression microarray analyses revealed that PATZ1 is strongly related to cancer signatures and cellular proliferation. We further discovered that PATZ1 depletion led to an increased rate of colony formation, elevated Ki-67 expression and greater S phase entry. Importantly, the increased cancer cell proliferation was accompanied with suppressed expression of the cyclin-dependent kinase inhibitor CDKN1B. Consistently, we found that PATZ1 binds to the genomic loci flanking the transcriptional start site of CDKN1B and positively regulates its transcription. Notably, we demonstrated that PATZ1 is a p53 partner and p53 is essential for CDKN1B regulation. In conclusion, our study provides novel mechanistic insights into the inhibitory role of PATZ1 in liver cancer progression, thereby yielding a promising therapeutic intervention to alleviate tumor burden.

The role of Visfatin and Resistin in an In Vitro Model of Obesity-Induced Invasive Liver Cancer

2020 ◽  
Author(s):  
Candace Miethe ◽  
Linda Torres ◽  
Jessica Beristain ◽  
Megan Zamora ◽  
Ramona Salcedo Price
Keyword(s):  
Liver Cancer ◽  
Cancer Progression ◽  
Neutralizing Antibodies ◽  
Normal Weight ◽  
Cancer Phenotype ◽  
Vitro Model ◽  
The Impact ◽  
Metalloproteinase 9

Background: Obesity is associated with the development of liver disease and its progression to hepatocellular carcinoma. This link may be attributed to adipocytokines such as growth visfatin, and resistin which have been shown to promote liver cancer incidence and progression. Studies have yet to determine the role of visfatin and resistin in liver cancer specifically in the context of obesity. The objective of this study was to investigate the effect of neutralizing visfatin and resistin in obese (OB) or normal weight (NW) sera to determine the contribution of these proteins in obesity-induced invasive liver cancer. Methods: Sera from OB or NW males was used to determine the efficacy of neutralizing visfatin and resistin to reduce the obesity-induced liver cancer phenotype. HepG2 and SNU-449 cells were exposed to OB and NW sera ± antibodies for visfatin or resistin. The neutralizing antibodies differentially suppressed invasion, ROS production, and matrix metalloproteinase-9 secretion. These changes corresponded with a decrease in phosphorylated ERK and Akt in HepG2 cells, but differences were not observed in CAP1 or β-catenin. In conclusion, visfatin and resistin have differential roles in obesity-associated liver cancer and may be potential targets to reverse the impact of obesity on liver cancer progression.

scholarly journals Prospects of application of inhibitors of PD-1/PD-L1 checkpoints in malignant tumors of the stomach and esophagogastric junction

2020 ◽  
pp. 15-21
Author(s):  
D. D. Sakaeva ◽  
A. A. Melnikova
Keyword(s):  
Esophagogastric Junction ◽  
Kinase Inhibitors ◽  
Malignant Tumors ◽  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Therapy Response ◽  
Treatment Method ◽  
Tumor Tissues ◽  
Advanced Stages

Malignant tumors of the stomach and esophagogastric junction in advanced stages progress quite aggressively, and the prospects for treatment of these patients remain unpromising. The use of checkpoint-inhibitors has proven to be an advanced treatment method for various types of cancer around the world. In theRussian Federation, nivolumab has been successfully registered as a monotherapy for common or recurrent stomach or esophagogastric junction cancer after two or more lines of systemic antitumor drug therapy. This literature review focuses on the use of registered checkpoint inhibitors (nivolumab, pembrolizumab, ipilimumab) as mono- and/or combined therapy in tumors of the stomach and esophagogastric junction, including tumors with high microsat- ellite instability (MSI-high). This review includes a description of the main therapeutic approaches using checkpoint inhibitors: prescription in mono-mode, in combination with other checkpoint inhibitors (ipilimumab) and cytotoxic drugs, and in combination with tyrosine kinase inhibitors (regorafenib). Issues of efficiency and tolerability of these combinations in patients in different therapeutic lines are considered. The role of possible predictors of therapy response is analyzed: biomarkers such as PD-Ll, MSI, dMMR and TMB expression in tumor tissues as well as immunofenotyping in fresh biopsy samples are evaluated. This article reviews and evaluates the strengths and weaknesses of checkpoint inhibitors and their possible uses.

