Abstract 322: The integrin α6A splice variant regulates Wnt/β-catenin and colorectal cancer cell proliferation through autophagic degradation of DVL2
Bibliographic record
Abstract
Abstract Introduction: Colorectal cancer (CRC) is the second cause of death by cancer in North America. Recently, we found that both subunits of the integrin α6β4 are up-regulated in colon primary tumours. The α6 integrin subunit exists as two distinct splice isoforms, α6A and α6B, and only the α6A isoform is up-regulated in CRC. Moreover, we discovered that the integrin formed by the α6A isoform is a pro-proliferative integrin regulating the Wnt/β-catenin pathway and tumorigenesis of CRC cells. However, the exact mechanism by which the α6A splice variant controls the Wnt/β-catenin pathway is still unknown. Aim: In the present study, we investigated the mechanism underlying the regulation of Wnt/β-catenin by the integrin α6Aβ4 in human CRC, focusing on the degradation of DVL2 by autophagy. Methods: In order to investigate the mechanism involved in the regulation of the Wnt/β-catenin pathway by the integrin α6Aβ4, expression of the splice variant α6A was specifically abolished, using a small-hairpin RNA approach, in the colon adenocarcinoma cell line T84. Results: Knockdown of the integrin α6A subunit resulted in a significant repression of a number of Wnt/β-catenin pathway end points, including a decrease in DVL2 protein levels. Further analysis demonstrated that the Wnt/β-catenin pathway is restored by pharmacological inhibition of GSK3β, (SB216763) or by over-expression of a mutated β-catenin (S37A). To determine if DVL2 is degraded by autophagy following the abolition of the integrin α6A splice variant, autophagy was activated using an mTOR inhibitor (rapamycin) or inhibited using bafilomycin A1. Western blot analysis showed that subsequent activation of autophagy in T84 shα6A cells led to a significant decrease in DVL2 protein levels followed by a decrease in Wnt/β-catenin pathway end points, while inhibition of autophagy led to a significant increase in DVL2 protein levels. However, no significant change in DVL2 protein levels was observed by the modulation of autophagy in T84 shctl cells. Subsequent analysis revealed comparable autophagy flux between T84 shctl and T84 shα6A cells. The targeting of DVL2 to the autophagosome in T84 shα6A cells was confirmed by a strong co-localization of DVL with p62/SQSTM1. In order to confirm the significant relevance of the decrease of DVL2, both shctl and shα6A cells were treated with a DVL-PDZ domain inhibitor. Preliminary results demonstrated that inhibition of the DVL-PDZ domain led to a decrease in proliferation only in T84 shctl cells. Conclusion: Our study demonstrated for the first time a novel function for the α6A integrin subunit in the control of the degradation of DVL2 by autophagy to regulate the Wnt/β-catenin pathway and cell proliferation. Taken together, these results highlight the possibility for a new therapeutic treatment for CRC taking advantage of autophagy and the mechanism of regulation of the Wnt/β-catenin by the integrin α6A subunit. Citation Format: Jean-Francois Groulx, Jean-Francois Beaulieu. The integrin α6A splice variant regulates Wnt/β-catenin and colorectal cancer cell proliferation through autophagic degradation of DVL2. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 322. doi:10.1158/1538-7445.AM2014-322
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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) | 0.002 | 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".