scholarly journals MUC3A Promotes Non-Small Cell Lung Cancer Progress via Activating NFκB Pathway and Attenuates Radiosensitivity

2020 ◽  
Author(s):  
Yingming Sun ◽  
Xiaoge Sun ◽  
Chengcheng You ◽  
Shijing Ma ◽  
Yuan Luo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Clinical Outcomes ◽  
Nuclear Translocation ◽  
Xenograft Model ◽  
High Expression ◽  
G1 Arrest ◽  
Nfκb Pathway

Abstract Background: MUC3A is highly expressed in lung adenocarcinoma, but its functions and effects on clinical outcomes are not well understood.Methods: Tissue microarray was used to analysis the relathionship between MUC3A and clinicalpathological charcristics of lung adenocarcinoma; Colony formation and MTT array ware used to detect cell proliferation; WB applied to investigate the protein amount; Transwell was applied to evaluate cell invasion; IF was used to observe the location and expression of targeted proteins; IP was use to prove the binding of proteins. Mcherry-GFP-LC3 II adenovirus and TEM were performed to observe cell autophagy. Xnograft mouse model were used to investigate the effect of MUC3A in vivo.Result: 92 patients’ tumor samples indicated that high expression of MUC3A was associated with poor prognosis, advanced staging, and low differentiation. Co-immunoprecipitation results revealed that MUC3A interacted with RELA. MUC3A activated the NFκB pathway via promoting RELA phosphorylation and interfering the binding of RELA to IκB. MUC3A knockdown significantly suppressed cell proliferation and induced G1 arrest. MUC3A deficiency increased radiation-induced DNA double strain breaks via impairing the BRCA-1/RAD51 pathway and nuclear translocation of P53 and XCRR6. Moreover, MUC3A deficiency induced autophagy in lung cancer cells. MUC3A knockdown significantly suppressed tumor growth in xenograft model and had a synergistic effect with radiation. Less nuclear translocation of RELA and P53 was also observed in tumor tissue in vivo.Conclusion: MUC3A was a potential oncogene, and its high expression was associated with unfavorable clinical outcomes. Patient with high expression of MUC3A should be more frequent follow-up and might benefit less from radiotherapy.

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 Oxymatrine Attenuates Tumor Growth and Deactivates STAT5 Signaling in a Lung Cancer Xenograft Model

Cancers ◽  
2019 ◽  
Vol 11 (1) ◽  
pp. 49 ◽  
Author(s):  
Young Yun Jung ◽  
Muthu K. Shanmugam ◽  
Acharan S. Narula ◽  
Chulwon Kim ◽  
Jong Hyun Lee ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Mouse Model ◽  
A549 Cells ◽  
Xenograft Model ◽  
Signaling Cascade ◽  
Anticancer Effects ◽  
Anti Cancer

Oxymatrine (OMT) is a major alkaloid found in radix Sophorae flavescentis extract and has been reported to exhibit various pharmacological activities. We elucidated the detailed molecular mechanism(s) underlying the therapeutic actions of OMT in non-small cell lung cancer (NSCLC) cells and a xenograft mouse model. Because the STAT5 signaling cascade has a significant role in regulating cell proliferation and survival in tumor cells, we hypothesized that OMT may disrupt this signaling cascade to exert its anticancer effects. We found that OMT can inhibit the constitutive activation of STAT5 by suppressing the activation of JAK1/2 and c-Src, nuclear localization, as well as STAT5 binding to DNA in A549 cells and abrogated IL-6-induced STAT5 phosphorylation in H1299 cells. We also report that a sub-optimal concentration of OMT when used in combination with a low dose of paclitaxel produced significant anti-cancer effects by inhibiting cell proliferation and causing substantial apoptosis. In a preclinical lung cancer mouse model, OMT when used in combination with paclitaxel produced a significant reduction in tumor volume. These results suggest that OMT in combination with paclitaxel can cause an attenuation of lung cancer growth both in vitro and in vivo.

Effect of MDV3100, a novel androgen receptor signaling inhibitor, on cell proliferation and tumor size in an apocrine breast cancer xenograft model.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3072-3072 ◽  
Author(s):  
Sebastián Bernales ◽  
Javier Guerrero ◽  
Francisco Gómez ◽  
Iván E. Alfaro ◽  
Andrew A Protter
Keyword(s):  
Breast Cancer ◽  
Cell Proliferation ◽  
Androgen Receptor ◽  
Tumor Size ◽  
Fatty Acid Synthase ◽  
Nuclear Translocation ◽  
Xenograft Model ◽  
Therapeutic Effects ◽  
Mouse Xenograft Model

