scholarly journals Monoacylglycerol Lipase Knockdown Inhibits Cell Proliferation and Metastasis in Lung Adenocarcinoma

2020 ◽  
Vol 10 ◽  
Author(s):  
Hao Zhang ◽  
Wei Guo ◽  
Fan Zhang ◽  
Renda Li ◽  
Yang Zhou ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Tumor Progression ◽  
Cyclin B1 ◽  
Clinical Samples ◽  
Monoacylglycerol Lipase ◽  
Advanced Tumor ◽  
Potential Biomarker ◽  
Proliferation And Metastasis

Abnormal metabolism is one of the hallmarks of cancer cells. Monoacylglycerol lipase (MGLL), a key enzyme in lipid metabolism, has emerged as an important regulator of tumor progression. In this study, we aimed to characterize the role of MGLL in the development of lung adenocarcinoma (LUAD). To this end, we used tissue microarrays to evaluate the expression of MGLL in LUAD tissue and assessed whether the levels of this protein are correlated with clinicopathological characteristics of LUAD. We found that the expression of MGLL is higher in LUAD samples than that in adjacent non-tumor tissues. In addition, elevated MGLL expression was found to be associated with advanced tumor progression and poor prognosis in LUAD patients. Functional studies further demonstrated that stable short hairpin RNA (shRNA)-mediated knockdown of MGLL inhibits tumor proliferation and metastasis, both in vitro and in vivo, and mechanistically, our data indicate that MGLL regulates Cyclin D1 and Cyclin B1 in LUAD cells. Moreover, we found that knockdown of MGLL suppresses the expression of matrix metalloproteinase 14 (MMP14) in A549 and H322 cells, and in clinical samples, expression of MMP14 is significantly correlated with MGLL expression. Taken together, our results indicate that MGLL plays an oncogenic role in LUAD progression and metastasis and may serve as a potential biomarker for disease prognosis and as a target for the development of personalized therapies.

scholarly journals EphA2 super-enhancer promotes tumor progression by recruiting FOSL2 and TCF7L2 to activate the target gene EphA2

2021 ◽  
Vol 12 (3) ◽  
Author(s):  
Shuang Cui ◽  
Qiong Wu ◽  
Ming Liu ◽  
Mu Su ◽  
ShiYou Liu ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Tumor Cells ◽  
Target Gene ◽  
Super Enhancer ◽  
Proliferation And Metastasis ◽  
Active Transcription ◽  
Hct 116 ◽  
Large Clusters

AbstractSuper-enhancers or stretch enhancers (SEs) consist of large clusters of active transcription enhancers which promote the expression of critical genes that define cell identity during development and disease. However, the role of many super-enhancers in tumor cells remains unclear. This study aims to explore the function and mechanism of a new super-enhancer in various tumor cells. A new super-enhancer that exists in a variety of tumors named EphA2-Super-enhancer (EphA2-SE) was found using multiple databases and further identified. CRISPR/Cas9-mediated deletion of EphA2-SE results in the significant downregulation of its target gene EphA2. Mechanistically, we revealed that the core active region of EphA2-SE comprises E1 component enhancer, which recruits TCF7L2 and FOSL2 transcription factors to drive the expression of EphA2, induce cell proliferation and metastasis. Bioinformatics analysis of RNA-seq data and functional experiments in vitro illustrated that EphA2-SE deletion inhibited cell growth and metastasis by blocking PI3K/AKT and Wnt/β-catenin pathway in HeLa, HCT-116 and MCF-7 cells. Overexpression of EphA2 in EphA2-SE−/− clones rescued the effect of EphA2-SE deletion on proliferation and metastasis. Subsequent xenograft animal model revealed that EphA2-SE deletion suppressed tumor proliferation and survival in vivo. Taken together, these findings demonstrate that EphA2-SE plays an oncogenic role and promotes tumor progression in various tumors by recruiting FOSL2 and TCF7L2 to drive the expression of oncogene EphA2.

scholarly journals MiR-223 Promotes Tumor Progression via Targeting RhoB in Gastric Cancer

