IL‐6 enriched lung cancer stem‐like cell population by inhibition of cell cycle regulators via DNMT1 upregulation
Open accessAbstract
Tumors are influenced by a microenvironment rich in inflammatory cytokines, growth factors and chemokines, which may promote tumor growth. Interleukin‐6 (IL‐6) is a multifunctional cytokine and known as a regulator of immune and inflammation responses. IL‐6 has also been reported to be associated with tumor progression and chemoresistance in different types of cancers. In our study, we demonstrated that IL‐6 enriches the properties of lung cancer stem‐like cells in A549 lung cancer cells cultured in spheroid medium. IL‐6 also promotes sphere formation and stem‐like properties of A549 cells by enhancing cell proliferation. Methylation‐specific polymerase chain reaction (PCR) was performed and revealed that IL‐6 increased methylation of p53 and p21 in A549 cancer cells. Western blot analysis and quantitative real‐time PCR demonstrated that IL‐6 increased the expression of DNA methyltransferase 1 (DNMT1) in A549 cells cultured in spheroid medium, but not the expression of DNMT3a or DNMT3b. Knockdown of DNMT1 eliminated IL‐6‐mediated hypermethylation of cell cycle regulators and enrichment of lung cancer stem‐like properties. In conclusion, our study, for the first time, shows that the IL‐6/JAK2/STAT3 pathway upregulates DNMT1 and enhances cancer initiation and lung cancer stem cell (CSC) proliferation by downregulation of p53 and p21 resulting from DNA hypermethylation. Upon blockage of the IL‐6/JAK2/STAT3 pathway and inhibition of DNMT1, the proliferation of lung CSCs was reduced and their formation of spheres and ability to initiate tumor growth were decreased. These data suggest that targeting of the IL‐6/JAK2/STAT3 signaling pathway and DNMT1 may become important strategies for treating lung cancer.
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The IL-6/JAK/STAT3 signalling pathway plays an important role in human malignancies such as CRC.
“The IL-6/JAK/STAT3 signalling pathway plays an important role in human malignancies such as CRC.12,15,46,48,49”
From PU.1-driven Th9 Cells Promote Colorectal Cancer in Experimental Colitis Models Through Il-6 Effects in Intestinal Epithelial Cells (2022) · cites this paper as [48]
The Discussion reports that IL-6/JAK2/STAT3 signalling promotes lung cancer stem-like cell proliferation and describes its activity in breast cancer cells, supporting a role in human malignancies. The passage mentioning colorectal cancer links it to chronic inflammation, but does not establish a role for this specific pathway in colorectal cancer. (LLM, conf=0.84)
Experimental — accuracy not yet measuredAt the molecular level, IL-6 increases the activity of DNMT1 with activating effects on JAK/STAT3, NF-κB and PI3K/AKT/mTOR signaling pathways, affecting regulation of autophagy-related functions required to maintain cellular homeostasis under stress such as a prenatal insult.
“At the molecular level, IL-6 increases the activity of DNA methyltransferases 1 (DNMT1) with activating effects on the JAK/STAT3, NF-κB and PI3K/AKT/mTOR signaling pathways [144–148] affecting the regulation of autophagy-related functions, that are required to maintain cellular homeostasis under stress [149], such as a prenatal insult.”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [144]
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- Authors
- Liu, C., Lin, J., Hsu, T., Su, K., Li, A. F., Hsu, H., & Hung, S.
- Affiliations
- Taipei Veterans General Hospital (TW)
- National Yang Ming University (TW)
- Corresponding author
- Hsu, Han‐Shui
- Hung, Shih‐Chieh
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2014-06-27
- Volume
- 136
- Issue
- 3
- Pages
- 547-559
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- OpenAlex
- W1529595331
- Cited by
- 169
- References
- 43
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 14 · 2023: 11 · 2022: 17 · 2021: 19 · 2020: 18 · 2019: 16 · 2018: 11 · 2017: 17 · 2016: 16 · 2015: 9 · 2014: 2
- FWCI
- 7.07
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Council
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Keywords
- interleukin-6, DNMT1, DNA hypermethylation, p53, p21, JAK2/STAT3 signaling, cell cycle regulators, tumor microenvironment, A549 cells, spheroid formation, tumor initiation, chemoresistance
- MeSH terms
- DNA (Cytosine-5-)-Methyltransferase 1, Animals, Cell Cycle, DNA (Cytosine-5-)-Methyltransferases, Humans, Lung Neoplasms, Neoplastic Stem Cells, Interleukin-6, Up-Regulation, Tumor Suppressor Protein p53, Spheroids, Cellular, DNA Methylation, Cell Line, Tumor, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, STAT3 Transcription Factor, Mice, Janus Kinase 2
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