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Downstream targets of ID1 transcription factor in Non-Small Cell Lung Carcinoma (NSCLC)

ABSTRACT: ID-1, known as inhibitor of differentiation or a helix loop helix transcription factor which lack the basic DNA binding domain. It is known to bind to bHLH transcription factor and inhibit those bHLH to bind to the promoter thus inhibiting further transcription. Overexpression of ID-1 has been correlated with a variety of human cancers including breast, prostate, pancreatic, ovarian, endometrial, bladder cancer and melanomas. Recently known that if ID-1 is depleted, it abrogates cell proliferation, invasion and migration of cells in NSCLC. Further ID-1 expression is induced by Nicotine and EGF through the activation of nAChRs and EGFR. Here microarray analysis was done to compare differential gene expression patterns upon nicotine and EGF stimulation of A549 and H1650 cells and how ID1 depletion changes these patterns. We find that multiple genes are affected and the role of these genes in lung cancer will be elucidated. In this study we show that ID-1 regulates the expression of three genes STMN3, TPD52 and GSPT1 in NSCLC by activating the promoter of these genes either directly or indirectly. We also show that depletion of STMN3, TPD52 and GSPT1 prevented Nicotine and EGF induced cell proliferation, invasion and migration of cells in NSCLC. Two cell lines (A549, H1650) each having 5 samples.

ORGANISM(S): Homo sapiens

SUBMITTER: Perumal Deepak

PROVIDER: S-ECPF-GEOD-38944 | biostudies-other |

REPOSITORIES: biostudies-other

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Downstream targets of ID1 transcription factor in Non-Small Cell Lung Carcinoma (NSCLC)

Project description:ID-1, known as inhibitor of differentiation or a helix loop helix transcription factor which lack the basic DNA binding domain. It is known to bind to bHLH transcription factor and inhibit those bHLH to bind to the promoter thus inhibiting further transcription. Overexpression of ID-1 has been correlated with a variety of human cancers including breast, prostate, pancreatic, ovarian, endometrial, bladder cancer and melanomas. Recently known that if ID-1 is depleted, it abrogates cell proliferation, invasion and migration of cells in NSCLC. Further ID-1 expression is induced by Nicotine and EGF through the activation of nAChRs and EGFR. Here microarray analysis was done to compare differential gene expression patterns upon nicotine and EGF stimulation of A549 and H1650 cells and how ID1 depletion changes these patterns. We find that multiple genes are affected and the role of these genes in lung cancer will be elucidated. In this study we show that ID-1 regulates the expression of three genes STMN3, TPD52 and GSPT1 in NSCLC by activating the promoter of these genes either directly or indirectly. We also show that depletion of STMN3, TPD52 and GSPT1 prevented Nicotine and EGF induced cell proliferation, invasion and migration of cells in NSCLC.

2013-04-15 | GSE38944 | GEO

Downstream targets of ID1 transcription factor in Non-Small Cell Lung Carcinoma (NSCLC)

2013-04-15 | E-GEOD-38944 | biostudies-arrayexpress

Reactivation of MASPIN in non-small cell lung carcinoma (NSCLC) cells by artificial transcription factors (ATFs).

Project description:Tumor suppressor genes have antiproliferative and antimetastatic functions, and thus, they negatively affect tumor progression. Reactivating specific tumor suppressor genes would offer an important therapeutic strategy to block tumor progression. Mammary Serine Protease Inhibitor (MASPIN) is a tumor suppressor gene that is not mutated or rearranged in tumor cells, but is silenced during metastatic progression by transcriptional and epigenetic mechanisms. In this work, we have investigated the ability of Artificial Transcription Factors (ATFs) to reactivate MASPIN expression and to reduce tumor growth and metastatic dissemination in Non-Small Cell Lung Carcinoma (NSCLC) cell lines carrying a hypermethylated MASPIN promoter. We found that the ATFs linked to transactivator domains were able to demethylate the MASPIN promoter. Consistently, we observed that co-treatment of ATF-transduced cells with methyltransferase inhibitors enhanced MASPIN expression as well as induction of tumor cell apoptosis. In addition to tumor suppressive functions, restoration of endogenous MASPIN expression was accompanied by inhibition of metastatic dissemination in nude mice. ATF-mediated reactivation of MASPIN lead to changes in cell motility and to induction of E-CADHERIN. These data suggest that ATFs are able to reprogram aggressive lung tumor cells towards a more epithelial, differentiated phenotype, and thus, represent novel therapeutic agents for metastatic lung cancers.

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Customised, Individualised Treatment of Metastatic Non-Small-Cell Lung Carcinoma (NSCLC).

Project description:A series of phase II and randomised phase III trials in Asia and Europe have confirmed recently that advanced stage non-small-cell lung carcinoma patients with adenocarcinoma subtypes harbouring specific mutations when subjected to targeted therapy experience equivalent survival outcomes as those treated with chemotherapy and are spared from its side effects. The concept of chemotherapy for all is fading, and therapy optimisation has emerged as a paradigm shift in treatment. This article briefly describes cellular mechanisms involved in lung carcinogenesis which provide a molecular basis for targeted therapy. Advances in molecular biology have improved our understanding of mechanisms involved in primary or secondary drug resistance. Evolving biomarkers of prognostic and predictive importance, and the impact of translational research on outcomes are also covered. A marker is considered prognostic if it predicts the outcome, regardless of the treatment, and predictive if it predicts the outcome of a specific therapy.

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Expression data from non-small cell lung carcinoma (NSCLC)

Project description:The analytical validation of a 15 gene prognostic signature for early-stage, completely resected, non-small-cell lung carcinoma that distinguishes between patients with good and poor prognoses.

