Cited by 230Cytokine Signaling Pathways and InteractionsAngiogenesis and VEGF in CancerPleural and Pulmonary Diseases

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Autocrine IL-6-induced Stat3 activation contributes to the pathogenesis of lung adenocarcinoma and malignant pleural effusion

Yeh, H-H, Lai, W-W, Chen, H H W, Liu, H-S, Su, W-C·2006·Oncogene

DOI 10.1038/sj.onc.1209464

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Abstract

Malignant pleural effusion (MPE) is a poor prognostic sign for patients with non-small-cell lung cancer (NSCLC). The generation of MPE is largely regulated by vascular endothelial growth factor (VEGF), and upregulation of VEGF by Stat3 has been observed in several types of tumor cells. In this study, we demonstrate constitutively activated Stat3 in several human lung cancer cell lines and in tumor cells infiltrated in the pleurae of patients with adenocarcinoma cell lung cancer (ADCLC) and MPE. The observations suggest that activated Stat3 plays a role in the pathogenesis of ADCLC. In PC14PE6/AS2 cells, a Stat3-positive human ADCLC cell line, autocrine IL-6 activated Stat3 via JAKs, not via Src kinase. PC14PE6/AS2 cells express higher VEGF mRNA and protein than do Stat3-negative PC14PE6/AS2/dnStat3 cells. In an animal model, PC14P6/AS2/dnStat3 cells produced no MPE and less lung metastasis than did PC14P6/AS2 cells. PC14PE6/AS2 cells also expressed higher VEGF protein, microvessel density, and vascular permeability in tumors than did PC14P6/AS2/dnStat3 cells. Therefore, we hypothesize that autocrine IL-6 activation of Stat3 in ADCLC may be involved in the formation of malignant pleural effusion by upregulating VEGF. Higher levels of IL-6 and VEGF were also found in the pleural fluids of patients with ADCLC than in patients with congestive heart failure. The autocrine IL-6/Stat3/VEGF signaling pathway may also be activated in patients with ADCLC and MPE. These findings provide novel targets for the management of MPE.