2022 ◽  
Vol 2022 ◽  
pp. 1-10
Author(s):  
You Hu ◽  
Bin Yi ◽  
Xin Chen ◽  
Lu Xu ◽  
Xiaojun Zhou ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Tumor Progression ◽  
Cancer Progression ◽  
Tumor Development ◽  
Migration And Invasion ◽  
Cellular Mechanisms ◽  
Borrmann Type ◽  
Potential Biomarker

Gastric cancer (GC) is among the most prevalent causes of cancer-related death globally. MiR-223 has been implicated in a variety of cellular mechanisms linked to cancer progression. However, the miR-223 expressions and its function in GC are unknown. We discovered that miR-223 expression was raised in GC tissues in comparison with nearby normal tissues in this investigation. Additionally, multiplied miR-223 expression was strongly linked with TNM stage ( p = 0.022 ), live metastasis ( p = 0.004 ),lymph node metastasis ( p = 0.004 ),and Borrmann type and was associated with an unfavorable prognostic for patients with GC. Furthermore, suppressing miR-223 significantly increased cell death and prevented cell migration and invasion in vitro. Additionally, miR-223 silencing decreased tumor development in vivo. Additionally, we discovered that miR-223 enhanced GC development by specifically targeting RhoB. In summary, our findings reveal that miR-223 increases tumor progression in GC by targeting RhoB, suggesting that it could serve to be a potential biomarker for the prediction of the disease.

REG4 as a novel biomarker of lung adenocarcinoma with mutated KRAS and TTF-1 low expression.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14541-e14541
Author(s):  
Hui Yu ◽  
Si Sun
Keyword(s):  
Lung Adenocarcinoma ◽  
Rna Sequencing ◽  
Underlying Mechanism ◽  
Clinical Samples ◽  
Cancer Center ◽  
Pcr Analysis ◽  
Cancer Pathogenesis ◽  
Low Expression

e14541 Background: Recent research has classified lung adenocarcinoma patients with KRAS mutation into three subtypes by co-occurring genetic events in TP53 (KP subgroup), STK11/LKB1 (KL subgroup) and CDKN2A/B inactivation coupled with low expression of the TTF-1 (KC subgroup). The aim of this study was to identify novel biomarkers through searching the candidate molecules that contributing to lung adenocarcinoma pathogenesis, especially KC subtype. Methods: We analyzed the publicly available database and identified the candidate REG4 using the E-GEOD-31210 dataset, and then confirmed by TCGA dataset. In addition, an independent cohort of 55 clinical samples was analyzed by quantitative real-time PCR analysis. Functional studies and RNA sequencing were performed after the silencing REG4 expression. Results: REG4, an important regulator of gastro-intestinal carcinogenesis, was highly expressed in KRAS mutated lung adenocarcinoma with low expression of TTF-1 (KC subtype). The results were validated both by gene expression analysis and immunohistochemistry study in an independent 55 clinical samples from Fudan University Shanghai Cancer Center. Further in vitro and in vivo functional assays revealed silencing REG4 expression significantly reduce cancer cell proliferation and tumorigenesis. Moreover, RNA sequencing and GSEA analysis displayed that REG4 knockdown might induce the cell cycle arrest by regulating G2/M checkpoint and E2F targets. Conclusions: Our results indicate that REG4 plays an important role in KRAS-driven lung cancer pathogenesis and is a novel biomarker of lung adenocarcinoma subtype. Future studies are required to clarify the underlying mechanism of REG4 in the division and proliferation of KC tumors and its potential therapeutic value.

Lactate Secreted by PKM2 Upregulation Promotes Galectin-9-Mediated Immunosuppression via Inhibiting NF-κB Pathway in HNSCC

2020 ◽  
Author(s):  
Hanyue Chang ◽  
Qiaoshi Xu ◽  
Jiayi Li ◽  
Mingyu Li ◽  
Zhiyuan Zhang ◽  
...  
Keyword(s):  
Tumor Progression ◽  
Critical Role ◽  
Lactate Production ◽  
Migration And Invasion ◽  
The Novel ◽  
Proliferation And Metastasis ◽  
Lactate Transporter ◽  
Rate Limiting

