SPARC promoter hypermethylation in colon cancer and the effect of 5-Aza-2’deoxycytidine in enhancing SPARC gene expression and therapy sensitivity.
Bibliographic record
Abstract
2888 SPARC is a matricellular glycoprotein that has variable expression in many types of cancers. Its expression may be dependent on epigenetic mechanisms, as hypermethylation of the SPARC promoter accounts for loss of SPARC gene expression in pancreatic and lung cancers. Our laboratory previously observed a decrease in SPARC in colorectal cancers (CRC) and showed an inverse correlation between low levels of SPARC and chemotherapy sensitivity. These observations led us to wonder if a similar epigenetic effect may be at play, and whether a therapeutic strategy using demethylating agents may enhance SPARC expression and improve therapy sensitivity in CRC. Therefore, theAIM of this study was to determine if methylation of the SPARC promoter is a potential mechanism responsible for decreased SPARC expression in CRC. METHODS: DNA extracted from CRC cell lines (MIP 101, RKO, HCT 116, and HT29) underwent bisulfite treatment prior to the determination of SPARC promoter methylation status using methylation-specific PCR (MSP). The effect of SPARC promoter methylation on gene expression, and cell viability following exposure to 5-Aza-2’deoxycytidine (5-Aza), a demethylating agent, in combination with 5-Fluorouracil (5-FU) was also assessed. Our preliminary RESULTS demonstrated hypermethylation in MIP101 and RKO cells in the entire region spanning the SPARC promoter, but incomplete methylation in HCT 116 and HT29 cells was observed. Evaluation of a limited number of clinical samples of CRCs revealed that in 33% of cases, SPARC promoter methylation was present. These results suggest that in a subset of CRCs, SPARC promoter hypermethylation may contribute to repressing its transcription. This methylation status could be reversed in all four cell lines following exposure to 8 µM 5-Aza, with concomitant increases at the transcriptional level. Furthermore, in HCT 116 cells, a significant decrease in cell viability could be observed following incubation of 5-Aza and 100µM of 5-FU in comparison to 5-FU alone: from 99.6%+ 5.3viable cells (5-FU treated only) to 77.4% + 8.1. In CONCLUSION, SPARC promoter methylation may play a role in the transcriptional downregulation of SPARC in CRC, and the addition of a demethylating agent that upregulates SPARC expression may be a useful adjunct in the treatment of CRC.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.002 | 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".