Abstract 5215: IL-17RA expression by NSCLC is vital for restraining homeostatic tumor cell proliferation and baseline cytokine production
Bibliographic record
Abstract
Abstract Background: Lung cancer is the leading cause of cancer-related death worldwide. The Cancer Genome Atlas shows over 30% of non-small cell lung cancer (NSCLC) samples carrying genetic alterations in the IL17RA gene, and deletion of IL17RA is linked to poor overall survival rates. IL17RA is a transmembrane protein with multiple intracellular signaling motifs. The SEFIR domain is required for IL17-induced signaling, which is negatively regulated by A20 (TNFAIP3) via a self-feedback loop. The objective of our study is to examine the impact of IL17RA-deletion in NSCLC and the underlying molecular mechanisms. Methods: Two complementary approaches were used in our study. IL17RA knockdown subclones were created in murine lung cancer cell lines (LLC and CMT167) via shRNA. Human NCIH23 cells carry homozygous deletion of IL17RA gene, whereas human A549 cells possess normal copy number of IL17RAgene. We expressed IL17RA in both human cell lines via a lentiviral vector. The effects of IL17RA expression on the tumor cell proliferation and the production of soluble mediators were compared in paired cell lines, with and without IL17RA expression. Domain-specific IL17RA mutants were constructed in NCIH23 cells to dissect their functional contributions. Western blots and human phosphorylation pathway profiling arrays were used to study how signaling pathways were affected by IL17RA-deletion. Results: The knockdown of IL17RA significantly augmented the proliferation of cancer cells in LLC and CMT167 cells. Conversely, the expression of full-length IL17RA in both NCIH23 and A549 cells diminished proliferation rates. Furthermore, IL17RA knockdown increased the production of multiple proinflammatory cytokines, chemokines, and growth factors, whereas IL17RA expression in NCIH23 markedly inhibited their production. We showed that the SEFIR domain was not required for the effects of IL17RA expression on restraining tumor cell proliferation, while it is known to be vital for IL17A-induced cytokine production. The reduced expression of IL17RA was consistently associated with diminished A20 expression in all tested cell lines. Finally, we demonstrate that IL17RA-deletion caused a marked increase of Glycogen synthase kinase 3 beta (GSK3β) Serine-9 phosphorylation, an inactivated form of GSK3β, in NCIH23 cells. Conclusion: Collectively, our data clearly demonstrate that IL17RA expression is critically required for restraining homeostatic tumor cell proliferation and baseline cytokine production via a previously undefined IL17RA-A20-GSK3β axis. Citation Format: Dongpu Li, Jun Wang. IL-17RA expression by NSCLC is vital for restraining homeostatic tumor cell proliferation and baseline cytokine production [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5215.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.007 | 0.003 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".