Autocrine IL-6-induced Stat3 activation contributes to the pathogenesis of lung adenocarcinoma and malignant pleural effusion
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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Overexpression of RTK ligands, such as IL-6 or transforming growth factor-α, can lead to persistent STAT3 activation via autocrine signaling through their receptors.
“Overexpression of RTK ligands, such as IL-6 or transforming growth factor-α, can also lead to persistent STAT3 activation via autocrine signaling through their receptors.57,58”
From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [57]
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“This is especially the case for adenocarcinoma with epidermal growth factor receptor mutation, which suggests that IL-6 is a key player in lung adenocarcinoma tumorigenesis.(54,55) A recent report using IKK and IL-6 knockout mice demonstrated that IKK /NF- B activation controls the development of liver metastasis by w…”
BackgroundIhara, S., Kida, H., Arase, H., Tripathi, L., Chen, Y.-A., Kimura, T., Yoshida, M., Kashiwa, Y., Hirata, H., Fukamizu, R., et al. (2012) · Cancer Research · doi:10.1158/0008-5472.can-11-4062 · Cited by 56 · see citing works
Vascular Changes and Hypoxia in Periodontal Disease as a Link to Systemic Complications
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Self-citationIL-6 family cytokines in respiratory health and disease
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The Akt1/IL-6/STAT3 pathway regulates growth of lung tumor initiating cells
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“In fact, although the most prominent role of IL-6 is to regulate immune and inflammatory responses [47], IL-6 has also been implicated in the regulation of growth, drug resistance and metastatic spread of tumors [48, 49].”
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“VEGF is upregulated by inflammatory cytokines such as IL-6 [9], tumor necrosis factor-a (TNF-a) [10], and IL-8 [11], and may play a major role in inflammatory diseases such as rheumatoid arthritis [12], asthma [13], Churg-Strauss syndrome [14] and Behcet’s disease [15].”
BackgroundMetformin reverses mesenchymal phenotype of primary breast cancer cells through STAT3/NF-κB pathways
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“We established the human lung adenocarcinoma PC14PE6/AS2 (AS2) cell line, which has increased metastatic susceptibility and constitutively activated endogenous Stat3, in our laboratory (23).”
BackgroundMethodSelf-citationTocilizumab inhibits neuronal cell apoptosis and activates STAT3 in cerebral infarction rat model
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“Another important regulatory relationship regarding STAT3 is that IL-6 plays vital roles in activating STAT3, which is crucial for the blocked apoptosis during inflammatory processes, as well as the pathogenesis of diseases [24], such as lung adenocarcinoma and malignant pleural effusion [25].”
Zoledronic Acid Is Effective against Experimental Malignant Pleural Effusion
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“For instance, IL-6 and its receptor were implicated in the progression of non–small cell lung carcinoma (NSCLC) [12] and were shown to induce enhanced STAT3 activity [13,14].”
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“IL-6 promotes lung cancer growth and metastasis [11,13] and we [10] have demonstrated that IL-12 dampens IL-6 production in mouse splenocytes.”
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“It has been shown that IL-6 displays carcinogenic effects through the activation of the STAT3 pathway [84, 85, 93, 94].”
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“Large quantities of IL6 in malignant pleural effusions (MPEs) have been reported in lung cancer patients 39 ; thus, we isolated lung adenocarcinoma cells from the MPEs (termed “ MPECs ” ) of 15 NSCLC patients to study the glycosylation pattern of lung cancer cell-derived IL6.”
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Gender Dependence for a Subset of the Low-Abundance Signaling Proteome in Human Platelets
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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
- Published
- 2006-03-06
- Volume
- 25
- Issue
- 31
- Pages
- 4300-4309
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- 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
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › 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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