Abstract 2396: Function of HLTF in the development of colon cancer and in the maintenance of genomic stability
Bibliographic record
Abstract
Abstract HLTF (Helicase like Transcription Factor) is a DNA helicase protein which is homologous to SNF/SWI family. It has also been shown to be a functional homolog of yeast rad5, required for the maintenance of genomic stability through the ubiquitination of proliferating cell nuclear antigen (PCNA). Although the physiologic role of HLTF is largely unknown, inactivation of HLTF by promoter methylation has been demonstrated in more than 40% human colon cancers. In this study, we have applied mouse transgenic approaches to determine whether loss of HLTF function could be important for colorectal carcinogenesis. HLTF knockout mice were created by the deletion of first 5 exons of HLTF genome. The complete loss of HLTF expression in these mice was confirmed by Northern blot and RT-PCR assays. HLTF knockout mice did not show any developmental defects within a 2-year observation, indicating that HLTF is dispensable for normal development, and loss of HLTF function alone is not sufficient to drive colon carcinogenesis. To determine whether loss of HLTF function could cooperate with other tumor suppressors in the formation of colon cancers, we have bred HLTF knockout mice with the mutant mice for p53 and Apc (adenomtous polyposis coli). In HLTF−/−/Apc+/− mice, the significantly increased formation of intestinal adenocarcinoma and colon cancers were observed. Although very few HLTF−/−/p53−/− mice developed colon cancers, these mice had increased incidence of lymphoma formation. This finding suggests that loss of HLTF function could not only promote colon cancer formation, but also for other types of tumor. Cytogenetic analysis of colon cancer cells derived from HLTF−/−Apc+/− mice demonstrated a high incidence of gross chromosomal instabilities, including Robertsonian fusions, fragments and aneuploidy. All these genetic alterations were not observed in the intestinal tumor cells from Apc+/−, implicating that loss of HLTF function could induce genomic instability which contributes to colorectal carcinogenesis. To further establish the role of HLTF in the maintenance of genomic stability, we have also derived HLTF deficient mouse embryonic stem (ES) cells, and demonstrated that HLTF−/− ES cells exhibited similar, but a milder genetic alterations as observed in HLTF deficient colon cancer cells. Taken together, our work provides direct genetic evidence that loss of HLTF function as observed in a majority of human colon cancers is able to promote colorectal carcinogenesis. This function could be mediated by the induced genomic instability. 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 2396. doi:10.1158/1538-7445.AM2011-2396
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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".