scholarly journals BCAT1 Promotes Lung Adenocarcinoma Progression Through Enhanced Mitochondrial Respiration and NF-κB Pathway Activation

2021 ◽  
Author(s):  
Mengdan Yu ◽  
Qianwei Zhao ◽  
Jinxia Li ◽  
Fang Xu ◽  
Zhibiao Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Mitochondrial Respiration ◽  
Mrna Level ◽  
Metabolic Reprogramming ◽  
Sequencing Analysis ◽  
Pathway Activation ◽  
Local Lymph Node ◽  
And Migration

Abstract BCAT1 is up-regulated and acts as an oncogenic factor in many types of cancers, but its role in lung adenocarcinoma (LUAD) development is not clearly understood. Here we found BCAT1 protein level was up-regulated in tumor tissues, which was positively associated with TNM stage and local lymph node metastasis of LUAD patients. BCAT1 knockdown inhibited cell growth and mobility while BCAT1 overexpression promoted LUAD development both in vitro and in vivo. BCAAs metabolism and mitochondrial respiration were enhanced in BCAT1 overexpression cells, which were more sensitive to Leucine and Isoleucine supplements, compared to control cells. Moreover, RNA sequencing analysis suggested that differentially expressed genes (DEGs) in BCAT1 overexpression LUAD cells were enriched in metabolism, signal transduction, and immune response processes, and BCAT1 overexpression decreased NFKBIB mRNA level that induced NF-κB pathway activation in LUAD cells. As an inhibitor of NF-κB pathway, ammonium pyrrolidinedithiocarbamate (PDTC) treatment predominately counteracted the effect of NF-κB pathway activation and inhibited LUAD cells proliferation and migration, especially cells with BCAT1 overexpression. Taken together, our findings point a key role for BCAT1 in promoting LUAD development through metabolic reprogramming and NF-κB pathway activation, which provides promising molecular biomarker and therapeutic targets for LUAD diagnosis and treatment.

scholarly journals Inhibitory Effect of a Glutamine Antagonist on Proliferation and Migration of VSMCs via Simultaneous Attenuation of Glycolysis and Oxidative Phosphorylation

2021 ◽  
Vol 22 (11) ◽  
pp. 5602
Author(s):  
Hyeon Young Park ◽  
Mi-Jin Kim ◽  
Seunghyeong Lee ◽  
Jonghwa Jin ◽  
Sungwoo Lee ◽  
...  
Keyword(s):  
Mammalian Target Of Rapamycin ◽  
Inhibitory Effect ◽  
Metabolic Reprogramming ◽  
Neointima Formation ◽  
Artery Ligation ◽  
Carotid Artery Ligation ◽  
And Migration ◽  
Proliferation And Migration

Excessive proliferation and migration of vascular smooth muscle cells (VSMCs) contribute to the development of atherosclerosis and restenosis. Glycolysis and glutaminolysis are increased in rapidly proliferating VSMCs to support their increased energy requirements and biomass production. Thus, it is essential to develop new pharmacological tools that regulate metabolic reprogramming in VSMCs for treatment of atherosclerosis. The effects of 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist, have been broadly investigated in highly proliferative cells; however, it is unclear whether DON inhibits proliferation of VSMCs and neointima formation. Here, we investigated the effects of DON on neointima formation in vivo as well as proliferation and migration of VSMCs in vitro. DON simultaneously inhibited FBS- or PDGF-stimulated glycolysis and glutaminolysis as well as mammalian target of rapamycin complex I activity in growth factor-stimulated VSMCs, and thereby suppressed their proliferation and migration. Furthermore, a DON-derived prodrug, named JHU-083, significantly attenuated carotid artery ligation-induced neointima formation in mice. Our results suggest that treatment with a glutamine antagonist is a promising approach to prevent progression of atherosclerosis and restenosis.

scholarly journals The TWIST1-centered competing endogenous RNA network promotes proliferation, invasion, and migration of lung adenocarcinoma

Oncogenesis ◽  
2019 ◽  
Vol 8 (11) ◽  
Author(s):  
Wenjie Xia ◽  
Qixing Mao ◽  
Bing Chen ◽  
Lin Wang ◽  
Weidong Ma ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Migration And Invasion ◽  
Circular Rnas ◽  
Messenger Rnas ◽  
Competing Endogenous Rna ◽  
Invasion And Migration ◽  
Non Coding Rnas ◽  
And Migration

