scholarly journals Lactate Metabolism Regulates Tumour Growth and Progression in Glioblastoma

2021 ◽  
Author(s):  
Lucia Longhitano ◽  
Nunzio Vicario ◽  
Daniele Tibullo ◽  
Cesarina Giallongo ◽  
Giuseppe Broggi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Metabolic Reprogramming ◽  
In Vivo Model ◽  
Glycolytic Metabolism ◽  
Mesenchymal Transition ◽  
Signalling Molecule ◽  
Extracellular Lactate ◽  
Human Gbm

Abstract Background. Tumor microenvironment (TME) plays a pivotal role in establishing malignancy and it is associated with high glycolytic metabolism and increased lactate production accumulating in TME through monocarboxylate transporters (MCTs). Several lines of evidence suggest that lactate also serves as a signalling molecule through its receptor HCAR1thus functioning as a paracrine and autocrine signalling molecule in TME. The aim of the present study was to investigate the role of lactate in glioblastoma (GBM) progression and metabolic reprogramming in an in vitro and in vivo model.Methods. Cell proliferation, migration and clonogenicity assay were performed in vitro on three different human GBM cell lines. Protein expression of MCT1, MCT4 and pharmacological lactate receptor (GPR81) were evaluated both in vitro and in a zebrafish GBM in vivo model. These results were further validated in patient-derived GBM biopsies.Results. Our results showed that lactate significantly increased cell proliferation, migration and colony formation capacity of GBM cells, both in vitro and in vivo. We also showed that lactate increased MCT1 and HCAR1 expression. Moreover, lactate modulated epithelial-mesenchymal transition protein markers E-Cadherin and β-Catenin. Interestingly, lactate induced mitochondrial mass and OXPHOS gene suggesting an improved mitochondrial fitness. Similar effects were observed after treatment with 3,5-Dihydroxybenzoic acid, a known agonist of GPR81. Consistently, GBM zebrafish model exhibited an altered metabolism and increased expression of MCT1 and HCAR1 leading to high levels of extracellular lactate and thus supporting tumor cell proliferation. Our data from human GBM biopsies also showed that in high proliferative GBM biopsies, Ki67 positive cells expressed significantly higher levels of MCT1 compared to low proliferative GBM cells.Conclusions. Our data suggest that lactate favours proliferation of neighbourhood cells by cooperating with their glycolytic metabolism, sensing and removing extracellular lactate. In particular, lactate and its transporter and receptor play a major role in GBM proliferation and migration thus representing a potential target to develop new strategies to counteract tumor progression and recurrencies.

scholarly journals Mitochondrial arginase-2 is essential for IL-10 metabolic reprogramming of inflammatory macrophages

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jennifer K. Dowling ◽  
Remsha Afzal ◽  
Linden J. Gearing ◽  
Mariana P. Cervantes-Silva ◽  
Stephanie Annett ◽  
...  
Keyword(s):  
Metabolic Regulation ◽  
Mitochondrial Dynamics ◽  
Interleukin 10 ◽  
Metabolic Reprogramming ◽  
In Vivo Model ◽  
Macrophage Polarisation ◽  
Inflammatory Status ◽  
Inflammatory Macrophages

AbstractMitochondria are important regulators of macrophage polarisation. Here, we show that arginase-2 (Arg2) is a microRNA-155 (miR-155) and interleukin-10 (IL-10) regulated protein localized at the mitochondria in inflammatory macrophages, and is critical for IL-10-induced modulation of mitochondrial dynamics and oxidative respiration. Mechanistically, the catalytic activity and presence of Arg2 at the mitochondria is crucial for oxidative phosphorylation. We further show that Arg2 mediates this process by increasing the activity of complex II (succinate dehydrogenase). Moreover, Arg2 is essential for IL-10-mediated downregulation of the inflammatory mediators succinate, hypoxia inducible factor 1α (HIF-1α) and IL-1β in vitro. Accordingly, HIF-1α and IL-1β are highly expressed in an LPS-induced in vivo model of acute inflammation using Arg2−/− mice. These findings shed light on a new arm of IL-10-mediated metabolic regulation, working to resolve the inflammatory status of the cell.