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KIT (CD117) expression in a subset of non-small cell lung carcinoma (NSCLC) patients.

Project description:We have previously described the expression of CD44, CD90, CD117 and CD133 in NSCLC tumors, adjacent normal lung, and malignant pleural effusions (MPE). Here we describe the unique subset of tumors expressing CD117 (KIT), a potential therapeutic target. Tumor and adjacent tissue were collected from 58 patients. Six MPE were obtained before therapy. Tissue was paraffin embedded for immunofluorescent microscopy, disaggregated and stained for flow cytometry or cryopreserved for later culture. The effect of imatinib on CD117(high)/KIT+ tumors was determined on first passage cells; absolute cell counts and flow cytometry were readouts for drug sensitivity of cell subsets. Primary tumors divided into KIT(neg) and KIT+ by immunofluorescence. By more sensitive flow cytometric analysis, CD117+ cytokeratin+ cells were detected in all tissues (1.1% of cytokeratin+ cells in normal lung, 1.29% in KIT "negative" tumors, 40.7% in KIT+ tumors, and 0.4% in MPE). In KIT+/CD117(high), but not KIT+/CD117(low) tumors, CD117 was overexpressed 3.1-fold compared to normal lung. Primary cultures of CD117(high) tumors were sensitive to imatinib (5 µM) in short term culture. We conclude that NSCLC tumors divide into CD117(low) and CD117(high). Overexpression of CD117 in CD117(high) NSCLC supports exploring KIT as a therapeutic target in this subset of patients.

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TP53 transcription factor for the NEDD9/HEF1/Cas-L gene: potential targets in Non-Small Cell Lung Cancer treatment.

Project description:Lung cancer is a serious public health problem. Although there has been significant progress in chemotherapy, non-small cell lung cancer is still resistant to current treatments, primarily because of the slow rate of cell development. It is thus important to find new molecules directed against targets other than proliferation agents. Considering the high proportion of mutant proteins in tumor cells, and the high rate of mutation of the TP53 gene in all cancers, and in NSCLC in particular, this gene is a perfect target. Certain new molecules have been shown to restore the activity of mutated p53 protein, for example PRIMA-1, which reactivates the His273 mutant p53. In a previous study, we presented triazine A190, a molecule with a cytostatic activity that blocks cells in the G1 phase and induces apoptosis. Here, we show that A190 not only restores mutant p53 activity, but also induces an overexpression of the NEDD9 gene, leading to apoptotic death. These findings might offer hope for the development of new targeted therapies, specific to tumor cells, which spare healthy cells.

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Initial Insights on the Proteomic Profile of Filipino Non-Small Cell Lung Carcinoma (NSCLC)

Project description:NSCLC remains to be the leading cause of cancer incidence and mortality in the Philippines. Early diagnosis, better understanding on the mechanisms of drug resistance, and proper treatment monitoring is necessary to lower the incidence and mortality rate of NSCLC. This study was able to provide initial insights on the proteomic profile of Filipino NSCLC by quantitative proteomic analysis and identification of aberrant expressions in the tumor tissue relative to the adjacent normal tissue specimen. A total of 4518 proteins were identified and from this, 1855 proteins were found to be significantly upregulated and downregulated. Functional and pathway analysis was done to the upregulated and downregulated proteins with at least 4-fold expression change. Pathway analysis revealed the possible activation of the upregulated protein, MUC1, which is a known oncogenic driver involved in the stimulation of pathways that promote angiogenesis in NSCLC tumor, and prevention of apoptosis. STAT1 and STAT3, also found upregulated in the tumor specimen, were known to have interactions with MUC1 which results to expression of proteins for cell proliferation. The analysis also suggests the stabilization of HIF which allows cell growth in the hypoxic tumor environment, and the activation of EIF signaling correlated with low survival rate of NSCLC patients. Our data demonstrate the rich proteomic information that can be obtained from comprehensive profiling of the NSCLC proteome and applications for better understanding of NSCLC tumorigenicity.

2022-02-10 | PXD027710 | Pride

Induction of Activating Transcription Factor 3 Is Associated with Cisplatin Responsiveness in Non-Small Cell Lung Carcinoma Cells.

Project description:Non-small cell lung carcinoma (NSCLC) is the most common cause of cancer deaths, with platin-based combination chemotherapy the most efficacious therapies. Gains in overall survival are modest, highlighting the need for novel therapeutic approaches including the development of next-generation platin combination regimens. The goal of this study was to identify novel regulators of platin-induced cytotoxicity as potential therapeutic targets to further enhance platin cytotoxicity. Employing RNA-seq transcriptome analysis comparing two parental NSCLC cell lines Calu6 and H23 to their cisplatin-resistant sublines, Calu6cisR1 and H23cisR1, activating transcription factor 3 (ATF3) was robustly induced in cisplatin-treated parental sensitive cell lines but not their resistant sublines, and in three of six tumors evaluated, but not in their corresponding normal adjacent lung tissue (0/6). Cisplatin-induced JNK activation was a key regulator of this ATF3 induction. Interestingly, in both resistant sublines, this JNK induction was abrogated, and the expression of an activated JNK construct in these cells enhanced both cisplatin-induced cytotoxicity and ATF3 induction. An FDA-approved drug compound screen was employed to identify enhancers of cisplatin cytotoxicity that were dependent on ATF3 gene expression. Vorinostat, a histone deacetylase inhibitor, was identified in this screen and demonstrated synergistic cytotoxicity with cisplatin in both the parental Calu6 and H23 cell lines and importantly in their resistant sublines as well that was dependent on ATF3 expression. Thus, we have identified ATF3 as an important regulator of cisplatin cytotoxicity and that ATF3 inducers in combination with platins are a potential novel therapeutic approach for NSCLC.

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