3072 Background: MDV3100, a new androgen receptor (AR) signaling inhibitor, has demonstrated therapeutic effects in men with post-docetaxel prostate cancer (AFFIRM). AR is also expressed in the majority of breast cancers. Molecular profiling of estrogen receptor negative (ER-) breast cancer classifies this disease into basal and molecular apocrine subtypes. Apocrine breast cancer represents ~50% of ER- tumors and is characterized by a steroid response gene signature that includes AR expression. Here we report the effects of MDV3100 on the growth of the ER-/AR+ breast cancer cell line MDA-MB-453 in tissue culture and in an in vivo xenograft mouse model. Methods: MDA-MB-453 cells were maintained in 5% complete or 5% charcoal-stripped serum supplemented with dihydrotestosterone (CSS-DHT). The DHT induced nuclear translocation of AR was determined by subcellular fractionation followed by western blot. AR target gene expression was measured by qPCR. To generate a mouse xenograft model, 5-6 wk old female NOD-SCID-IL2Rgc–/– mice were injected ortotopically with 6x106 MDA-MB-453 cells into the fourth inguinal gland and were administered exogenous DHT (12.5 mg in a 60 day release pellet) or control pellets. When tumor size reached 100 mm3, mice were treated with 10 mg/kg/day MDV3100 or vehicle (0.5% methocel solution) by oral gavage for 33 days. Results: Viability of MDA-MB-453 cells treated with 10 uM MDV3100 was reduced by 10% after 3 days and 27% after 6 days. Treatment with 25 uM MDV3100 reduced cell viability by 27% after 3 days and 36% after 6 days. Similar results were obtained when cells maintained in CSS-DHT were treated with MDV3100. Treatment with MDV3100 blocked DHT-induced nuclear translocation and concordantly reduced the expression of AR-targets fatty acid synthase, prolactin receptor, and gross cystic disease protein-15. In the xenograft model, MDV3100 inhibited tumor growth by 78% as compared to tumors treated with vehicle. Conclusions: MDV3100 reduced cell proliferation in apocrine cell lines. MDV3100 also suppressed exogenous DHT-induced growth of ER-/AR+ tumors in vivo. These results support the evaluation of MDV3100 as a treatment for apocrine tumors.

scholarly journals Magnolol Inhibits the Growth of Non-Small Cell Lung Cancer via Inhibiting Microtubule Polymerization

2017 ◽  
Vol 42 (5) ◽  
pp. 1789-1801 ◽  
Author(s):  
Jia Shen ◽  
Hailin Ma ◽  
Tiancheng Zhang ◽  
Hui Liu ◽  
Linghua Yu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Cycle ◽  
Cell Proliferation ◽  
Colony Formation ◽  
Xenograft Model ◽  
Small Cell ◽  
Cell Cycle Regulators ◽  
Small Cell Lung ◽  
Microtubule Polymerization

Background: The tubulin/microtubule system, which is an integral component of the cytoskeleton, plays an essential role in mitosis. Targeting mitotic progression by disturbing microtubule dynamics is a rational strategy for cancer treatment. Methods: Microtubule polymerization assay was performed to examine the effect of Magnolol (a novel natural phenolic compound isolated from Magnolia obovata) on cellular microtubule polymerization in human non-small cell lung cancer (NSCLC) cells. Cell cycle analysis, mitotic index assay, cell proliferation assay, colony formation assay, western blotting analysis of cell cycle regulators, Annexin V-FITC/PI staining, and live/dead viability staining were carried out to investigate the Magnolol’s inhibitory effect on proliferation and viability of NSCLS cells in vitro. Xenograft model of human A549 NSCLC tumor was used to determine the Magnolol’s efficacy in vivo. Results: Magnolol treatment effectively inhibited cell proliferation and colony formation of NSCLC cells. Further study proved that Magnolol induced the mitotic phase arrest and inhibited G2/M progression in a dose-dependent manner, which were mechanistically associated with expression alteration of a series of cell cycle regulators. Furthermore, Magnolol treatment disrupted the cellular microtubule organization via inhibiting the polymerization of microtubule. We also found treatment with NSCLC cells with Magnolol resulted in apoptosis activation through a p53-independent pathway, and autophgy induction via down-regulation of the Akt/mTOR pathway. Finally, Magnolol treatment significantly suppressed the NSCLC tumor growth in mouse xenograft model in vivo. Conclusion: These findings identify Magnolol as a promising candidate with anti-microtubule polymerization activity for NSCLC treatment.

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 C1GALT1, Negatively Regulated by miR-181d-5p, Promotes Tumor Progression via Upregulating RAC1 in Lung Adenocarcinoma

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaoxia Dong ◽  
Yongyu Liu ◽  
Xinzhou Deng ◽  
Jun Shao ◽  
Shuangyue Tian ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Bioinformatic Analysis ◽  
Tumor Formation ◽  
Negative Regulator ◽  
Migration And Invasion ◽  
Loss Of Function