scholarly journals Sp1-Induced Upregulation of LBX2-AS1 Aggravates The Progression of Glioblastoma By Targeting The miR-491-5p/LIF Axis

2021 ◽  
Author(s):  
Wentao Li ◽  
Ismatullah Soufiany ◽  
Xiao Lyu ◽  
Lin Zhao ◽  
Chenfei Lu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Lines ◽  
Cancer Progression ◽  
Epithelial To Mesenchymal Transition ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Stat3 Signaling ◽  
Regulatory Effects

Abstract Background: Mounting evidences have shown the importance of lncRNAs in tumorigenesis and cancer progression. LBX2-AS1 is an oncogenic lncRNA that has been found abnormally expressed in gastric cancer and lung cancer samples. Nevertheless, the biological function of LBX2-AS1 in glioblastoma (GBM) and potential molecular mechanism are largely unclear. Methods: Relative levels of LBX2-AS1 in GBM samples and cell lines were detected by qRT-PCR and FISH. In vivo and in vitro regulatory effects of LBX2-AS1 on cell proliferation, epithelial-to-mesenchymal transition (EMT) and angiogenesis in GBM were examined through xenograft models and functional experiments, respectively. The interaction between Sp1 and LBX2-AS1 was assessed by ChIP. Through bioinformatic analyses, dual-luciferase reporter assay, RIP and Western blot, the regulation of LBX2-AS1 and miR-491-5p on the target gene leukemia Inhibitory factor (LIF) was identified. Results: LBX2-AS1 was upregulated in GBM samples and cell lines, and its transcription was promoted by binding to the transcription factor Sp1. As a lncRNA mainly distributed in the cytoplasm, LBX2-AS1 upregulated LIF, and activated the LIF/STAT3 signaling by exerting the miRNA sponge effect on miR-491-5p, thus promoting cell proliferation, EMT and angiogenesis in GBM. Besides, LBX2-AS1 was unfavorable to the progression of glioma and the survival. Conclusion: Upregulated by Sp1, LBX2-AS1 promotes the progression of GBM by targeting the miR-491-5p/LIF axis. It is suggested that LBX2-AS1 may be a novel diagnostic biomarker and therapeutic target of GBM.

scholarly journals ORMDL1 is upregulated and associated with favorable outcome in colorectal cancer

2020 ◽  
Author(s):  
Qian Wang ◽  
Wanjun Liu ◽  
Si Chen ◽  
Qianxin Luo ◽  
Yichen Li ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Colony Formation ◽  
Transmembrane Protein ◽  
Cohort Analysis ◽  
Negative Regulator ◽  
Morphologic Change ◽  
Mesenchymal Transition

AbstractBackgroundORMDL1 gene encodes a transmembrane protein for endoplasmic reticulum and is known as crucial negative regulator for sphingolipid biogenesis. However, it has been rarely studied in tumor-related context. Therefore, its prognostic value and functional significance in colorectal cancer (CRC) remain to be explored.MethodsTCGA CRC cohort analysis, qRT-PCR, and immunohistochemistry (IHC) were used to examine the ORMDL1 expression level. The association between ORMDL1 expression and various clinical characteristics were analyzed by Chi-square tests. CRC patients’ overall survival (OS) was analyzed by Kaplan-Meier analysis. In vitro and in vivo cell-based assays were performed to explore the role of ORMDL1 in cell proliferation, invasion and migration. Transcriptional changes of cells either with ORMDL1 knockdowned or overexpressed were compared and analyzed.ResultsORMDL1 was upregulated in CRC tissues either in TCGA cohort or in our cohort. Interestingly, its expression was significantly lower in patients with metastasis compared to patients without metastasis, and high expression group had longer OS than low expression group. Knockdown of ORMDL1 expression can promote proliferation, colony formation and invasion, while attenuate migration in CRC cell lines. In opposite, forced overexpression of ORMDL1 reduced cell proliferation, colony formation and invasion, while enhanced cell migration. Epithelial-to-mesenchymal transition (EMT) related genes were enriched among differentially expressed genes when ORMDL1 was knockdowned in cells, which was consistent with morphologic change by microscopy observation. Finally, stable knockdown of ORMDL1 can promote cancer cell proliferation in vivo to some extent.ConclusionORMDL1 is upregulated and may serve as biomarker to predict favourable outcome in colorectal cancer.