Abstract The proposed competing endogenous RNA (ceRNA) mechanism suggested that diverse RNA species, including protein-coding messenger RNAs and non-coding RNAs such as long non-coding RNAs, pseudogenes and circular RNAs could communicate with each other by competing for binding to shared microRNAs. The ceRNA network (ceRNET) is involved in tumor progression and has become a hot research topic in recent years. To date, more attention has been paid to the role of non-coding RNAs in ceRNA crosstalk. However, coding transcripts are more abundant and powerful than non-coding RNAs and make up the majority of miRNA targets. In this study, we constructed a mRNA-mRNA related ceRNET of lung adenocarcinoma (LUAD) and identified the highlighted TWIST1-centered ceRNET, which recruits SLC12A5 and ZFHX4 as its ceRNAs. We found that TWIST1/SLC12A5/ZFHX4 are all upregulated in LUAD and are associated with poorer prognosis. SLC12A5 and ZFHX4 facilitated proliferation, migration, and invasion in vivo and in vitro, and their effects were reversed by miR-194–3p and miR-514a-3p, respectively. We further verified that SLC12A5 and ZFHX4 affected the function of TWIST1 by acting as ceRNAs. In summary, we constructed a mRNA-mRNA related ceRNET for LUAD and highlighted the well-known oncogene TWIST1. Then we verified that SLC12A5 and ZFHX4 exert their oncogenic function by regulating TWIST1 expression through a ceRNA mechanism.

scholarly journals HER2 missense mutations have distinct effects on oncogenic signaling and migration

2015 ◽  
Vol 112 (45) ◽  
pp. E6205-E6214 ◽  
Author(s):  
Daniel J. Zabransky ◽  
Christopher L. Yankaskas ◽  
Rory L. Cochran ◽  
Hong Yuen Wong ◽  
Sarah Croessmann ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Missense Mutations ◽  
Breast Cancers ◽  
Oncogenic Signaling ◽  
Pathway Activation ◽  
And Migration ◽  
Endogenous Loci

Recurrent human epidermal growth factor receptor 2 (HER2) missense mutations have been reported in human cancers. These mutations occur primarily in the absence of HER2 gene amplification such that most HER2-mutant tumors are classified as “negative” by FISH or immunohistochemistry assays. It remains unclear whether nonamplified HER2 missense mutations are oncogenic and whether they are targets for HER2-directed therapies that are currently approved for the treatment of HER2 gene-amplified breast cancers. Here we functionally characterize HER2 kinase and extracellular domain mutations through gene editing of the endogenous loci in HER2 nonamplified human breast epithelial cells. In in vitro and in vivo assays, the majority of HER2 missense mutations do not impart detectable oncogenic changes. However, the HER2 V777L mutation increased biochemical pathway activation and, in the context of a PIK3CA mutation, enhanced migratory features in vitro. However, the V777L mutation did not alter in vivo tumorigenicity or sensitivity to HER2-directed therapies in proliferation assays. Our results suggest the oncogenicity and potential targeting of HER2 missense mutations should be considered in the context of cooperating genetic alterations and provide previously unidentified insights into functional analysis of HER2 mutations and strategies to target them.

scholarly journals Anti-Tumor Effects of Biomimetic Sulfated Glycosaminoglycans on Lung Adenocarcinoma Cells in 2D and 3D In Vitro Models

Molecules ◽  
2020 ◽  
Vol 25 (11) ◽  
pp. 2595
Author(s):  
Nada Al Matari ◽  
George Deeb ◽  
Hiba Mshiek ◽  
Ansam Sinjab ◽  
Humam Kadara ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
In Vitro Models ◽  
Trypan Blue Exclusion ◽  
Cell Functions ◽  
Adenocarcinoma Cells ◽  
Diphenyltetrazolium Bromide ◽  
And Migration ◽  
Sphere Formation

