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Thesis _Ishrat Nourin Khan_Final_Edited_5_5_264.92 MB
Embargoed Access, Embargo ends: 06/29/2027
Dissertation
Association of interleukin-1α (IL-1α) expression with tumor aggressiveness in head and neck squamous cell carcinoma
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2026
DOI: 10.25820/etd.008337
Abstract
Interleukin-1α is a pleiotropic cytokine that plays a pivotal role in triggering tumor-associated inflammation. Its expression is upregulated in multiple solid malignancies, including head and neck squamous cell carcinoma (HNSCC), and it has been associated with a more aggressive tumor phenotype with poor clinical outcomes in HNSCC. Inside cells, IL-1α can remain in three biologically active forms: Precursor/full-length (FL), Propiece/N-terminal (NT) and matured/C-terminal (CT) IL-1α. FL and NT IL-1α contain a nuclear localization sequence (NLS) that facilitates their nuclear translocation. The pro-tumorigenic role of IL-1α is mainly attributed to extracellular IL-1α (CT or FL (partially)) by modulating the downstream signaling cascade mediated by IL-1 receptor 1 (IL-1R1). On the other hand, the role of intracellular IL-1α (FL and NT), especially nuclear IL-1α, has not been studied much. In this study, we aim to investigate the role of IL-1α in tumor aggressiveness, its underlying mechanisms and whether blocking nuclear IL-1α can control this aggressiveness.
First, we showed differences in tumor expression and subcellular localization of IL-1α between HPV positive (HPV+) and HPV negative (HPV-) HNSCCs. Here, we found that tumor expression of IL-1α was significantly increased in HPV− tumors (IHC) and cell lines (western blot) compared with HPV+ tumors and cell lines, with no difference in IL-1α release. Expression of IL-1α was observed in both nuclear and cytoplasmic compartments, with predominant nuclear expression. Gene expression of IL1A was significantly increased in HPV- tumors/cell lines compared to HPV+ tumors/cell lines. Moreover, increased IL1A gene expression was significantly associated with worse survival in HPV- tumors. Overall, we found that HPV- HNSCC, an aggressive form, shows higher IL-1α expression.
To understand the mechanism behind IL-1α tumor aggression, we constructed three IL1A constructs (Full-length [FL], N-terminal [NT], and C-terminal [CT]) and transduced them into Cal27 HNSCC cells to validate IL-1α expression. We then examined the biological differences in the effect of the transduced IL-1a constructs. We observed that overexpression of CT IL-1α, but not the FL or NT constructs, led to increased cell proliferation, membrane fluidity, basal oxidative stress, intracellular iron levels, lipid peroxidation, EMT changes, drug resistance, and a shift toward glutamate utilization compared to control cell lines. Finally, cells expressing CT IL-1α (but not FL or NT) were highly sensitive to the ferroptosis inducer RSL3. Together, this work suggests that IL-1α expression led to an aggressive phenotype, triggering an oxidative and ferroptotic environment, while portraying vulnerability towards ferroptosis-inducing agents.
To examine whether blocking nuclear translocation of IL-1α or overall suppression of IL-1α can reduce tumor growth and progression. For this, the NLS of IL-1α was mutated to block nuclear translocation (a triple lysine (K) to aspartic acid (D) substitution mutation or knock-in) in Cal27 HNSCC cells and validated for IL-1α expression. Changes in cytokine expression levels, transcriptomic and metabolic profiles, in vitro cell proliferation and tumor growth in vivo were observed. We found that knock-in IL-1α led to increased inflammatory cytokine release, transcriptomic changes with metabolic shifts and in vivo tumor growth delay. In contrast, IL-1α knockdown cells showed reduced release of inflammatory cytokines with no change in in vitro tumor cell growth. Overall, these results reveal that blocking nuclear translocation of IL-1α is a novel therapeutic approach.
Finally, I have summarized the key findings and proposed future studies to understand the underlying mechanisms of IL-1α mediated tumor aggressiveness and the potential therapeutic approaches to control it. Altogether this study emphasizes the importance of IL-1α in cancer aggressiveness, identifies a potential mechanism underlying this phenotype, and provides a basis for a promising therapeutic strategy that warrants further investigation.
Details
- Title: Subtitle
- Association of interleukin-1α (IL-1α) expression with tumor aggressiveness in head and neck squamous cell carcinoma
- Creators
- Ishrat Nourin Khan
- Contributors
- Andrean Simons-Burnett (Advisor)Munir Tanas (Committee Member)Prajwal Gurung (Committee Member)Shujie Yang (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Human Toxicology
- Date degree season
- Spring 2026
- DOI
- 10.25820/etd.008337
- Publisher
- University of Iowa
- Number of pages
- xii,162 pages
- Copyright
- Copyright 2026 Ishrat Nourin Khan
- Language
- English
- Date submitted
- 04/28/2026
- Description illustrations
- illustrations, graphs, tables
- Description bibliographic
- Includes bibliographical references.
- Public Abstract (ETD)
Interleukin-1α (IL-1α) is a cytokine which plays an important role in promoting inflammation. When associated with cancer, inflammation is deadly and can make cancer aggressive. IL-1α is increased in many cancers including head and neck squamous cell carcinoma (HNSCC), and importantly, these patients have fast-growing/aggressive cancer with poor outcomes in clinic. IL-1α can remain in three biologically active forms: full-length (FL) IL-1α with a nuclear localization sequence (NLS), which breaks into an N-terminal (NT) fragment (retaining the NLS) and a C-terminal (CT) fragment. However, we do not yet know which form of IL-1α makes cancer more aggressive, and the associated mechanisms remain unknown.
In our study, we demonstrated that Human Papilloma Virus negative (HPV-) HNSCCs, a more aggressive type of HNSCC, exhibit higher IL-1α expression, and patients with greater IL-1α expression have poor clinical outcomes. To identify the mechanism underlying this dangerous phenotype, three forms of IL-1α were highly expressed. We found that CT highly expressed cells showed more dangerous phenotypes, including changes in cell proliferation, EMT, drug resistance, oxidative stress and metabolic shifts. These CT highly expressed cells are also easily killed by ferroptotic agents. To test whether blocking IL-1α nuclear localization can reduce tumor growth, we altered the NLS (responsible for nuclear localization) of IL-1α and found that it delays tumor growth in animals.
Overall, our results suggest that high IL-1α expression contributes to cancer aggressiveness, and targeting IL-1α nuclear localization offers a promising avenue for developing novel and unique treatment approaches.
- Academic Unit
- Interdisciplinary Graduate Program in Human Toxicology
- Record Identifier
- 9985177173802771
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