Rapamycin inhibits hepatic stellate cell proliferation in vitro and limits fibrogenesis in an in vivo model of liver fibrosis

1999 ◽  
Vol 117 (5) ◽  
pp. 1198-1204 ◽  
Author(s):  
Jianliang Zhu ◽  
Jian Wu ◽  
Edward Frizell ◽  
Shu-Ling Liu ◽  
Reza Bashey ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Liver Fibrosis ◽  
Hepatic Stellate Cell ◽  
Stellate Cell ◽  
In Vivo Model ◽  
Proliferation In Vitro

scholarly journals SMARCC1 Suppresses Tumor Progression by Inhibiting the PI3K/AKT Signaling Pathway in Prostate Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Zhao-Ming Xiao ◽  
Dao-Jun Lv ◽  
Yu-zhong Yu ◽  
Chong Wang ◽  
Tao Xie ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Signaling Pathway ◽  
Cell Cycle Progression ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Transition ◽  
Proliferation And Metastasis ◽  
Cell Proliferation And Metastasis

BackgroundSWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin subfamily C member 1 (SMARCC1) protein is a potential tumor suppressor in various cancers. However, its role in prostate cancer (PCa) remains controversial. The aim of this study was to determine the biological function of SMARCC1 in PCa and explore the underlying regulatory mechanisms.MethodsThe expression of SMARCC1 was validated in PCa tissues by immunohistochemistry. Meanwhile, function experiments were used to evaluate the regulatory role on cell proliferation and metastasis in PCa cells with SMARCC1 depletion both in vitro and in vivo. The expression levels of relevant proteins were detected by Western blotting.ResultsOur finding showed that SMARCC1 was significantly downregulated in prostate adenocarcinoma, with a higher Gleason score (GS) than that in low GS. The decreased expression of SMARCC1 was significantly correlated with a higher GS and poor prognosis. Additionally, we found that silencing of SMARCC1 dramatically accelerated cell proliferation by promoting cell cycle progression and enhancing cell migration by inducing epithelial mesenchymal transition (EMT). Furthermore, depletion of SMARCC1 facilitated PCa xenograft growth and lung metastasis in murine models. Mechanistically, the loss of SMARCC1 activated the PI3K/AKT pathway in PCa cells.ConclusionSMARCC1 suppresses PCa cell proliferation and metastasis via the PI3K/AKT signaling pathway and is a novel therapeutic target.

scholarly journals LINC00460 / DHX9/IGF2BP2 complex promotes colorectal cancer proliferation and metastasis by mediating HMGA1 mRNA stability depending on m6A modification

2020 ◽  
Author(s):  
Pingfu Hou ◽  
Sen Meng ◽  
Minle Li ◽  
Tian Lin ◽  
Sufang Chu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Molecular Mechanism ◽  
Mrna Stability ◽  
Functional Characterization ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Hmga1 Expression

Abstract Background: Increasing studies have shown that long noncoding RNAs (lncRNAs) are pivotal regulators participating in carcinogenic progression and tumor metastasis in colorectal cancer (CRC). Although lncRNA long intergenic noncoding RNA 460 (LINC00460) has been reported in CRC, the role and molecular mechanism of LINC00460 in CRC progression still requires exploration.Methods: The expression levels of LINC00460 were analyzed by using a tissue microarray containing 498 CRC tissues and their corresponding non-tumor adjacent tissues. The correlations between the LINC00460 expression level and clinicopathological features were evaluated. The functional characterization of the role and molecular mechanism of LINC00460 in CRC was investigated through a series of in vitro and in vivo experiments.Results: LINC00460 expression was increased in human CRC, and high LINC00460 expression was correlated with poor five-year overall survival and disease-free survival. LINC00460 overexpression sufficiently induced the epithelial–mesenchymal transition and promoted tumor cell proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo. In addition, LINC00460 enhanced the protein expression of high-mobility group AT-hook 1 (HMGA1) by directly interacting with IGF2BP2 and DHX9 to bind the 3′ untranslated region (UTR) of HMGA1 mRNA and increased the stability of HMGA1 mRNA. In addition, the N6-methyladenosine (m6A) modification of HMGA1 mRNA by METTL3 enhanced HMGA1 expression in CRC. Finally, it suggested that HMGA1 was essential for LINCC046-induced cell proliferation, migration, and invasion.Conclusions: LINC00460 may be a novel oncogene of CRC through interacting with IGF2BP2 and DHX9 and bind to the m6A modified HMGA1 mRNA to enhance the HMGA1 mRNA stability. LINC00460 can serve as a promising predictive biomarker for the diagnosis and prognosis among patients with CRC.