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BackgroundMethod
Zelnorm, an agonist of 5-Hydroxytryptamine 4-receptor, acts as a potential antitumor drug by targeting JAK/STAT3 signaling
Zhang, L., Song, Q., Zhang, X., Li, L., Xu, X., Xu, X., Li, X., Wang, Z., Lin, Y., Li, X., et al. (2019) · Investigational New Drugs · doi:10.1007/s10637-019-00790-8 · Cited by 17
Autophagy facilitates cytokine-induced ICAM-1 expression
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Jak/Stat Pathway in Waldenström's Macroglobulinemia
Hodge, L. S., & Ansell, S. M. (2011) · Clinical Lymphoma Myeloma & Leukemia · doi:10.3816/clml.2011.n.023 · Cited by 15
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“The parental PC14PE6 cell line was generously provided by Dr Fidler (MD Anderson Cancer Center, Houston, TX, USA), and its derivative PC14PE6/AS2 (AS2) cell line was subsequently established in our laboratory.(28) The AS2 cells were maintained in Minimum Essential Medium Alpha Modification (α-MEM; Life Technologies) s…”
Self-citation
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Constitutive STAT5 activation correlates with better survival in cervical cancer patients treated with radiation therapy.
Chen, H. H. W., Chou, C.-Y., Wu, Y.-H., Hsueh, W.-T., Hsu, C., Guo, H.-R., Lee, W.-Y., & Su, W. (2012) · International Journal of Radiation Oncology, Biology, Physics · doi:10.1016/j.ijrobp.2010.11.043 · Cited by 13
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Autocrine IL-6 regulates GRO-α production in thymic epithelial cells
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Acacetin Inhibits Cell Proliferation and Induces Apoptosis in Human Hepatocellular Carcinoma Cell Lines
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“26 Yeh et al 27 revealed that STAT3 activation induced by IL-6 contributed to lung adenocarcinoma development.”
MicroRNAs Present in Malignant Pleural Fluid Increase the Migration of Normal Mesothelial Cells In Vitro and May Help Discriminate between Benign and Malignant Effusions
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“Other molecules that are involved in pleural ﬂuid (PF) formation include signal transducer and activator of transcription 3 (STAT3), vascular endothelial growth factor (VEGF) [6,7], transforming growth factor β (TGF-β ) [8], interleukin (IL)-10 [9], and IL-6 [10].”
Background
Study protocol of a phase 1 clinical trial establishing the safety of intrapleural administration of liposomal curcumin: curcumin as a palliative treatment for malignant pleural effusion (IPAL-MPE)
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Background
Covid-19 And Cancer: Insights Into Their Association And Influence On Genetic And Epigenetic Landscape
Ghosh, M. K., Kumar, S., Ganguly, K. K., Ghosh, P., Tabassum, S., Basu, B., & Basu, M. (2023) · Epigenomics · doi:10.2217/epi-2023-0052 · Cited by 22
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Method
B cell receptor-induced IL-10 production from neonatal mouse CD19+CD43- cells depends on STAT5-mediated IL-6 secretion
Sakai, J., Yang, J., Chou, C., Wu, W. W., & Akkoyunlu, M. (2023) · eLife · doi:10.7554/elife.83561 · Cited by 11
“As JAKs are activated by cytokine receptors and several studies proposed autocrine IL-6 signaling in tumor cell lines ( Kawashima et al., 2001 ; Yeh et al., 2006 ; Gao et al., 2007 ; Hartman et al., 2011 ; Rodriguez-Barrueco et al., 2015 ), we envisaged an autocrine activity of IL-6 produced by…”
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Suppressing STAT3 activity protects the endothelial barrier from VEGF-mediated vascular permeability
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A Novel Aldisine Derivative Exhibits Potential Antitumor Effects by Targeting JAK/STAT3 Signaling
Wang, D.-P., Wu, L., Li, R., He, N., Zhang, Q.-Y., Zhao, C., & Jiang, T. (2023) · Marine Drugs · doi:10.3390/md21040218 · Cited by 6
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Background
Local biomaterial-assisted antitumour immunotherapy for effusions in the pleural and peritoneal cavities caused by malignancies.
Sun, Y.-J., Hu, Y., Wan, C., Lovell, J., Jin, H.-L., & Yang, K.-Y. (2021) · Biomaterials Science · doi:10.1039/d1bm00971k · Cited by 6
Low incidence of IL6ST (gp130) mutations in exon 6 in lung cancer of a Chinese cohort
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Pleural Effusions in Lung Cancer: Detection and Treatment
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“On the other hand, tumour cells activate proinflammatory and proangiogenic transcription programs controlled by nuclear transcription factor (NF)-kB [38] and signal transduction of transcription activator (STAT)3 [39].”
Background
CELL-BASED THERAPY IMPROVES CELL VIABILITY AND INCREASES AIRWAY SIZE IN AN EXPLANT MODEL
Roszell, B. R., Seaton, A., Fong, G., & Finck, C. (2009) · Experimental Lung Research · doi:10.1080/01902140902718353 · Cited by 5
“Notably, IL-6 signaling has been linked to VEGF promoter activity, and may provide a mechanistic link to both cellular viability and morphogenesis in our model [43].”
Background
Alterations in IL-6/STAT3 Signaling by Korean Mistletoe Lectin Regulate the Self-Renewal Activity of Placenta-Derived Mesenchymal Stem Cells
Kim, G. D., Choi, J. H., Lim, S. M., Jun, J. H., Moon, J. W., & Kim, G. J. (2019) · Nutrients · doi:10.3390/nu11112604 · Cited by 5
EGFR and KRAS mutations do not enrich for the activation of IL-6, JAK1 or phosphorylated STAT3 in resected lung adenocarcinoma
Clay, T. D., Russell, P. A., Do, H., Sundararajan, V., Conron, M., Wright, G. M., Solomon, B., Dobrovic, A., McLachlan, S., & Moore, M. M. (2017) · Medical Oncology · doi:10.1007/s12032-017-1031-1 · Cited by 5
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Serum JAK/STAT profile is related to the IL expression but not with the outcome in pancreatic adenocarcinoma patients
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Tumor Dormancy Resulting from Subcutaneous Injection to SCID Mice with Cultured Nasopharyngeal Carcinoma Cells Is Mediated via IFN-γ Induction of a Highly Differentiated Phenotype
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Self-citation
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Authors: Yeh, H.-H., Lai, W.-W., Chen, H. H. W., Liu, H.-S., & Su, W.-C.
Affiliations: National Cheng Kung University (TW)
National Cheng Kung University Hospital (TW)
Corresponding author: Liu, H-S
Su, W-C
ORCID: Su, W-C
Venue: Oncogene
Publisher: Springer Science and Business Media LLC
Published: 2006-03-06
Volume: 25
Issue: 31
Pages: 4300-4309
ISSN: 0950-9232 (ISSN-L)
1476-5594
DOI: 10.1038/sj.onc.1209464
OpenAlex: W2022200777
Cited by: 230
References: 0
Citations by year: 2026: 4 · 2025: 5 · 2024: 6 · 2023: 13 · 2022: 14 · 2021: 13 · 2020: 11 · 2019: 15 · 2018: 8 · 2017: 11 · 2016: 9 · 2015: 16 · 2014: 6 · 2013: 16 · 2012: 17
FWCI: 6.26
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Oncogene (publishedVersion)
PubMed (publishedVersion)
Topics: Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Pleural and Pulmonary Diseases
Keywords: malignant pleural effusion, lung adenocarcinoma, interleukin-6, STAT3 activation, autocrine signaling, vascular endothelial growth factor, JAK signaling, non-small cell lung cancer, lung metastasis, tumor angiogenesis, pleural fluid biomarkers, microvessel density, vascular permeability
MeSH terms: Adenocarcinoma, Animals, Female, Humans, Lung Neoplasms, Male, Mice, Inbred BALB C, Mice, Nude, Interleukin-6, Pleural Effusion, Malignant, Vascular Endothelial Growth Factor A, Cell Line, Tumor, STAT3 Transcription Factor, Mice

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Autocrine IL-6-induced Stat3 activation contributes to the pathogenesis of lung adenocarcinoma and malignant pleural effusion

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