Role of STAT3 in lung cancer

Dutta, Pranabananda; Sabri, Nafiseh; Li, Jinghong; Li, Willis X.

doi:10.1080/21623996.2014.999503

Cited by 77 publications

(74 citation statements)

References 124 publications

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“…Recent studies have reported activation of the JAK/STAT pathway in sex-determining region Y box 2 (SOX2)-driven, LKB1-deficient mouse model of squamous cell lung cancer (47) and increase of IL-6 production and subsequent activation of STAT3 in LKB1-deficient mouse model of LADC (48,49). As IL-6/JAK/STAT signaling axis plays important roles in cell proliferation, survival, invasion, chemoresistance, and immunosuppression, (48,(50)(51)(52)(53), targeting CPS1 might alter tumor microenvironment and improve efficiency of immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma

Çeliktaş

Tanaka

Tripathi

et al. 2016

JNCI J Natl Cancer Inst

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Background: Liver kinase B1 (LKB1) is a tumor suppressor in lung adenocarcinoma (LADC). We investigated the proteomic profiles of 45 LADC cell lines with and without LKB1 inactivation. Carbamoyl phosphate synthetase 1 (CPS1), the first ratelimiting mitochondrial enzyme in the urea cycle, was distinctively overexpressed in LKB1-inactivated LADC cell lines. We therefore assessed the role of CPS1 and its clinical relevance in LKB1-inactivated LADC. Methods: Mass spectrometric profiling of proteome and metabolome and function of CPS1 were analyzed in LADC cell lines. CPS1 and LKB1 expression in tumors from 305 LADC and 160 lung squamous cell carcinoma patients was evaluated by immunohistochemistry. Kaplan-Meier and Cox regression analyses were applied to assess the association between overall survival and CPS1 and LKB1 expression. All statistical tests were two-sided. Results: CPS1 knockdown reduced cell growth, decreased metabolite levels associated with nucleic acid biosynthesis pathway, and contributed an additive effect when combined with gemcitabine, pemetrexed, or CHK1 inhibitor AZD7762. Tissue microarray analysis revealed that CPS1 was expressed in 65.7% of LKB1-negative LADC, and only 5.0% of LKB1-positive LADC. CPS1 expression showed statistically significant association with poor overall survival in LADC (hazard ratio ¼ 3.03, 95% confidence interval ¼ 1.74 to 5.25, P < .001). Conclusions: Our findings suggest functional relevance of CPS1 in LKB1-inactivated LADC and association with worse outcome of LADC. CPS1 is a promising therapeutic target in combination with other chemotherapy agents, as well as a prognostic biomarker, enabling a personalized approach to treatment of LADC.

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Section: Discussionmentioning

confidence: 99%

Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma

Çeliktaş

Tanaka

Tripathi

et al. 2016

JNCI J Natl Cancer Inst

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confidence: 99%

“…In lung cancer, activation of STAT3 and NF-κB are frequently observed and their roles have been analyzed experimentally [12][13][14][15][16] . Moreover, STAT3 and ELK-1 are activated by EGFR (epidermal growth factor receptor) 13,14 . In addition, a recent report has shown that expression of a microRNA, which directly suppresses MCL1 mRNA, is suppressed in lung cancer 17 , suggesting that MCL1 mRNA expression is activated by transcriptional and post-transcriptional regulation in lung cancer.…”

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confidence: 99%

The anti-apoptotic protein MCL1, a novel target of lung cancer therapy

Tanaka¹

2017

J Cancer Treat & Diagnosis

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Evasion of apoptosis is one of the typical hallmarks of cancer and a major mechanism for cancer development, tumor growth, and acquisition of resistance to chemotherapy. The anti-apoptotic Bcl-2 protein family, particularly MCL1 and BCL-XL, play an important role in acquisition of apoptosis evasion. MCL1 is a highly unstable protein that is constantly degraded by the ubiquitinproteasome system. An increase in MCL1 protein has been reported in many cancers, including lung cancer, through high mRNA expression or impairment of its degradation systems. To date, much evidence has shown that MCL1 is important for cancer cell survival and drug resistance in lung cancers. In this review, we discuss the role and mechanism of high MCL1 expression in lung cancer.

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“…STAT3 is a member of the STAT protein family, which is phosphorylated by the receptor-associated kinases in response to cytokines and growth factors, and then forms heterodimers that translocate to the cell nucleus where they function as transcription activators. It has been widely reported that STAT3 play significant roles in the cell growth, EMT, oncogenic transformation, tumorigenesis, progression and immune evasion of lung cancer [46][47][48]. The E2F1 transcription factor is realized as a regulator of the cell cycle as well as a potent mediator of DNA damage-induced apoptosis and the checkpoint response.…”

Section: Discussionmentioning

confidence: 99%

Microarray Profiling of TGF-β1-Induced Long Non-Coding RNA Expression Patterns in Human Lung Bronchial Epithelial BEAS-2B Cells

Pei

Zhu

et al. 2018

Cell Physiol Biochem

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Background/Aims: TGF-β1 mediated radiation-induced bystander effects (RIBE) have been linked with malignant transformation and tumorigenesis. However, the underlying mechanisms are not fully understood. Methods: To reveal new molecules of regulatory functions in this process, lncRNA microarray was performed to profile both lncRNA and mRNA expression patterns in human lung bronchial epithelial BEAS-2B cells treated with TGF-β1 at a concentration measured in the medium conditioned by directly irradiated BEAS-2B cells. The potential functions of the differentially expressed lncRNAs were predicted by GO and KEGG pathway analyses of their co-expressed mRNAs. Cis- and trans-regulation of the lncRNAs were analyzed and the interaction networks were constructed using Cytoscape. qRT-PCR was conducted to validate the results of microarray profiling. CCK-8 assay was employed for functional validation of 3 identified lncRNAs. Results: 224 lncRNAs were found to be dysregulated, among which 6 lncRNAs were chosen for expression validation by qRT-PCR assay. Pathway analyses showed that differentially expressed lncRNAs are highly correlated with cell proliferation, transformation, migration, etc. Trans-regulation analyses showed that the differentially expressed lncRNAs most likely participate in the pathways regulated by four transcriptional factors, FOS, STAT3, RAD21 and E2F1, which have been identified to be involved in the modulation of oncogenic transformation, cell cycle progression, genomic instability, etc. lnc-THEMIS-2 and lnc-ITGB6-4, predicted to be regulated by STAT3 and E2F1 respectively, were found to rescue the decrease of cell viability induced by TGF-β1 treatment. Conclusion: Our findings suggest that the differentially expressed lncRNAs induced by TGF-β1 play crucial roles in the oncogenic transformation and tumorigenesis, which provide a better understanding of the underlying mechanisms related to tumorigensis induced by LD/LDR radiations.

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Role of STAT3 in lung cancer

Cited by 77 publications

References 124 publications

Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma

Role of CPS1 in Cell Growth, Metabolism, and Prognosis in LKB1-Inactivated Lung Adenocarcinoma

The anti-apoptotic protein MCL1, a novel target of lung cancer therapy

Microarray Profiling of TGF-β1-Induced Long Non-Coding RNA Expression Patterns in Human Lung Bronchial Epithelial BEAS-2B Cells

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