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FNDC1 Competitively Binds Gbeta2 to Suppress the beta-Catenin-Destruction Complex and Promote Gastric Cancer Malignancy

FASEB J. 2026 Mar 31;40(6):e71634. doi: 10.1096/fj.202503587R.

ABSTRACT

Gastric cancer (GC) is a leading cause of cancer-related deaths and has high recurrence rate. Although fibronectin domain-containing protein 1 (FNDC1) is implicated in GC progression, its molecular mechanisms remain unclear. Multi-omics analyses (TCGA, GEO datasets) were used to assess FNDC1 expression and clinical correlation. In vitro (cell proliferation, invasion, EMT markers) and in vivo (xenograft) experiments, combined with molecular assays (Co-IP, WB, ChIP), explored FNDC1's function and mechanism. FNDC1 was significantly upregulated in GC, correlating with advanced clinicopathological features and poor prognosis. Knockdown of FNDC1 suppressed GC cell proliferation, invasion, and metastasis by inhibiting EMT and Wnt/Ξ²-catenin signaling. Mechanistically, FNDC1 competitively bound the WD5 domain (residues 224-254) of GΞ²2, disrupting GΞ²Ξ³-Dvl1 interaction. This prevented Dvl1 degradation, promoted Axin1 ubiquitination, and destabilized the Ξ²-catenin-destruction complex (GSK3 Ξ²-APC-Axin1), leading to Ξ²-catenin accumulation and Wnt pathway activation. FNDC1 drives GC malignancy by targeting the GΞ²2-Dvl1 axis to activate Wnt/Ξ²-catenin signaling, suggesting FNDC1 as a novel prognostic biomarker and therapeutic target.

PMID:41808415 | PMC:PMC12976582 | DOI:10.1096/fj.202503587R

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CDRRM: Contrast-Driven Rubric Generation for Reliable and Interpretable Reward Modeling

arXiv:2603.08035v1 Announce Type: new Abstract: Reward modeling is essential for aligning Large Language Models(LLMs) with human preferences, yet conventional reward models suffer from poor interpretability and heavy reliance on costly expert annotations. While recent rubric-based approaches enhance evaluation transparency, they lack systematic quality control, yielding noisy and redundant criteria, failing to mitigate persistent biases (e.g., verbosity, position) in LLM evaluators, and creating a scalability-reliability trade-off. To address these limitations, we propose CDRRM (Contrast-Driven Rubric Reward Model), a framework built on a novel Contrast-then-Synthesis paradigm for high-quality rubric generation and guided preference judgment. CDRRM first conducts multi-dimensional contrastive profiling on preference pairs to identify causal discriminative factors, then synthesizes these insights into compact, context-aware rubrics to guide preference judg- ments. Extensive experiments on three authoritative benchmarks (RewardBench, RMBench, RMB) demonstrate that CDRRM achieves state-of-the-art performance across diverse domains and effectively mitigates aforementioned evaluation biases. Notably, our approach delivers exceptional data efficiency: training the rubric generator on only 3k high-quality samples empowers a frozen pre-trained judge model to outperform fully fine-tuned baselines. This work offers a scalable, interpretable, and data-efficient path for reward modeling.
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