Abstract 1192: Regulation of CCND2, HMGA2, and the IGF pathway by LIN28B in HPV negative head and neck squamous cell carcinoma (HNSCC)
Bibliographic record
Abstract
Abstract Background: Lin28 and Lin28B have recently been implicated in the post-transcriptional regulation of Let-7/miR-98 biogenesis. While Lin28B over-expression has been associated with worse clinical outcome in several human cancers, the prognostic significance of Lin28B expression and the molecular mechanism(s) by which it drives tumour progression remains largely unknown. Methods: Let-7-Resist Lin28B-expression plasmid was stably transfected into the FaDu human hypopharyngeal squamous cell carcinoma line. MicoRNA expression profiling was conducted using the Nanostring nCounter Analysis System. Genome-wide micro-array and in silico analyses were utilized to identify Let-7/miR-98 targets. Cell viability and apoptosis were measured using MTS assay and flow cytometry, respectively. In vivo experiments were conducted using SCID mice. Results: qRT-PCR analysis of genes involved in the miRNA biogenesis pathway (DICER, LIN28, LIN28B, and TUT4) suggested an inverse relationship between the expression of Lin28B and mature Let-7 miRNA. Over-expression of Lin28B mediated significant increase in the migration of FaDu cells in vitro, and tumor growth in SCID mice, which in turn, was associated with marked reduction in the Let-7 family of microRNAs. Using a tri-Pronged approach by combining prediction algorithms, experimentally-derived mRNA profiling, along with gene expression data in primary HNSCC samples identified several upregulated Let-7/miR98 gene targets in Lin28B-FaDu cells, including CCND2, HMGA2, and regulators of the insulin growth factor (IGF) mitogenic pathway. Concordantly, treating FaDu-Lin28B cells with IGF (10-50 nM) led to a 26% and 50% increase in cell viability under stress conditions (serum starvation), whereas treating FaDu-GFP cells with IGF had no effect on viability, suggesting the relevance of the IGF axis in FaDu-Lin28B cells. Furthermore, analyzing publicly available data sets on primary HPV positive vs. HPV negative HNSCC samples revealed a significantly higher expression of HMGA2, and genes that regulate the IGF pathway in the latter group of tumours, suggesting a possible role for Lin28B, Let-7/miR-98 and their downstream targets in mediating the more aggressive behavior of HPV negative HNSCC. Conclusions: Our data report for the first time, a potentially important role for Lin28B in regulating the IGF mitogenic pathway, as one possible mechanism in driving the biological behaviour of HPV negative HNSCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1192. doi:10.1158/1538-7445.AM2011-1192
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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) | 0.001 | 0.000 |
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".