Down Regulation of the Expression of ELMO3 by COX2 Inhibitor Suppresses Tumor Growth and Metastasis in Non-Small-Cell Lung Cancer

Pan, Cailong; Zhang, Yong; Meng, Qingcai; Dai, Guoliang; Jiang, Zhitao; Bao, Huihui

doi:10.3389/fonc.2019.00363

Cited by 17 publications

(11 citation statements)

References 19 publications

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“…COX2/PGE 2 pathway is associated with tumor EMT and metastasis. Inhibition of COX2/PGE 2 pathway can effectively suppress tumor growth, EMT and metastasis of non small cell lung cancer or extrahepatic cholangiocarcinoma through PLA2G4A/PGE 2 /STAT3 pathway [40,41]. Our results show that DIM can inhibit expression of COX2 and PGE 2 and COX2 selective inhibitor Celecoxib limits the capabilities of ESCC migration and invasion as well as reverses EMT process.…”

Section: Discussionmentioning

confidence: 62%

3,3′-Diindolylmethane modulates aryl hydrocarbon receptor of esophageal squamous cell carcinoma to reverse epithelial-mesenchymal transition through repressing RhoA/ROCK1-mediated COX2/PGE2 pathway

Zhu

Zhou

et al. 2020

J Exp Clin Cancer Res

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Background: Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive tumors in the world. Aryl hydrocarbon receptor (AHR) has been reported to promote tumor metastasis and epithelial-mesenchymal transition (EMT) is a vital process of conferring cancer cells capabilities of migration and invasion. However, the mechanism by which modulation of AHR can inhibit tumor metastasis remains unknown. Thus, we aim to investigate the underlying mechanism regarding reversing EMT process of ESCC through modulation of AHR. Methods: We used AHR selective modulator 3,3′-diindolylmethane (DIM) to treat ESCC cell lines TE1 and KYSE150 so as to examine alterations of migration and invasion by wound healing and Transwell assay. Western blotting (WB) and qPCR were performed to detect relative genes and proteins changes regarding EMT process. Cell transfection was utilized for confirming pathways involved in DIM-induced reversal of EMT and in vivo assay was conducted for verification of the underlying mechanism. Co-IP assay was conducted for detecting protein-protein interactions.

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Section: Discussionmentioning

confidence: 62%

3,3′-Diindolylmethane modulates aryl hydrocarbon receptor of esophageal squamous cell carcinoma to reverse epithelial-mesenchymal transition through repressing RhoA/ROCK1-mediated COX2/PGE2 pathway

Zhu

Zhou

et al. 2020

J Exp Clin Cancer Res

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“…COX2 expression increases in the TME during LLC tumor growth and COX2 inhibitors slow LLC tumor growth. 13 14 Direct CDA treatment potentiated COX2 gene transcription rapidly in tumor lesions and TDLNs, and elevated COX2 transcription persisted for over 6 hours in both TME sites ( figure 2C, D ).…”

Section: Resultsmentioning

confidence: 89%

“… 29 30 Aspirin boosted antitumor responses to PD-1 blockade but synergistic effects were modest, even though treatment was initiated only 3 days after tumor engraftment. 30 COX2 inhibitors also slowed LLC tumor growth, 13 14 although effects were modest, despite administering drug continuously starting 4 days after tumor engraftment. 13 In the current study, celecoxib monotherapy had no survival benefit in mice with established LLC tumors, despite its potent synergistic effects when combined with CDA treatment.…”

Section: Discussionmentioning

confidence: 99%

“… 30 COX2 inhibitors also slowed LLC tumor growth, 13 14 although effects were modest, despite administering drug continuously starting 4 days after tumor engraftment. 13 In the current study, celecoxib monotherapy had no survival benefit in mice with established LLC tumors, despite its potent synergistic effects when combined with CDA treatment. Celecoxib potentiated CDA-induced expression of genes associated with inflammation and immunity, including cytokines, extracellular matrix remodeling enzymes and GZMB expressed by effector T cells.…”

Section: Discussionmentioning

confidence: 99%

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Overcoming resistance to STING agonist therapy to incite durable protective antitumor immunity