scholarly journals TMEM88 is a Prognostic Biomarker and Correlates With Immune Infiltrates in Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Andrew Liman ◽  
Yang Gu ◽  
Pengpeng Liu ◽  
Quanyan Liu
Keyword(s):  
Liver Cancer ◽  
Cancer Progression ◽  
Prognostic Biomarker ◽  
Progression Free Survival ◽  
Free Survival ◽  
Multiple Tumor ◽  
Normal Tissues ◽  
Tumor Types ◽  
Disease Stages

Abstract BackgroundTransmembrane protein 88 (TMEM88) has emerged as a newly discovered cancer-related protein that acts as a cancer-promoting or cancer-inhibiting regulator in multiple tumor types. However, the exact role of TMEM88 in liver cancer is undetermined. The current study was designed to determine the expression of TMEM88 in liver cancer. ResultsTMEM88 expression was significantly lower in several human cancers, but higher in liver and bile cancer, than in corresponding normal tissues. TMEM88 expression in HCC tissues correlated with prognosis. Low TMEM88 expression associated with poorer overall survival, disease-specific survival, progression-free survival, and relapse-free survival in multiple cohorts of HCC patients, particularly at late disease stages (grade 2 and 3). TMEM88 showed strong correlation with tumor-infiltrating B cells, CD4+ and CD8+ T cells, macrophages, neutrophils, and dendritic cells. ConclusionThese findings demonstrate that TMEM88 is a potential prognostic biomarker that determines cancer progression and correlated with tumor immune cells infiltration in HCC.

scholarly journals Insulin Receptor Isoform A Modulates Metabolic Reprogramming of Breast Cancer Cells in Response to IGF2 and Insulin Stimulation

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1017 ◽  
Author(s):  
Vella ◽  
Nicolosi ◽  
Giuliano ◽  
Morrione ◽  
Malaguarnera ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Insulin Receptor ◽  
Cancer Progression ◽  
Aerobic Glycolysis ◽  
Combined Treatment ◽  
Metabolic Reprogramming ◽  
Metabolic Role ◽  
Consumption Rates ◽  
Proliferation And Invasion

Previously published work has demonstrated that overexpression of the insulin receptor isoform A (IR-A) might play a role in cancer progression and metastasis. The IR has a predominant metabolic role in physiology, but the potential role of IR-A in cancer metabolic reprogramming is unknown. We aimed to characterize the metabolic impact of IR-A and its ligand insulin like growth factor 2 (IGF2) in human breast cancer (BC) cells. To establish autocrine IGF2 action, we generated human BC cells MCF7 overexpressing the human IGF2, while we focused on the metabolic effect of IR-A by stably infecting IGF1R-ablated MCF7 (MCF7IGF1R-ve) cells with a human IR-A cDNA. We then evaluated the expression of key metabolism related molecules and measured real-time extracellular acidification rates and oxygen consumption rates using the Seahorse technology. MCF7/IGF2 cells showed increased proliferation and invasion associated with aerobic glycolysis and mitochondrial biogenesis and activity. In MCF7IGF1R-ve/IR-A cells insulin and IGF2 stimulated similar metabolic changes and were equipotent in eliciting proliferative responses, while IGF2 more potently induced invasion. The combined treatment with the glycolysis inhibitor 2-deoxyglucose (2DG) and the mitochondrial inhibitor metformin blocked cell invasion and colony formation with additive effects. Overall, these results indicate that IGF2 and IR-A overexpression may contribute to BC metabolic reprogramming.

scholarly journals Tumor-Associated Macrophages: A Potential Target for Cancer Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Yifan Tan ◽  
Min Wang ◽  
Yang Zhang ◽  
Shengyang Ge ◽  
Fan Zhong ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Malignant Tumors ◽  
Therapeutic Strategies ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Tumor Associated Macrophages ◽  
Supportive Role ◽  
High Degree ◽  
Significant Attention

Macrophages, an important class of innate immune cells that maintain body homeostasis and ward off foreign pathogens, exhibit a high degree of plasticity and play a supportive role in different tissues and organs. Thus, dysfunction of macrophages may contribute to advancement of several diseases, including cancer. Macrophages within the tumor microenvironment are known as tumor-associated macrophages (TAMs), which typically promote cancer cell initiation and proliferation, accelerate angiogenesis, and tame anti-tumor immunity to promote tumor progression and metastasis. Massive infiltration of TAMs or enrichment of TAM-related markers usually indicates cancer progression and a poor prognosis, and consequently tumor immunotherapies targeting TAMs have gained significant attention. Here, we review the interaction between TAMs and cancer cells, discuss the origin, differentiation and phenotype of TAMs, and highlight the role of TAMs in pro-cancer functions such as tumor initiation and development, invasive metastasis, and immunosuppression. Finally, we review therapies targeting TAMs, which are very promising therapeutic strategies for malignant tumors.