scholarly journals The lncRNA DLX6-AS1 promoted cell proliferation, invasion, migration and epithelial-to-mesenchymal transition in bladder cancer via modulating Wnt/β-catenin signaling pathway

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Jinan Guo ◽  
Zhixin Chen ◽  
Hongtao Jiang ◽  
Zhou Yu ◽  
Junming Peng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Bladder Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Bladder Cancer Cell ◽  
Mesenchymal Transition ◽  
Bladder Cancer Cells

Abstract Background Bladder cancer is the most common human urological malignancies with poor prognosis, and the pathophysiology of bladder cancer involves multi-linkages of regulatory networks in the bladder cancer cells. Recently, the long noncoding RNAs (lncRNAs) have been extensively studied for their role on bladder cancer progression. In this study, we evaluated the expression of DLX6 Antisense RNA 1 (DLX6-AS1) in the cancerous bladder tissues and studied the possible mechanisms of DLX6-AS1 in regulating bladder cancer progression. Methods Gene expression was determined by qRT-PCR; protein expression levels were evaluated by western blot assay; in vitro functional assays were used to determine cell proliferation, invasion and migration; nude mice were used to establish the tumor xenograft model. Results Our results showed the up-regulation of DLX6-AS1 in cancerous bladder cancer tissues and bladder cell lines, and high expression of DLX6-AS1 was correlated with advance TNM stage, lymphatic node metastasis and distant metastasis. The in vitro experimental data showed that DLX6-AS1 overexpression promoted bladder cancer cell growth, proliferation, invasion, migration and epithelial-to-mesenchymal transition (EMT); while DLX6-AS1 inhibition exerted tumor suppressive actions on bladder cancer cells. Further results showed that DLX6-AS1 overexpression increased the activity of Wnt/β-catenin signaling, and the oncogenic role of DLX6-AS1 in bladder cancer cells was abolished by the presence of XAV939. On the other hand, DLX6-AS1 knockdown suppressed the activity of Wnt/β-catenin signaling, and the tumor-suppressive effects of DLX6-AS1 knockdown partially attenuated by lithium chloride and SB-216763 pretreatment. The in vivo tumor growth study showed that DLX6-AS1 knockdown suppressed tumor growth of T24 cells and suppressed EMT and Wnt/β-catenin signaling in the tumor tissues. Conclusion Collectively, the present study for the first time identified the up-regulation of DLX6-AS1 in clinical bladder cancer tissues and in bladder cancer cell lines. The results from in vitro and in vivo assays implied that DLX6-AS1 exerted enhanced effects on bladder cancer cell proliferation, invasion and migration partly via modulating EMT and the activity of Wnt/β-catenin signaling pathway.

SOX10 induces epithelial–mesenchymal transition and contributes to nasopharyngeal carcinoma progression

2018 ◽  
Vol 96 (3) ◽  
pp. 326-331 ◽  
Author(s):  
Ping He ◽  
Xiaojie Jin
Keyword(s):  
Cell Proliferation ◽  
Nasopharyngeal Carcinoma ◽  
Cell Lines ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition

Objective: The aim of this study was to investigate the role of SOX10 in nasopharyngeal carcinoma (NPC) and the underlying molecular mechanisms. Methods: The expression of SOX10 was initially assessed in human NPC tissues and a series of NPC cell lines through quantitative real-time PCR (qRT-PCR) and Western blot. Then, cell proliferation, cycle, migration, and the invasiveness of NPC cells with knockdown of SOX10 were examined by MTT, flow cytometry, and Transwell migration and invasion assays, respectively. Finally, nude mice tumorigenicity experiments were performed to evaluate the effects of SOX10 on NPC growth and metastasis in vivo. Results: SOX10 was significantly increased in NPC tissues and cell lines. In-vitro experiments revealed that loss of SOX10 obviously inhibited cell proliferation, migration, and invasiveness, as well as the epithelial–mesenchymal transition (EMT) process in NPC cells. In-vivo experiments further demonstrated that disrupted SOX10 expression restrained NPC growth and metastasis, especially in lung and liver. Conclusion: Taken together, our data confirmed the role of SOX10 as an oncogene in NPC progression, and revealed that SOX10 may serve as a novel biomarker for diagnosis of NPC, as well as a potential therapeutic target against this disease.

scholarly journals Overexpression of Glypican 5 (GPC5) Inhibits Prostate Cancer Cell Proliferation and Invasion via Suppressing Sp1-Mediated EMT and Activation of Wnt/β-Catenin Signaling

2018 ◽  
Vol 26 (4) ◽  
pp. 565-572 ◽  
Author(s):  
Yu Sun ◽  
Kai Xu ◽  
Miao He ◽  
Guilian Fan ◽  
Hongming Lu
Keyword(s):  
Prostate Cancer ◽  
Cell Proliferation ◽  
Epithelial Mesenchymal Transition ◽  
Cancer Cell Proliferation ◽  
Mesenchymal Transition ◽  
The Family ◽  
Signaling Activation ◽  
Proliferation And Invasion

Glypican 5 (GPC5) belongs to the family of heparan sulfate proteoglycans (HSPGs). It was initially known as a regulator of growth factors and morphogens. Recently, there have been reports on its correlation with the tumorigenic process in the development of some cancers. However, little is known about its precise role in prostate cancer (PCa). In the present study, we explored the expression pattern and biological functions of GPC5 in PCa cells. Our results showed that GPC5 was lowly expressed in PCa cell lines. Upregulation of GPC5 significantly inhibited PCa cell proliferation and invasion in vitro as well as attenuated tumor growth in vivo. We also found that overexpression of GPC5 inhibited the epithelial‐mesenchymal transition (EMT) and Wnt/β-catenin signaling activation, which was mediated by Sp1. Taken together, we suggest GPC5 as a tumor suppressor in PCa and provide promising therapeutic strategies for PCa.

scholarly journals Endometrial PTEN Deficiency Leads to SMAD2/3 Nuclear Translocation

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4990
Author(s):  
Núria Eritja ◽  
Raúl Navaridas ◽  
Anna Ruiz-Mitjana ◽  
Maria Vidal-Sabanés ◽  
Joaquim Egea ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Nuclear Translocation ◽  
Tumor Promoter ◽  
In Vivo Model ◽  
Endometrial Cells ◽  
Genetic Ablation ◽  
Cellular Effects ◽  
Double Deletion

TGF-β has a dichotomous function, acting as tumor suppressor in premalignant cells but as a tumor promoter for cancerous cells. These contradictory functions of TGF-β are caused by different cellular contexts, including both intracellular and environmental determinants. The TGF-β/SMAD and the PI3K/PTEN/AKT signal transduction pathways have an important role in the regulation of epithelial cell homeostasis and perturbations in either of these two pathways’ contributions to endometrial carcinogenesis. We have previously demonstrated that both PTEN and SMAD2/3 display tumor-suppressive functions in the endometrium, and genetic ablation of either gene results in sustained activation of PI3K/AKT signaling that suppresses TGF-β-induced apoptosis and enhances cell proliferation of mouse endometrial cells. However, the molecular and cellular effects of PTEN deficiency on TGF-β SMAD2/3 signaling remain controversial. Here, using an in vitro and in vivo model of endometrial carcinogenesis, we have demonstrated that loss of PTEN leads to a constitutive SMAD2/3 nuclear translocation. To ascertain the function of nuclear SMAD2/3 downstream of PTEN deficiency, we analyzed the effects of double deletion PTEN and SMAD2/3 in mouse endometrial organoids. Double PTEN/SMAD2/3 ablation results in a further increase of cell proliferation and enlarged endometrial organoids compared to those harboring single PTEN, suggesting that nuclear translocation of SMAD2/3 constrains tumorigenesis induced by PTEN deficiency.

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