Abstract Background: Pyruvate kinase M2 (PKM2) is a key rate-limiting enzyme in glycolysis, and which plays a critical role in tumor progression in various malignancies. However, whether PKM2 can promote head and neck squamous cell carcinoma (HNSCC) progression and immunosuppression remains unknown. Methods: PKM2 expression was evaluated using immunohistochemical staining. The biological functions of PKM2 were investigated in vitro and in vivo. Lactate production and the expression of galectin-9, a critical immunosuppression molecule, were detected after PKM2 knockdown and overexpression in HNSCC cells. Results: Overexpression of PKM2 correlates with poor prognosis in HNSCC patients. Silencing PKM2 markedly inhibits proliferation and metastasis capacity in vivo and in vitro, and vice versa. Furthermore, lactate production induced by PKM2 significantly promotes migration and invasion. A positive correlation between PKM2 and galectin-9 expression is observed in HNSCC tissues. Finally, the induction of galectin-9 expression by PKM2 can be affected by a lactate transporter inhibitor.Conclusion: Our findings demonstrate that PKM2 promotes tumor progression and galectin-9-mediated immunosuppression via NF-κB signaling inhibition in HNSCC, which bridges metabolism and immunosuppression. The novel PKM2-lactate-galectin-9 axis might be a potential therapeutic target in HNSCC.

scholarly journals ALCAP2 inhibits lung adenocarcinoma cell proliferation, migration and invasion via the ubiquitination of β-catenin by upregulating the E3 ligase NEDD4L

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Weijie Zhang ◽  
Ruochen Zhang ◽  
Yuanyuan Zeng ◽  
Yue Li ◽  
Yikun Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Nuclear Translocation ◽  
E3 Ligase ◽  
Migration And Invasion ◽  
Drug Candidate ◽  
Proliferation And Metastasis

AbstractLung cancer is recognized as the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) being the predominant subtype, accounting for approximately 85% of lung cancer cases. Although great efforts have been made to treat lung cancer, no proven method has been found thus far. Considering β, β-dimethyl-acryl-alkannin (ALCAP2), a natural small-molecule compound isolated from the root of Lithospermum erythrorhizon. We found that lung adenocarcinoma (LUAD) cell proliferation and metastasis can be significantly inhibited after treatment with ALCAP2 in vitro, as it can induce cell apoptosis and arrest the cell cycle. ALCAP2 also significantly suppressed the volume of tumours in mice without inducing obvious toxicity in vivo. Mechanistically, we revealed that ALCAP2-treated cells can suppress the nuclear translocation of β-catenin by upregulating the E3 ligase NEDD4L, facilitating the binding of ubiquitin to β-catenin and eventually affecting the wnt-triggered transcription of genes such as survivin, cyclin D1, and MMP9. As a result, our findings suggest that targeting the oncogene β-catenin with ALCAP2 can inhibit the proliferation and metastasis of LUAD cells, and therefore, ALCAP2 may be a new drug candidate for use in LUAD therapeutics.

scholarly journals The intrinsic role and mechanism of tumor expressed-CD38 on lung adenocarcinoma progression

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Long Gao ◽  
Yuan Liu ◽  
Xiaohong Du ◽  
Sai Ma ◽  
Minmin Ge ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Enzymatic Activity ◽  
Lung Adenocarcinoma ◽  
Tumor Progression ◽  
Cancer Cells ◽  
Lung Cancer Cells ◽  
In Vitro Assays ◽  
Knock Out

AbstractIt has been recently reported that CD38 expressed on tumor cells of multiple murine and human origins could be upregulated in response to PD-L1 antibody therapy, which led to dysfunction of tumor-infiltrating CD8+ T immune cells due to increasing the production of adenosine. However, the role of tumor expressed-CD38 on neoplastic formation and progression remains elusive. In the present study, we aimed to delineate the molecular and biochemical function of the tumor-associated CD38 in lung adenocarcinoma progression. Our clinical data showed that the upregulation of tumor-originated CD38 was correlated with poor survival of lung cancer patients. Using multiple in vitro assays we found that the enzymatic activity of tumor expressed-CD38 facilitated lung cancer cell migration, proliferation, colony formation, and tumor development. Consistently, our in vivo results showed that inhibition of the enzymatic activity or antagonizing the enzymatic product of CD38 resulted in the similar inhibition of tumor proliferation and metastasis as CD38 gene knock-out or mutation. At biochemical level, we further identified that cADPR, the mainly hydrolytic product of CD38, was responsible for inducing the opening of TRPM2 iron channel leading to the influx of intracellular Ca2+ and then led to increasing levels of NRF2 while decreasing expression of KEAP1 in lung cancer cells. These findings suggested that malignant lung cancer cells were capable of using cADPR catalyzed by CD38 to facilitate tumor progression, and blocking the enzymatic activity of CD38 could be represented as an important strategy for preventing tumor progression.