ROLE OF AYURVEDA MEDICINE WITH RELEVANCE OF LIVER CANCER

2020 ◽  
Vol 4 (3) ◽  
Author(s):  
Sonia Kukreti Bhatt
Keyword(s):  
Nervous System ◽  
Liver Cancer ◽  
Malignant Tumors ◽  
Arterial System ◽  
Herbal Drugs ◽  
Indigenous Medicine ◽  
Key Words Cancer ◽  
Plant Drugs ◽  
Natural Drugs

Ayurveda, the oldest Indian indigenous medicine system of plant drugs is known from very early times for preventing or suppressing various tumors using these natural drugs. And nowadays scientists are keener to researches on complementary and alternative medicine for the management of cancer. In Ayurvedic concept, according to ‘Charaka’ and ‘SushrutaSamhitas’ cancer is described as inflammatory or non-inflammatory swelling and mentioned either as ‘Granthi’ (minor neoplasm) or ‘Arbuda‘ (major neoplasm). The nervous system (Vata or air), the venous system (Pitta or fire) and the arterial system (Kapha or water) are three basics of Ayurveda and very important for normal body function. In malignant tumors all three systems get out of control (Tridoshas) and lose mutual coordination that causes tissue damage, resulting critical condition. Tridoshas cause excessive metabolic crisis resulting in proliferation. Key words: Cancer, Charaka, Arbuda, Herbal drugs, TCM.  

scholarly journals Exosomal SNHG16 secreted by CSCs promotes glioma development via TLR7

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ruijie Zhang ◽  
Peng Li ◽  
Heli Lv ◽  
Nana Li ◽  
Suliang Ren ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Malignant Tumors ◽  
Glioma Cells ◽  
Pcr Assay ◽  
Qrt Pcr ◽  
Non Coding Rna ◽  
Long Non Coding Rna ◽  
U251 Cells

Abstract Background Glioma is one of the most common central nervous system malignant tumors, accounting for 45~60% of adult intracranial tumors. However, the clinical treatment of glioma is limited. It is of great significance to seek new therapeutic methods for glioma via gene therapy. Methods Long non-coding RNA (lncRNA) SNHG16 expression level was measured by microarray and qRT-PCR assay; ISH was used to identify the location of SNHG16. Cancer stem cells (CSCs) were separated from glioma tissues and identified using immunofluorescence. Exosomes were isolated from CSCs and cancer cells and identified by TEM and western blot. MTT, wound healing, transwell, and colony formation assay were performed to explore the role of SNHG16 or si-SNHG16 from CSCs on progression of glioma cells. RIP was used to verify the interaction between SNHG16 and TLR7. The experiment of Xenograft used for exploring the function of SNHG16/ TLR7/MyD88/NFκB/c-Myc on growth on glioma in vivo. Results Microarray assay showed long non-coding RNA (lncRNA) SNHG16 was upregulated in glioma. Followed qRT-PCR also showed an increase of SNHG16 in glioma tissues; high expression of SNHG16 indicated a poor prognosis in glioma patients. Interestingly, SNHG16 was packaged into exosomes and derived from CSCs. Functional analysis showed exo-SNHG16 secreted by CSCs promoted the progression of glioma cell lines SHG44 and U251. Furthermore, SNHG16 interacted with TLR7 and activated NFκB/c-Myc signaling in glioma cells. And the silencing of TLR7 inhibited the progression of SHG44 and U251 cells by exo-SNHG16 from CSCs. In vivo tumorigenesis experiments showed that exo-SNHG16 induced glioma progression by activating TLR7/MyD88/NFκB/c-Myc signaling. Conclusion Our study suggested CSC-derived exo-SNHG16 promoted cancer progression by activating TLR7/MyD88/NFκB/c-Myc signaling pathway.

Sign in / Sign up

Export Citation Format

Share Document