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 PD-L1 lncRNA splice promotes lung adenocarcinoma progression via enhancing c-Myc activity

2020 ◽  
Author(s):  
Shuang Qu ◽  
Zichen Jiao ◽  
Geng Lu ◽  
Bing Yao ◽  
Ting Wang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Great Promise ◽  
Non Coding Rna ◽  
Adenocarcinoma Cells ◽  
T Cell Immune Responses ◽  
Lung Adenocarcinoma Cells ◽  
Novel Strategy ◽  
L1 Protein

ABSTRACTAlthough blockade of programmed death-ligand 1 (PD-L1) to enhance T cell immune responses shows great promise in tumor immunotherapy, the efficacy of such immune-checkpoint inhibition strategy is limited for patients with solid tumors. The mechanism underlying the limited efficacy of PD-L1 inhibitors remains unclear. Here, we show that human lung adenocarcinoma, regardless of PD-L1 protein positive or negative, all produce a long non-coding RNA isoform of PD-L1 (PD-L1-lnc) via alternative splicing, which promotes lung adenocarcinoma proliferation and metastasis. PD-L1-lnc in various lung adenocarcinoma cells is significantly upregulated by IFNγ in a manner similar to PD-L1 mRNA. Both in vitro and in vivo studies demonstrate that PD-L1-lnc increases proliferation and invasion but decreases apoptosis of lung adenocarcinoma cells. Mechanistically, PD-L1-lnc directly binds to c-Myc and enhances c-Myc transcriptional activity downstream in lung adenocarcinoma cells. Our results provide targeting PD-L1-lnc−c-Myc axis as a novel strategy for lung cancer therapy.

LncRNA HCG18 contributes to the progression of hepatocellular carcinoma via miR-214-3p/CENPM axis

2020 ◽  
Vol 168 (5) ◽  
pp. 535-546 ◽  
Author(s):  
Yuepei Zou ◽  
Zhonghua Sun ◽  
Shuangming Sun
Keyword(s):  
Hepatocellular Carcinoma ◽  
Messenger Rna ◽  
Animal Experiments ◽  
Non Coding Rna ◽  
Diphenyltetrazolium Bromide ◽  
And Migration ◽  
Hcc Cells ◽  
Proliferation And Migration

Abstract Long non-coding RNA (lnc) HCG18 has been reported to contribute progression of a variety of tumours. However, its roles in hepatocellular carcinoma (HCC) remains unknown. In the current study, we intended to uncover the biological functions of HCG18 in HCC. Quantitative real-time polymerase chain reaction (qRT-PCR) was conducted to detect the expression of HCG18, microRNA-214-3p (miR-214-3p) and centromere protein M (CENPM) messenger RNA (mRNA). The role of HCG18 in the growth and migration were assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, colony formation assay, wound healing assay and flow cytometry in vitro and animal experiments in vivo. The results showed that HCG18 was highly expressed in HCC tissues. HCG18 silencing inhibited the proliferation and migration while induced the apoptosis of HCC cells. Besides, miR-214-3p was down-regulated in HCC cells. Further experiments revealed that miR-214-3p could directly bind to HCG18 and exerted an anti-tumour role to counteracted siHCG18-1-mediated influence in HCC cells. Moreover, miR-214-3p could directly interact with CENPM mRNA and down-regulating the expression of CENPM. While HCG18 could up-regulate the expression of CENPM through acting as a sponge of miR-214-3p. Therefore, those results suggested HCG18 functioned as an oncogene to promote the proliferation and migration of HCC cells via miR-214-3p/CENPM axis.

scholarly journals Kinesin Family Member 18A (KIF18A) Contributes to the Proliferation, Migration, and Invasion of Lung Adenocarcinoma Cells In Vitro and In Vivo

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Fu-Tao Chen ◽  
Fu-Kuan Zhong
Keyword(s):  
Tumor Growth ◽  
Lung Adenocarcinoma ◽  
Clinical Stage ◽  
Migration And Invasion ◽  
Expression Levels ◽  
Adenocarcinoma Cells ◽  
Lung Adenocarcinoma Cells ◽  
Tumor Growth And Metastasis