scholarly journals Upregulated Collagen COL10A1 Remodels the Extracellular Matrix and Promotes Malignant Progression in Lung Adenocarcinoma

2020 ◽  
Vol 10 ◽  
Author(s):  
Yingkuan Liang ◽  
Wenjie Xia ◽  
Te Zhang ◽  
Bing Chen ◽  
Hui Wang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Lung Adenocarcinoma ◽  
Tumor Progression ◽  
Expression Profiles ◽  
Ectopic Expression ◽  
Loss Of Function ◽  
Mechanism Study ◽  
Cell Progression

Collagens are major components of the ECM in various organs, including the lungs. Ectopic expression of collagens can regulate the tumor progression and disease outcome through remodeling of the extracellular matrix (ECM). However, it remains largely unexplored whether collagens are involved in the tumor progression of lung adenocarcinoma (LUAD). Analysis of three LUAD transcriptional expression profiles showed that COL10A1 mRNA expression was up-regulated and associated with poor prognosis. Gain- and loss-of-function studies were performed to observe that up-regulated COL10A1 promotes LUAD cell proliferation and invasion in vitro and in vivo. In molecular mechanism study, we found that COL10A1 interacts with DDR2 and affects the downstream FAK signaling pathway to regulate LUAD cell progression. The expression of COL10A1 on tissue microarray (TMA) was also measured to explore the association between COL10A1 expression and patient outcome. The results addressed that COL10A1 is up-regulated and positively correlated with lymph node metastasis in lung adenocarcinoma, and the COL10A1 expression is also an independent prognostic factor. In summary, the up-regulated COL10A1 remodels the ECM and the COL10A1/DDR2/FAK axis regulates the proliferation and metastasis of LUAD cells, implying that COL10A1 is a promising therapeutic target and prognostic marker for LUAD patients.

scholarly journals Hypoxic tumor-derived exosomal miR-31-5p promotes lung adenocarcinoma metastasis by negatively regulating SATB2-reversed EMT and activating MEK/ERK signaling

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Fengqiang Yu ◽  
Mingqiang Liang ◽  
Yu Huang ◽  
Weidong Wu ◽  
Bin Zheng ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Tumor Progression ◽  
Epithelial Mesenchymal Transition ◽  
Biological Effects ◽  
Erk Signaling ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Exosomal Mirna

Abstract Background Exosomes have emerged as critical mediators of intercellular communication. Hypoxia is widely recognized as a key regulator of tumor aggressiveness, and significantly affects exosome release by tumor cells. However, the effects of exosomes derived from hypoxic lung adenocarcinoma (LUAD) cells are poorly understood. Methods Samples of miRNA isolated from hypoxic LUAD cell-derived exosomes (HExo) and normoxic LUAD cell-derived exosomes (NExo) were sequenced to identify miRNAs that might mediate tumor progression. Exosomal miRNA was co-cultured with LUAD cells to assess its biological effects on cell migration and metastasis both in vitro and in vivo. The cellular target of exosomal miRNA was confirmed by dual-luciferase assays. Western blot studies showed that exosomal miRNA regulated the related pathway. The availability of circulating exosomal miRNA derived from plasma was also evaluated. Results We found that HExo could significantly enhance the migration and invasion of normoxic LUAD cells. MiRNA sequencing results suggested that miR-31-5p was largely internalized within HExo and could be taken up by normoxic LUAD cells. Exosomal miR-31-5p was found to directly target Special AT-Rich Sequence-Binding Protein 2 (SATB2)-revered epithelial mesenchymal transition and significantly increase activation of MEK/ERK signaling, thereby contributing to tumor progression both in vitro and in vivo. Furthermore, higher levels of circulating exosomal miR-31-5p were detected in LUAD patients, especially in patients with metastatic disease. Conclusions Our findings demonstrate that exosomal miR-31-5p exerts a crucial role in LUAD progression, and could serve as a diagnostic biomarker for LUAD.

