402.4: The therapeutic potential of targeting nuclear receptor retinoic acid-related orphan receptor gamma in hepatocellular carcinoma.
Bibliographic record
Abstract
Background: Hepatocellular carcinoma (HCC) primarily arises though inflammation-associated etiologic factors that lead to liver cirrhosis. Type 3 immunity which is characterized by cells that produce the pro-inflammatory IL-17A cytokine, which is modulated by the master transcriptional factor retinoid acid-related orphan receptor gamma (RORy), plays a significant role in acute and chronic allograft rejection. Moreover, over-expression of the cytokine and its transcription factor are implicated in inflammatory pathways that lead to metabolic syndrome, cirrhosis and the development of several cancers, including cirrhosis-induced HCC. Currently, liver transplantation is the most effective therapy for HCC. Advanced disease, however, is a contradiction due to the risk of recurrence. We therefore investigated whether RORy is expressed in human and mouse HCC cell lines, and if targeting the receptor affects HCC cell viability, proliferation, and colony formation. Methods: Human HCC cell line HuH-7 and mouse HCC cell lines Hepa1-6 and Hep-55.1c were used. RORy-targeting silencing RNA (siRORC) sequences were designed and a novel RORy inverse agonist (C#10) generated at the McGill University Health Center Research Institute were used to inhibit RORy activity. The assays used to test the effects of siRORC and C#10 inhibition in HCC cells include cell viability assays, colony formation assays, cell proliferation assays, RT-qPCR, immunofluorescence microscopy and western blot. Results: HCC cell lines HuH-7, Hepa1-6, and Hep-55.1c highly express nuclear receptor RORy. siRORC and C#10 reduced RORy expression in all 3 cell lines. Cell viability was decreased significantly in a dose dependent manner upon a 72 hour treatment with siRORC and inverse agonist C#10.Colony formation assays revealed a visible and statistically significant reduction in HCC cell growth with siRORC and increasing concentrations of C#10.In addition, cell proliferation rate is reduced with siRORC and reverse agonist C#10 treatment. Conclusion: Human and mouse HCC cells highly express RORy. Targeting RORy with siRORC or RORy inverse agonist C#10 suppressed cell viability, cell proliferation and colony formation of all three cell lines. This data suggests that RORy is a potential target for HCC and may have the dual benefit of preventing allograft rejection and HCC recurrence after liver transplantation. Avrith Liver Transplant Endowment Fund. MUHC-Foundation. MGH-Foundation Start Up Funds.
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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) | 0.003 | 0.001 |
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".