Uev1A-Ubc13 promotes colorectal cancer metastasis through regulating<i>CXCL1</i>expression via NF-кB activation
Bibliographic record
Abstract
// Zhaojia Wu 1 , Heather Neufeld 2 , Eminao Torlakovic 2, 3 and Wei Xiao 1 1 Department of Microbiology and Immunology, University of Saskatchewan, Saskatoon S7N 5E5, Canada 2 Department of Pathology and Laboratory Medicine, University of Saskatchewan, Saskatoon S7N 5E5, Canada 3 Current address: Department of Laboratory Hematology, Toronto General Hospital/UHN, Toronto M5G 2C4, Canada Correspondence to: Wei Xiao, email: wei.xiao@usask.ca Keywords: colorectal cancer; metastasis; Uev1A; NF-кB; CXCL1 Received: May 01, 2017 Accepted: February 20, 2018 Published: March 23, 2018 ABSTRACT Colorectal cancer is the second most common cause of cancer-related death worldwide. Uncontrolled growth and distant metastasis are hallmarks of colorectal cancer. However, the precise etiological factors and the mechanisms are diverse and still largely unclear. The potential proto-oncogene UEV1A encodes a ubiquitin conjugating enzyme variant, which is required for Ubc13-catalyzed K63-linked poly-ubiquitination of target proteins and the activation of NF-кB, a transcription factor known to be involved in innate immunity, anti-apoptosis, inflammation and cancer. In order to understand the roles of Uev1A in colon cancer progression, we experimentally manipulated the Uev1A level in HCT116 colon cancer cells and found that UEV1A overexpression alone is sufficient to promote invasion in vitro and metastasis in vivo . This process is mediated by NF-κB activation and depends on its physical interaction with Ubc13. No expression of Uev1A was detected in histologically normal human colonic mucosa, but its expression was detected in human colorectal adenocarcinoma, which was closely correlated with nuclear p65 levels, an indicator of NF-κB activation. Uev1A protein was detected in 46% of primary tumors and 79% of metastatic tumors examined. Our experimental data establish that among NF-κB target genes, Uev1A-regulated CXCL1 expression plays a critical role in colon cell invasion and metastasis, a notion supported by the colon adenocarcinoma survey. Furthermore, experimental depletion of Uev1 in HCT116 cells reduces CXCL1 expression, and prevents cell invasion and tumor growth in a xenograft mouse model. These results identify Uev1A as a potential therapeutic target in the treatment of metastatic colorectal cancers.
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".