Lemos

McCardle

et al. 2020

J Immunother Cancer

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BackgroundActivating the Stimulator of Interferon Genes (STING) adaptor incites antitumor immunity against immunogenic tumors in mice, prompting clinical trials to test STING activators. However, STING signaling in the tumor microenvironment (TME) during development of Lewis lung carcinoma (LLC) suppresses antitumor immunity to promote tumor growth. We hypothesized that local immune balance favoring suppression of antitumor immunity also attenuates antitumor responses following STING activation. The purpose of this study was to evaluate how STING activation impacts antitumor responses in mice bearing LLC tumors.MethodsMice bearing established LLC tumors were treated with synthetic cyclic diadenyl monophosphate (CDA) to activate STING. Mice were monitored to assess LLC tumor growth, survival and protective antitumor immunity. Transcriptional and metabolic analyses were used to identify pathways responsive to CDA, and mice were co-treated with CDA and drugs that disrupt these pathways.ResultsCDA slowed LLC tumor growth but most CDA-treated mice (77%) succumbed to tumor growth. No evidence of tumor relapse was found in surviving CDA-treated mice at experimental end points but mice were not immune to LLC challenge. CDA induced rapid increase in immune regulatory pathways involving programmed death-1 (PD-1), indoleamine 2,3 dioxygenase (IDO) and cyclooxygenase-2 (COX2) in the TME. PD-1 blockade enhanced antitumor responses to CDA and increased mouse survival but mice did not eliminate primary tumor burdens. Two IDO inhibitor drugs had little or no beneficial effects on antitumor responses to CDA. A third IDO inhibitor drug synergized with CDA to enhance tumor control and survival but mice did not eliminate primary tumor burdens. In contrast, co-treatments with CDA and the COX2-selective inhibitor celecoxib controlled tumor growth, leading to uniform survival without relapse, and mice acquired resistance to LLC re-challenge and growth of distal tumors not exposed directly to CDA. Thus, mice co-treated with CDA and celecoxib acquired stable and systemic antitumor immunity.ConclusionsSTING activation incites potent antitumor responses and boosts local immune regulation to attenuate antitumor responses. Blocking STING-responsive regulatory pathways synergizes with CDA to enhance antitumor responses, particularly COX2 inhibition. Thus, therapy-induced resistance to STING may necessitate co-treatments to disrupt regulatory pathways responsive to STING in patients with cancer.

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“…The RRBS results for the ELMO3 (NM_024712) gene, located on chromosome 16, showed that the promoter was significantly hypomethylated at five CpG sites in adenoma. 17 None of these CpG sites were methylated in tubulovillous adenoma and cancer samples compared with normal (Tables 2 and 3). The protein encoded by this gene is similar to a Caenorhabditis elegans protein that functions in phagocytosis of apoptotic cells and in cell migration.…”

Section: Rrbs Data Analysis Revealed Methylation Target Genesmentioning

confidence: 98%

Determination of distinctive hypomethylated genes in African American colorectal neoplastic lesions

Ashktorab

Washington

Zarnogi

et al. 2020

Therap Adv Gastroenterol

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Background: Few studies have analyzed progressive demethylation in the path to cancer. This is of utmost importance, especially in populations such as African Americans, who display aggressive tumors at diagnosis, and for whom markers of early neoplastic transformation are needed. Here, we determined hypomethylated targets in the path to colorectal cancer (CRC) using Reduced Representation Bisulfite Sequencing (RRBS). Methods: DNA was extracted from fresh frozen tissues of patients with different colon lesions (normal, tubular adenoma, tubulovillous adenoma, and five cancers). RRBS was performed on these DNA extracts to identify hypomethylated gene targets. Alignment, mapping, and methylation analyses were performed. Pathways affected by the hypomethylated gene targets were determined using Ingenuity Pathway Analysis (IPA). Results: Pairwise analyses of samples led to the identification of the following novel hypomethylated genes: ELMO3 (Engulfment and cell motility 3), SLC6A2 (Solute carrier family 6 member 2), SYNM (Synemin), and HMX2 (Homeobox 2). The ELMO3 promoter was significantly hypomethylated at five CpG sites, SYNM at two CpG sites, SLC6A2 at one CpG site, and the HMX2 gene at one CpG site. IPA placed these genes within important carcinogenic pathways. Conclusions: This work provides insight into the role of hypomethylation in colon carcinogenesis in African Americans. The identified targets affected many important pathways, as demonstrated through IPA. These targets might serve as biomarkers for early diagnosis and potential targets for therapy.

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Down Regulation of the Expression of ELMO3 by COX2 Inhibitor Suppresses Tumor Growth and Metastasis in Non-Small-Cell Lung Cancer

Cited by 17 publications

References 19 publications

3,3′-Diindolylmethane modulates aryl hydrocarbon receptor of esophageal squamous cell carcinoma to reverse epithelial-mesenchymal transition through repressing RhoA/ROCK1-mediated COX2/PGE2 pathway

3,3′-Diindolylmethane modulates aryl hydrocarbon receptor of esophageal squamous cell carcinoma to reverse epithelial-mesenchymal transition through repressing RhoA/ROCK1-mediated COX2/PGE2 pathway

Overcoming resistance to STING agonist therapy to incite durable protective antitumor immunity

Determination of distinctive hypomethylated genes in African American colorectal neoplastic lesions

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