Lung cancer development relies on cell proliferation and migration, which in turn requires interaction with extracellular matrix (ECM) components such as glycosaminoglycans (GAGs). The mechanisms through which GAGs regulate cancer cell functions are not fully understood but they are, in part, mediated by controlled interactions with cytokines and growth factors (GFs). In order to mechanistically understand the effect of the degree of sulfation (DS) of GAGs on lung adenocarcinoma (LUAD) cells, we synthesized sulfated alginate (AlgSulf) as sulfated GAG mimics with DS = 0.0, 0.8, 2.0, and 2.7. Human (H1792) and mouse (MDA-F471) LUAD cell lines were treated with AlgSulf of various DSs at two concentrations 10 and 100 µg/mL and their anti-tumor properties were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), trypan blue exclusion, and wound healing assays for 2D models and sphere formation assay for the 3D model. The proliferation and number of live MDA-F471 cells at the concentration of 100 µg/mL decreased significantly with the increase in the DS of biomimetic GAGs. In addition, the increase in the DS of biomimetic GAGs decreased cell migration (p < 0.001 for DS = 2.0 and 2.7 compared to control) and decreased the diameter and number of spheres formed (p < 0.001). The increased DS of biomimetic GAGs attenuated the expression of cancer stem cell (CSC)/progenitor markers in the 3D cultures. In conclusion, GAG-mimetic AlgSulf with increased DS exhibit enhanced anti-proliferative and migratory properties while also reducing growth of KRAS-mutant LUAD spheres in vitro. We suggest that these anti-tumor effects by GAG-mimetic AlgSulf are possibly due to differential binding to GFs and consequential decreased cell stemness. AlgSulf may be suitable for applications in cancer therapy after further in vivo validation.

scholarly journals GRP75-upregulated HMGA1 Expression Promotes Stage I Lung Adenocarcinoma Progression by Activating the JNK/c-JUN Signaling Pathway

2020 ◽  
Author(s):  
Guo-Bing Qiao ◽  
Ren-Tao Wang ◽  
Shu-Nan Wang ◽  
Shaolin Tao ◽  
Qun-You Tan ◽  
...  
Keyword(s):  
Cell Growth ◽  
Lung Adenocarcinoma ◽  
Signaling Pathway ◽  
Early Stage ◽  
High Mobility ◽  
Stage I ◽  
Sequencing Analysis ◽  
Hmga1 Expression

Abstract Background: Recurrence is a major challenge in early-stage lung adenocarcinoma (LUAD) treatment. However, the recurrence mechanism is still unclear, and no biomarkers can predict recurrence in early-stage LUAD. Here, we investigated the role and mechanism of high-mobility group AT-hook 1 (HMGA1) and glucose-regulated protein 75-kDa (GRP75) in stage I LUAD and evaluated their potential as biomarkers for predicting the recurrence and prognosis of stage I LUAD.Methods: A TCGA dataset was used to investigate the clinical significance of HMGA1 and GRP75 in early-stage LUAD. Western blotting and immunohistochemistry were used to measure protein expression levels. The biological functions of HMGA1 and GRP75 in LUAD were investigated both in vitro and in vivo through overexpression and knockdown experiments. The interaction and regulation between HMGA1 and GRP75 were evaluated with coimmunoprecipitation and ubiquitination assays. The downstream signaling pathway of the GRP75/HMGA1 axis was investigated by mRNA-sequencing analysis.Results: High expression of HMGA1 and GRP75 was associated with recurrence and a poor prognosis in stage I LUAD patients. In particular, HMGA1 had potential as an independent prognostic factor. Overexpression of GRP75 or HMGA1 promoted LUAD cell growth and metastasis, while silencing GRP75 or HMGA1 inhibited LUAD cell growth and metastasis. In vitro and clinical data showed that the expression level of GRP75 positively regulated HMGA1 in LUAD and that GRP75 played an HMGA1-dependent role. In addition, GRP75 prolonged the half-life of HMGA1 by inhibiting HMGA1 ubiquitination via direct binding to HMGA1. Finally, we demonstrated that the GRP75/HMGA1 axis played a role by activating JNK/c-JUN signaling in LUAD.Conclusions: The activation of GRP75/HMGA1/JNK/c-JUN signaling is an important mechanism that promotes the progression of stage I LUAD, and a high level of HMGA1 is a novel biomarker for predicting recurrence and prognosis in patients with stage I LUAD.