Glycosyltransferases are frequently dysregulated in lung cancer. Core 1 β 1, 3-galactosyltransferase 1 (C1GALT1), an enzyme highly expressed in various cancers, is correlated with tumor initiation and development. However, the role of C1GALT1 in lung cancer remains poorly understood. In this study, through bioinformatic analysis and clinical validation, we first discovered that C1GALT1 expression was upregulated in lung adenocarcinoma (LUAD) tissues and was closely related to poor prognosis in patients with LUAD. Gain- and loss-of-function experiments showed that C1GALT1 promoted LUAD cell proliferation, migration, and invasion in vitro, as well as tumor formation in vivo. Further investigation demonstrated that RAC1 expression was positively regulated by C1GALT1 in LUAD, whereas silencing Rac1 could reverse C1GALT1-induced tumor growth and metastasis. Moreover, miR-181d-5p was identified as a negative regulator for C1GALT1 in LUAD. As expected, the inhibitory effects of miR-181d-5p on LUAD cell proliferation, migration, and invasion were counteracted by restoration of C1GALT1. In summary, our results highlight the importance of the miR-181d-5p/C1GALT1/RAC1 regulatory axis during LUAD progression. Thus, C1GALT1 may serve as a potential therapeutic target for LUAD.

scholarly journals Human Schlafen 5 Inhibits Proliferation and Promotes Apoptosis in Lung Adenocarcinoma via the PTEN/PI3K/AKT/mTOR Pathway

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Xuefeng Gu ◽  
Li Zhou ◽  
Lei Chen ◽  
Huiqing Pan ◽  
Rui Zhao ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lung Adenocarcinoma ◽  
Signaling Pathway ◽  
Xenograft Model ◽  
Immunohistochemical Analysis ◽  
Mtor Pathway ◽  
Protein Levels ◽  
Mouse Xenograft Model

Background. Human Schlafen 5 (SLFN5) is reported to inhibit or promote the proliferation of several specific types of cancer cells by our lab and other researchers. We are curious about its implications in lung adenocarcinoma (LUAC), a malignant tumor with a high incidence rate and high mortality. Method. Lentiviral stable transfections of SLFN5-specific shRNA for knockdown and SLFN5 full-length coding sequence for overexpression were performed in LUAC cell for proliferation analysis in vitro and in vivo in nude mice. Clinical LUAC samples were collected for immunohistochemical analysis of SLFN5 protein levels. Results. We found that knockdown of endogenous SLFN5 upregulates cancer cell proliferation while inhibiting apoptosis. Besides, SLFN5 inhibition on proliferation was also observed in a nude mouse xenograft model. In contrast, overexpression of exogenous SLFN5 inhibited cell proliferation in vitro and in vivo and promoted apoptosis. As to the signaling pathway, we found phosphatase and tensin homolog on chromosome 10 (PTEN) was positively regulated by SLFN5, while its downstream signaling pathway AKT/mammalian target of rapamycin (mTOR) was inhibited. Moreover, compared with adjacent normal tissues, SLFN5 protein levels were markedly decreased in lung adenocarcinoma tissues. In conclusion, these suggest that human SLFN5 plays inhibitory roles in LUAC progression through the PTEN/PI3K/AKT/mTOR pathway, providing a potential target for developing drugs for lung cancer therapy in the future.

scholarly journals ESCO2 promotes lung adenocarcinoma progression by regulating hnRNPA1 acetylation

2021 ◽  
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 Zebrafish xenograft model of human lung cancer for studying the function of LINC00152 in cell proliferation and invasion

2020 ◽  
Author(s):  
Wenyi Shen ◽  
Juan Pu ◽  
Jing Sun ◽  
Bing Tan ◽  
Wei Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Cultured Cells ◽  
Human Cancer ◽  
Noncoding Rnas ◽  
Xenograft Model ◽  
Long Noncoding Rnas ◽  
Proliferation And Invasion

Abstract Background: Numerous studies have shown that long noncoding RNAs play important roles in human cancer progression. Although zebrafish xenografts have recently become a novel in vivo model for human cancer research, whether such models can be used to study the function of long noncoding RNAs remains unknown. Methods: In vitro studies validated the roles of LINC00152 in the proliferation and invasion of lung cancer cells. In vivo studies of zebrafish xenografts also confirmed these roles of LINC00152. In vivo confocal imaging was used to more accurately evaluate the function of LINC00152 in cell proliferation and migration. Pharmacological experiments were further performed to study the potential ability of LINC00152 downregulation combined with an EGFR inhibitor to treat tumors in cultured cells and the zebrafish xenograft model. Results: Silencing of LINC00152 suppressed cell proliferation and invasion in SPCA1 and A549 lung cancer cell lines in vitro . In the zebrafish xenograft model, knockdown of LINC00152 reduced the proliferation and migration of lung cancer cells, as indicated by the two imaging methods at different magnifications. Moreover, the knockdown of LINC00152 enhanced the inhibition effect of afatinib for lung cancer progression in cultured cells and the zebrafish xenograft model. Conclusion: Our study reveals the oncogenic roles and potential for LINC00152 to be a target for tumor treatment in lung cancer using zebrafish xenograft models, and the findings suggest that this model could be used for functional and application studies of human long noncoding RNAs in tumor biology.

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