Requirement of Stat3 but not Stat1 activation for epidermal growth factor receptor- mediated cell growth In vitro.
Open accessAbstract
Stimulation of epidermal growth factor receptor (EGFR) by ligand(s) leads to activation of signaling molecules including Stat1 and Stat3, two members of the signal transducers and activators of transcription (STAT) protein family. Activation of Stat1 and Stat3 was constitutive in transformed squamous epithelial cells, which produce elevated levels of TGF-alpha, and was enhanced by the addition of exogenous TGF-alpha. Targeting of Stat3 using antisense oligonucleotides directed against the translation initiation site, resulted in significant growth inhibition. In addition, cells stably transfected with dominant negative mutant Stat3 constructs failed to proliferate in vitro. In contrast, targeting of Stat1 using either antisense or dominant-negative strategies had no effect on cell growth. Thus, TGF-alpha/EGFR-mediated autocrine growth of transformed epithelial cells is dependent on activation of Stat3 but not Stat1.
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Constitutive STAT3 signaling has been implicated in aberrant cell growth and proliferation in many cancers, including head and neck squamous cell carcinoma, colorectal carcinoma, melanoma, glioblastoma multiforme, multiple myeloma, non-small cell lung cancer, and others.
“Constitutive STAT3 signaling has been implicated in aberrant cell growth and proliferation in many cancers, including head and neck squamous cell carcinoma, colorectal carcinoma, melanoma, glioblastoma multiforme, multiple myeloma, non-small cell lung cancer, and others.58,69–73”
From Critical analysis of the potential for targeting STAT3 in human malignancy (2013) · cites this paper as [58]
The Discussion (page unavailable in our copy) links constitutive STAT3 activation to aberrant proliferation in head and neck squamous cell carcinoma cells. It does not establish that link for the other listed cancers—colorectal carcinoma, melanoma, glioblastoma, multiple myeloma, or non-small cell lung cancer—so it supports only part of the cited sentence. (LLM, conf=0.88)
Experimental — accuracy not yet measuredOverexpression 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 [58]
The Abstract and Discussion support constitutive Stat3 activation in transformed epithelial cells that produce elevated TGF-α, and describe signaling through an autocrine TGF-α/EGFR pathway. Our copy does not establish the claimed IL-6 autocrine mechanism or describe IL-6 as an RTK ligand. (LLM, conf=0.87)
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Cites
A Specific Inhibitor of the Epidermal Growth Factor Receptor Tyrosine Kinase
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Activation and Association of Stat3 with Src in v-Src-Transformed Cell Lines
Cao, X., Tay, A., Guy, G. R., & Tan, Y. H. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.4.1595 · Cited by 359 · see citing works
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Research works printed but not linked: 3
- Schindler, C., X.Y. Fu, T. Improta, R. Aebersold, and J.E. Darnell, Jr. 1992. Proteins of transcription factor ISGF-3: one gene encodes the 91-and 84- kD ISGF-3 proteins that are activated by interferon ␣. Proc. Natl. Acad. Sci. USA. 89:7836-7839.
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Cited by
Sorted by citations
STATs in cancer inflammation and immunity: a leading role for STAT3
Yu, H., Pardoll, D., & Jove, R. (2009) · Nature reviews. Cancer · doi:10.1038/nrc2734 · Cited by 4,383 · see citing works
Bowman, T., Garcia, R., Turkson, J., & Jove, R. (2000) · Oncogene · doi:10.1038/sj.onc.1203527 · Cited by 1,743 · see citing works
Epling-Burnette, P. K., Liu, J. H., Catlett-Falcone, R., Turkson, J., Oshiro, M., Kothapalli, R., Li, Y., Wang, J.-M., Yang-Yen, H.-F., Karras, J., et al. (2001) · Journal of Clinical Investigation · doi:10.1172/jci9940 · Cited by 633 · see citing works
The potential and controversy of targeting STAT family members in cancer
Verhoeven, Y., Tilborghs, S., Jacobs, J., De Waele, J., Quatannens, D., Deben, C., Prenen, H., Pauwels, P., Trinh, X. B., Wouters, A., et al. (2020) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2019.10.002 · Cited by 409 · see citing works
Corvinus, F. M., Orth, C., Moriggl, R., Tsareva, S. A., Wagner, S., Pfitzner, E. B., Baus, D., Kaufman, R., Huber, L. A., Zatloukal, K., et al. (2005) · Neoplasia · doi:10.1593/neo.04571 · Cited by 427 · see citing works
Targeted inhibition of Stat3 with a decoy oligonucleotide abrogates head and neck cancer cell growth
Leong, P. L., Andrews, G. A., Johnson, D. E., Dyer, K. F., Xi, S., Mai, J. C., Robbins, P. D., Gadiparthi, S., Burke, N. A., Watkins, S. F., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0534764100 · Cited by 340 · see citing works
Self-citationThe STAT3 pathway as a therapeutic target in head and neck cancer: barriers and innovations
Geiger, J. L., Grandis, J. R., & Bauman, J. E. (2016) · Oral Oncology · doi:10.1016/j.oraloncology.2015.11.022 · Cited by 193 · see citing works
Self-citationCampbell, C. L., Jiang, Z., Savarese, D. M. F., & Savarese, T. M. (2001) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63940-5 · Cited by 151 · see citing works
Critical analysis of the potential for targeting STAT3 in human malignancy
Grandis, J., & Peyser (2013) · OncoTargets and Therapy · doi:10.2147/ott.s47903 · Cited by 24 · see citing works
“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) Other genomic events and rearrangements can also lead to kinase and STAT3 activation, such as that observed for the EGFRvIII protein, a const…”
Self-citation
- Authors
- Grandis, J. R., Drenning, S. D., Chakraborty, A., Zhou, M. Y., Zeng, Q., Pitt, A. S., & Tweardy, D. J.
- Affiliations
- University of Pittsburgh (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 1998-10-01
- Volume
- 102
- Issue
- 7
- Pages
- 1385-1392
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508986
- OpenAlex
- W2044991100
- Cited by
- 507
- References
- 2
- Citations by year
- 2026: 1 · 2025: 6 · 2024: 4 · 2023: 6 · 2022: 11 · 2021: 14 · 2020: 8 · 2019: 9 · 2018: 12 · 2017: 14 · 2016: 14 · 2015: 19 · 2014: 26 · 2013: 27 · 2012: 22
- FWCI
- 8.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mary Hillman Jennings Foundation
- National Institutes of Health (5k11ca001760-05, 5r03ca072526-02)
- National Cancer Institute (CA72526, CA72261, R01CA072261, CA01760)
- Topics
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- STAT3, STAT1, epidermal growth factor receptor, transforming growth factor-alpha, autocrine growth, squamous epithelial cells, cell proliferation, signal transducer and activator of transcription, dominant-negative STAT3, antisense oligonucleotides
- MeSH terms
- Carcinoma, Squamous Cell, Cell Division, Cells, Cultured, DNA-Binding Proteins, Epithelial Cells, Head and Neck Neoplasms, Carcinoma, Hepatocellular, Humans, Kinetics, Liver Neoplasms, Mouth Mucosa, Recombinant Proteins, Tumor Cells, Cultured, Trans-Activators, Transforming Growth Factor alpha, STAT1 Transcription Factor, STAT3 Transcription Factor, ErbB Receptors
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