ZNF280A Promotes Lung Adenocarcinoma Development through Regulating the Expression of EIF3C

2020 ◽  
Author(s):  
Hongsheng Liu ◽  
Yingzhi Qin ◽  
Na Zhou ◽  
Dongjie Ma ◽  
Yingyi Wang
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Small Cell Lung ◽  
Normal Tissues ◽  
Tumor Promotor ◽  
And Migration ◽  
First Time ◽  
The Relationship

Abstract Background: Lung cancer is the most commonly diagnosed malignant tumor worldwide. Lung adenocarcinoma (LUAD) is the most common histological subtype in non-small cell lung cancer (NSCLC). The relationship between ZNF280A and LUAD has not been demonstrated and remains unclear. Methods: In this study, it was demonstrated that ZNF280A was upregulated in LUAD tissues compared with the normal tissues. Further investigations indicated that the overexpression/knockdown of ZNF280A could promote/inhibit proliferation, colony formation and migration of LUAD cells, while inhibiting/promoting cell apoptosis. Moreover, knockdown of ZNF280A could also suppress tumorigenicity of LUAD cells in vivo. RNA-sequencing followed by Ingenuity pathway analysis (IPA) was performed for exploring downstream of ZNF280A and identified EIF3C as the potential target. Results: Furthermore, our study revealed that knockdown of EIF3C could inhibit development of LUAD in vitro, and alleviate the ZNF280A overexpression induced promotion of LUAD. Conclusions: In conclusion, our study showed, as the first time, ZNF280A as a tumor promotor for LUAD, whose function was carried out probably through the regulation of EIF3C.

scholarly journals ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation

2020 ◽  
Author(s):  
Hui-er Zhu ◽  
Tao Li ◽  
Shengnan Shi ◽  
De-xiong Chen ◽  
Weiping Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Nuclear Translocation ◽  
Lactate Production ◽  
Gene Set Enrichment Analysis ◽  
Metabolic Reprogramming ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion

Abstract Background: Emerging evidence indicates that metabolism reprogramming and abnormal acetylation modification play an important role in lung adenocarcinoma (LUAD) progression, although the mechanism is largely unknown. Methods: Here, we used three public databases (Oncomine, Gene Expression Omnibus [GEO], The Cancer Genome Atlas [TCGA]) to analyze ESCO2 (establishment of cohesion 1 homolog 2) expression in LUAD. The biological function of ESCO2 was studied using cell proliferation, colony formation, cell migration, and invasion assays in vitro, and mouse xenograft models in vivo. ESCO2 interacting proteins were searched using gene set enrichment analysis (GSEA) and mass spectrometry. Pyruvate kinase M1/2 (PKM) mRNA splicing assay was performed using RT-PCR together with restriction digestion. LUAD cell metabolism was studied using glucose uptake assays and lactate production. ESCO2 expression was significantly upregulated in LUAD tissues, and higher ESCO2 expression indicated worse prognosis for patients with LUAD. Results: We found that ESCO2 promoted LUAD cell proliferation and metastasis metabolic reprogramming in vitro and in vivo. Mechanistically, ESCO2 increased hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1) binding to the intronic sequences flanking exon 9 (EI9) of PKM mRNA by inhibiting hnRNPA1 nuclear translocation, eventually inhibiting PKM1 isoform formation and inducing PKM2 isoform formation. Conclusions: Our findings confirm that ESCO2 is a key factor in promoting LUAD malignant progression and suggest that it is a new target for treating LUAD.

scholarly journals ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Hui-er Zhu ◽  
Tao Li ◽  
Shengnan Shi ◽  
De-xiong Chen ◽  
Weiping Chen ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Nuclear Translocation ◽  
Lactate Production ◽  
Gene Set Enrichment Analysis ◽  
Metabolic Reprogramming ◽  
The Cancer Genome Atlas ◽  
Migration And Invasion

Abstract Background Emerging evidence indicates that metabolism reprogramming and abnormal acetylation modification play an important role in lung adenocarcinoma (LUAD) progression, although the mechanism is largely unknown. Methods Here, we used three public databases (Oncomine, Gene Expression Omnibus [GEO], The Cancer Genome Atlas [TCGA]) to analyze ESCO2 (establishment of cohesion 1 homolog 2) expression in LUAD. The biological function of ESCO2 was studiedusing cell proliferation, colony formation, cell migration, and invasion assays in vitro, and mouse xenograft models in vivo. ESCO2 interacting proteins were searched using gene set enrichment analysis (GSEA) and mass spectrometry. Pyruvate kinase M1/2 (PKM) mRNA splicing assay was performed using RT-PCR together with restriction digestion. LUAD cell metabolism was studied using glucose uptake assays and lactate production. ESCO2 expression was significantly upregulated in LUAD tissues, and higher ESCO2 expression indicated worse prognosis for patients with LUAD. Results We found that ESCO2 promoted LUAD cell proliferation and metastasis metabolic reprogramming in vitro and in vivo. Mechanistically, ESCO2 increased hnRNPA1 (heterogeneous nuclear ribonucleoprotein A1) binding to the intronic sequences flanking exon 9 (EI9) of PKM mRNA by inhibiting hnRNPA1 nuclear translocation, eventually inhibiting PKM1 isoform formation and inducing PKM2 isoform formation. Conclusions Our findings confirm that ESCO2 is a key factor in promoting LUAD malignant progression and suggest that it is a new target for treating LUAD.

