Abstract 5038: The repression of the extracellular matrix protein TGFBI induces chemoresistance in nasopharyngeal carcinoma
Bibliographic record
Abstract
Abstract Introduction: Nasopharyngeal carcinoma (NPC) is a malignancy that is strongly associated with Epstein-Barr virus (EBV). The five-year overall survival (OS) rate of locally-advanced NPC patients is ∼65%. Therapeutic options for such patients are limited; ionizing radiation is the primary mode of therapy for early-stage NPC, while chemoradiotherapy is used for more advanced stages. The use of chemotherapy (combined with radiation) provides a modest benefit in OS, but causes significant toxicities. The major cause of death in NPC is distant metastasis (DM), which remains a clinical challenge. In order to identify novel mechanisms underlying this process, our laboratory has recently completed global RNA sequencing of NPC samples which were fully clinically annotated. The extracellular matrix protein TGFBI (Transforming Growth Factor, Beta-Induced) was identified as a potential marker for chemoresistance. The objective of this study was to elucidate the role of TGFBI, and acquire greater insight into the biological pathways leading to chemoresistance and contributing to DM in NPC. Methods: Nasopharyngeal cell lines including NP69 (normal nasopharyngeal, SV-40 immortalized), and C666-1 (NPC, EBV positive) were used to assess the differential expression of TGFBI between normal and malignant cells. TGFBI under-expressing NP69 cells were engineered using shRNA vectors, and the impact of the loss of TGFBI expression was assessed by cell death, clonogenic, and migration assays. Downstream target gene expression was evaluated by quantitative real-time PCR (qRT-PCR) and Western blot. C666-1 cells, which had no expression of TGFBI (RNA or protein), were used as controls. Results: RNA-seq data identified poorer distant relapse-free survival in chemoradiotherapy-treated patients with low TGFBI expression vs. those with high TGFBI expression. In concordance with this observation, in vitro down-regulation of TGFBI induced cisplatin resistance via the phosphorylation of Akt and PTEN. TGFBI downregulation also increased cellular migration in spheroid cultures. Furthermore, TGFBI was identified to be a target of miR-449b, one of the 4 microRNAs in a DM prognostic signature that was previously identified by our group (Oncotarget 6:4537, 2015). In turn, over-expression of miR-449b in nasopharyngeal cells increased phospho-Akt expression, phenocopying the results observed in the TGFBI experiments. Conclusion: Together, these data suggest that the miR-449∼TGFBI-Akt axis plays a significant role in both treatment resistance and metastasis in NPC. Further studies will allow us to elucidate additional components of this pathway, and identify novel therapeutic targets which can benefit future patients with NPC. Citation Format: Pierre-Antoine Bissey, Jeff W. Bruce, Jacqueline Law, Kenneth W. Yip, Fei-Fei Liu. The repression of the extracellular matrix protein TGFBI induces chemoresistance in nasopharyngeal carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5038.
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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 | 0.000 |
| 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".