scholarly journals KRT23 Acts as an Oncogene in Hepatocellular Carcinoma by Regulating P21 via PI3K/AKT/GSK3β Pathway

2020 ◽  
Author(s):  
Dan Guo ◽  
Wenhui Ma ◽  
Ruhua Wang ◽  
Yarui Li ◽  
Abu Taiub mohammed Mohiuddin Chowdhury ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Proliferation ◽  
Western Blot ◽  
Cell Lines ◽  
Mutual Effect ◽  
Scratch Test ◽  
Potential Biomarker ◽  
Proliferation And Metastasis

Abstract Background:Hepatocellular carcinoma (HCC) is a leading cancer worldwide for which diagnosis, treatment and progression are largely unknown. Keratin23 is a potential biomarker forHCC development; however, regulatory mechanisms underlying its expression remain unclear. Inthis research we explored the expression and effect of KRT23 underlying HCC development. Materials and methods:GEPIA was applied to analyze the expression of KRT23 in HCC samples and Kaplan-Merier survival analysis for patients’ prognosis. Next, IHC was further conducted for confirming its expression in HCC tissues. Meanwhile qRT-PCR and western blot analysis were applied to examine the expression of KRT23 on both mRNA and protein level in HCC cell lines compared with immortal hepatocyte LO2. Cell experiments including MTT assay, apoptosis analysis, cell cycle assay and clone formation assay were conducted for cell proliferation while transwell assay and scratch test for metastasis in vitro. Moreover, xenograft tumors in nude mice were further conducted for verification in vivo. As for mechanism in depth, immunofluorescence and western blot were operated to explore the effect of KRT23 on EMT and PI3K/AKT/GSK3βsignaling pathway. Furthermore, Co-immunoprecipitation was applied for interaction between KRT23 and P21. Functional rescue experiments were conducted to further testify their mutual effect.Results:For this research, we discovered the high expression of KRT23 in HCC samples and cell lines. Functionally, KRT23 knockdown reduced cell proliferation and metastasis in vitro and vivo. Furthermore, KRT23 participated in EMT progression and interacted with P21 to mediate PI3K/AKT/GSK3βpathway in HCC development.Conclusion:To summarize, KRT23 accelerated HCC proliferation and metastasis by regulating P21 via PI3K/AKT/GSK3βpathway.

scholarly journals MiR-124-3p/ZC3H15 Regulates Gastric Cancer Progression by Blocking FBXW7 Mediated Degradation of c-Myc

2020 ◽  
Author(s):  
Jianbing Hou ◽  
Yudong Liu ◽  
Du Yan ◽  
Pan Huang ◽  
Zhongze Wang ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Progression ◽  
Biological Role ◽  
Potential Biomarker ◽  
Proliferation And Metastasis ◽  
Gastric Cancer Progression ◽  
Cell Proliferation And Metastasis

Abstract BACKGROUND: Zinc finger CCCH-type containing 15 (ZC3H15), a highly conserved eukaryotic protein, was involved in tumorigenesis and may be a potential biomarker in hepatocellular carcinoma (HCC) and acute myeloid leukemia (AML). However, the biological role of ZC3H15 in gastric cancer (GC) is unclear.METHODS: The potential correlation between ZC3H15 expression and GC prognosis was assessed based on the patient data analysis. The biological role of ZC3H15 in regulating cell proliferation and metastasis was evaluated in vitro and in vivo. In addition, the potential mechanism of ZC3H15 was investigated. RESULTS: we found that ZC3H15 expression was positively correlated with GC progression, including cell growth, metastasis and cancerogenesis. Through further investigations, we found that ZC3H15 could modulate c-Myc protein stability via suppressing the transcription of FBXW7, which was mainly responsible for c-Myc degradation. In addition, we revealed that miR-124-3p, a tumor suppressor of GC, was negatively associated with ZC3H15. We revealed that miR-124-3p was a critical upstream modulator of ZC3H15 in GC.CONCLUSIONS: Taken together, our studies unearth the important roles of ZC3H15 in GC development and suggest that miR-124-3p/ZC3H15/c-Myc axis may be a potential target for the treatment of GC.

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