scholarly journals TAMI-29. MULTIFACTORIAL UPREGULATION OF ID1 DRIVES DIPG INVASIVENESS AND IS THERAPEUTICALLY TARGETABLE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii219-ii219
Author(s):  
Viveka Nand Yadav ◽  
Micah K Harris ◽  
Stefanie Stallard ◽  
Rinette Woo ◽  
Robert Siddaway ◽  
...  
Keyword(s):  
Brain Regions ◽  
Normal Brain ◽  
Sequencing Analysis ◽  
Invasion And Migration ◽  
Mutational Status ◽  
Potential Strategy ◽  
Developing Mouse Brain ◽  
And Migration

Abstract Diffuse intrinsic pontine gliomas (DIPGs) are lethal brain tumors with no effective therapies other than radiation. Inhibitor of DNA binding (ID) proteins, key regulators of lineage commitment during embryogenesis, are implicated in tumorigenesis in multiple human cancers. Prior work showed that recurrent H3F3A and ACVR1 mutations increase ID1 expression in cultured astrocytes. However, this has not been validated in human DIPG. The regulation and targetability of ID1 in DIPG has not been explored either. Exome and transcriptome sequencing analysis of multi-focal DIPG tumors and normal brain tissue from autopsy (n=52) revealed that ID1 expression is significantly elevated in DIPG tissues. Higher ID1 expression correlates with reduced survival in DIPG patients and increased regional invasion in multi-focal autopsy samples. Analyses of developing mouse brain RNA/ChiP-Seq data revealed high ID1 expression and H3K27ac promoter binding in prenatal hind brain compared to all other prenatal and postnatal brain regions. ChIP-qPCR for H3K27ac and H3K27me3 revealed that ID1 gene regulatory regions are epigenetically poised for upregulation in DIPG tissues compared to normal brain, regardless of H3/ACVR1 mutational status. These data support that the developing pons is regionally poised for ID1 activation. Genetic (shRNA) ID1 knockdown in primary human H3.3K27M-DIPG cells (DIPG007) resulted in significantly reduced invasion and migration in vitro. Additionally, DIPG-ID1-KO cells showed improved sensitivity to radiation therapy. Phospho-kinase array analysis of DIPG cells revealed that Akt and WNK1 activity were significantly downregulated upon ID1 knockdown, which was previously shown in lung tumors. Treatment of DIPG007 cells with cannabidiol (CBD) reduced ID1 expression levels and viability/proliferation of DIPG cells in vitro. ID1 knockdown and CBD treatment studies in vivo are ongoing. In summary, our findings indicate that multifactorial (genetic and regional) epigenetic upregulation of ID1 drives DIPG invasiveness and targeting ID1 using CBD may be a potential strategy for the treatment of DIPGs.

Prognostic value of Mortalin correlates with roles in epithelial–mesenchymal transition and angiogenesis in lung adenocarcinoma

2021 ◽  
Author(s):  
Ziqi Meng ◽  
Rui Zhang ◽  
Xuwei Wu ◽  
Meihua Zhang ◽  
Songnan Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Malignant Phenotype ◽  
Poor Overall Survival ◽  
Mesenchymal Transition ◽  
In Vivo Experiments ◽  
And Migration

Abstract Mortalin is involved in the malignant phenotype of many cancers. However, the specific molecular mechanisms involving Mortalin in lung adenocarcinoma remain unclear. In this study, we showed that both Mortalin mRNA and protein are overexpressed in lung adenocarcinoma. In addition, Mortalin overexpression was positively-correlated with poor overall survival. In vitro experiments showed that Mortalin silencing inhibited the proliferation, colony formation, and migration abilities of A549 and H1299 cells. Mortalin promotes EMT progression, angiogenesis, and tumor progression by activating the Wnt/β-catenin signaling pathway In vivo experiments further confirmed that Mortalin promoted malignant progression of lung adenocarcinoma. Taken together, our data suggest that Mortalin represents an attractive prognostic marker and therapeutic target in lung adenocarcinoma patients.

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