AP4 modulated by the PI3K/AKT pathway promotes prostate cancer proliferation and metastasis of prostate cancer via upregulating L-plastin
Bibliographic record
Abstract
The transition from androgen-dependent to metastatic castration-resistant prostate cancer (PCa) is a lethal event of uncertain molecular aetiology. Our previous studies demonstrated that L-plastin is involved in PCa invasion and metastasis and is upregulated by androgen and oestrogen in the hormone-dependent PCa cell line LNCaP. We recently found that L-plastin expression is consistently activated even after androgen deprivation, suggesting that androgen-independent transcription factors may regulate its expression. Herein, we performed sequential deletion and luciferase analysis of the L-plastin promoter and found that an androgen-independent regulatory factor prominently located in the region close to the transcription initiation site (-216 to +118) may facilitate L-plastin upregulation. AP4 was then identified as the relevant transcription activator that directly binds to the L-plastin promoter, as confirmed by EMSAs, supershift assays and CHIP-qPCR experiments. Moreover, we determined that the AP4/L-plastin axis is regulated by the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, contributing to PCa metastasis and castration resistance. Furthermore, we found that AP4 promotes PCa metastasis by upregulating L-plastin expression in vitro and in vivo. We collected a total of 136 PCa tissues and corresponding adjacent normal tissues from patients who underwent prostatectomy at Sun Yat-Sen Memorial Hospital from 2005 to 2015 and measured AP4 and L-plastin protein levels by immunohistochemistry. The results showed that AP4 levels strongly correlated with those of its downstream target gene L-plastin, were significantly upregulated in PCa tissues, were positively correlated with lymph node metastasis and Gleason scores over 7, and were an independent prognostic factor for patient survival. In summary, these findings support a plausible mechanism by which the AP4/L-plastin axis is regulated by the PI3K/AKT pathway in human PCa and may represent a novel therapeutic target in PCa treatment.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.001 | 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) | 0.000 | 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 teacher head, 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".