Objective. To determine the expression levels of KIF18A in lung adenocarcinoma and its relationship with the clinicopathologic features of patients undergoing radical colectomy and explore the potential role in the progression of lung adenocarcinoma. Methods. Immunohistochemical assays were performed to explore the expression levels of KIF18A in 82 samples of lung adenocarcinoma and corresponding normal tissues. According to the levels of KIF18A expression in lung adenocarcinoma tissue samples, patients were classified into the KIF18A high expression group and low expression group. Clinical data related to the perioperative clinical features (age, gender, smoking, tumor size, differentiation, clinical stage, and lymph node metastasis), the potential correlation between KIF18A expression levels, and clinical features were analyzed, and the effects of KIF18A on lung adenocarcinoma cell proliferation, migration, and invasion were measured by colony formation assay, MTT assay, wound healing assay, and transwell assays. The possible effects of KIF18A on tumor growth and metastasis were measured in mice through tumor growth and tumor metastasis assays in vivo. Results. KIF18A in lung adenocarcinoma tissues. Further, KIF18A was significantly associated to clinical characteristic features including the tumor size (P=0.033) and clinical stage (P=0.041) of patients with lung adenocarcinoma. Our data also investigated that KIF18A depletion dramatically impairs the proliferation, migration, and invasion capacity of lung adenocarcinoma cells in vitro and inhibits tumor growth and metastasis in mice. Conclusions. Our study reveals the involvement of KIF18A in the progression and metastasis of lung adenocarcinoma and provides a novel therapeutic target for the treatment of lung adenocarcinoma.

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 GPR87 Promotes Metastasis through the AKT-eNOS-NO Axis in Lung Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 19
Author(s):  
Hye-Mi Ahn ◽  
Eun-Young Choi ◽  
Youn-Jae Kim
Keyword(s):  
Lung Adenocarcinoma ◽  
Cancer Progression ◽  
The Public ◽  
Adenocarcinoma Cells ◽  
No Signaling ◽  
Tcga Dataset ◽  
Patient Prognosis

Lung adenocarcinoma is one of the leading causes of cancer-related deaths. Despite the availability of advanced anticancer drugs for lung cancer treatment, the prognosis of patients still remains poor. There is a need to explore novel oncogenic mechanisms to overcome these therapeutic limitations. The functional experiments in vitro and in vivo were performed to evaluate the role of GPR87 expression on lung adenocarcinoma metastasis. The public lung adenocarcinoma TCGA dataset was used to determine the clinical relevance of GPR87 expression in patients with lung adenocarcinoma. GPR87 is upregulated in various cancer; however, the biological function of GPR87 has not yet been established in lung adenocarcinoma. In this study, we found that GPR87 expression is upregulated in lung adenocarcinoma and is associated with poor patient prognosis. Additionally, we showed that GPR87 overexpression promotes invasiveness and metastasis of lung adenocarcinoma cells. Furthermore, we demonstrated that AKT-eNOS-NO signaling is a novel downstream pathway of GPR87 in lung adenocarcinoma. Conversely, we confirmed that silencing of GPR87 expression suppressed these phenotypes. Our results reveal the oncogenic function of GPR87 in cancer progression and metastasis through the activation of eNOS as a key mediator. Therefore, we propose that targeting eNOS could be a novel therapeutic strategy to improve the clinical treatment of lung adenocarcinoma.

scholarly journals C/EBPα Suppresses Lung Adenocarcinoma Cell Invasion and Migration by Inhibiting β-Catenin

2017 ◽  
Vol 42 (5) ◽  
pp. 1779-1788 ◽  
Author(s):  
Jinchang Lu ◽  
Chunling Du ◽  
Junxia Yao ◽  
Bo Wu ◽  
Yanhong Duan ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Lung Adenocarcinoma ◽  
Cell Invasion ◽  
Migration And Invasion ◽  
Adenocarcinoma Cell ◽  
Invasion And Migration ◽  
Adenocarcinoma Cells ◽  
Lung Adenocarcinoma Cells ◽  
And Migration

Background/Aims: The transcription factor CCAAT/enhancer-binding protein α (C/EBPα) is a basic leucine zipper transcription factor that plays essential roles in tumor progression. Although decreased or absent C/EBPα expression in many cancers suggests a possible role for C/EBPα as a tumor suppressor, the functions of C/EBPα in lung adenocarcinoma remain unclear. Methods: Here, C/EBPα expression levels in 26 lung adenocarcinoma and para-carcinoma tissue samples were detected by qRT-PCR and immunohistochemistry. Cell transwell assays, wound healing assay and three-dimensional spheroid invasion assay were performed to assess the effects of C/EBPα on migration and invasion in lung adenocarcinoma cells in vitro. Western blotting was applied to analyze the potential mechanisms. Results: C/EBPα was found to be decreased in lung adenocarcinoma tissues compared to para-carcinoma tissues. Overexpression of C/EBPα significantly inhibited the migration and invasion of lung adenocarcinoma cells. In addition, C/EBPα overexpression suppressed the epithelial–mesenchymal transition (EMT) that was characterized by a gain of epithelial and loss of mesenchymal markers. Further study showed that C/EBPα suppressed the transcription of β-catenin and downregulated the levels of its downstream targets. Conclusion: Our data suggest that C/EBPα inhibits lung adenocarcinoma cell invasion and migration by suppressing β-catenin-mediated EMT in vitro. Thus, C/EBPα may be helpful as a potential target for treatment of lung adenocarcinoma.

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.

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