Abstract 5513: Role of the evolutionarily conserved TBX2 subfamily of transcription factors in the molecular pathogenesis of human lung adenocarcinoma
Bibliographic record
Abstract
Abstract T-box (TBX) transcription factors are evolutionary conserved genes and master regulators of transcription repression and activation. In mammals, 18 members were described functionally and structurally, of which the TBX2 subfamily (TBX2, TBX3, TBX4, TBX5) genes were shown to be expressed early on in the developing lung bud and tracheae. Despite these insights into the role of the TBX2 subfamily in normal lung organogenesis, little is known about the role of these genes in pathological pulmonary conditions in humans; particularly lung cancer, an aggressive malignancy that is the leading cause of cancer-deaths worldwide. To fill this void, our group previously surveyed the expression of TBX2 subfamily in various publicly available datasets and found that all four members were preferentially and highly expressed in human normal lung, but markedly and consistently suppressed in lung adenocarcinoma (LUAD) the most common histological subtype of lung cancer. We also showed that the subfamily was also suppressed in preneoplastic lesions preceding the development of LUADs. Following the above and to further elucidate the role of the TBX2 subfamily in LUAD pathogenesis, we first probed and confirmed abundant expression of protein products of the four members by immunostaining in adult human normal lung tissues. On the other hand, quantitative real-time PCR and western blotting analyses demonstrated overall suppressed expression of the genes and corresponding proteins in a panel of human LUAD cell lines. Transient over-expression of each of the four genes in human LUAD cell lines (H1299 and H1944) was found to overall significantly inhibit cancer cell growth and proliferation. Additionally, over-expression of the four genes induced apoptosis, evidenced by sub-G0/G1 accumulation following cell cycle analysis, in both cell lines (ranging from 40% to 90% compared to control). To understand genome-wide effects of TBX2 subfamily in LUAD, we interrogated global expression programs downstream of these transcription factors by RNA-Seq in H1299 cells engineered to over-express the four members separately. We unraveled novel signaling cues signifying canonical pathways found in our analysis to be directly regulated by members of the TBX2 subfamily. These included, among others, inhibition of cell cycle progression and glycolysis, suppression of pathways mediated by epidermal growth factor (EGFR) and WNT signaling and activation of the major anti-tumor immune marker interferon gamma (IFNG). All in all, our findings point to tumor suppressor roles for TBX2 subfamily in human LUAD pathogenesis and suggest “oncophenotypes” downstream of these factors as putative targets for lung cancer therapy. Citation Format: Athar Khalil, Nehme El-Hachem, Batoul Dekmak, Humam Kadara, Georges Nemer. Role of the evolutionarily conserved TBX2 subfamily of transcription factors in the molecular pathogenesis of human lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5513.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
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".