NDRG1 enhances the sensitivity to Cetuximab by promoting Stat1 ubiquitylation in colorectal cancer
Bibliographic record
Abstract
INTRODUCTION: Cetuximab (CTX) is an effective targeted drug for the treatment of metastatic colorectal cancer, but it is effective only in patients with wild-type KRAS genes. Even in this subset of patients, the sensitivity of CTX in patients with right hemi-colon cancer is much lower than that in patients with left hemi-colon cancer. This significantly limits its clinical application. Therefore, further elucidation of the underlying molecular mechanisms is needed. N-myc downstream-regulated gene 1 (NDRG1) plays an important role in solid tumor invasion and metastasis, but whether it can influence CTX sensitivity has not been thoroughly investigated. OBJECTIVE: Our study aimed to identify a novel mechanism by which NDRG1 affects CTX sensitivity. METHODS: Through mass spectrometry analysis of our previously constructed CTX-resistant RKO and HCT116 cells, we found that the signal transducer and activator of transcription-1 (Stat1) might be a potential target of NDRG1. By knocking out NDRG1 or/and Stat1 genes, we then applied the loss-of-function experiments to explore the regulatory relationship between NDRG1 and Stat1 and their roles in the cell cycle, epithelial-mesenchymal transition (EMT), and the sensitivity to CTX in these two colorectal cancer (CRC) cells. Finally, we used the nude-mouse transplanted tumor model and human CRC samples to verify the expression of NDRG1 and Stat1 and their impact on CTX sensitivity in vivo. RESULTS: Stat1 was upregulated in CTX-resistant cells, whereas NDRG1 was downregulated. Mechanically, NDRG1 was inversely correlated with Stat1 expression. It suppressed CRC cell proliferation, migration, and invasion, and promoted apoptosis and epithelial-mesenchymal transition (EMT) by inhibiting Stat1. In addition, NDRG1 directly interacted with Stat1 and promoted Smurf1-induced Stat1 ubiquitination. Importantly, this novel NDRG1-dependent regulatory loop also enhanced CTX sensitivity both in vitro and in vivo. CONCLUSION: Our study revealed that NDRG1 enhanced the sensitivity to Cetuximab by inhibiting Stat1 expression and promoting its ubiquitination in colorectal cancer, elucidating NDRG1 might be a potential therapeutic target for refractory CTX-resistant CRC tumors. But its clinical value still needs to be validated in a larger sample size as well as a different genetic background.
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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".