LINC00476 cooperates with ARIH2 and suppresses pancreatic cancer progression by inducing VIM ubiquitination: experimental research
Background: - Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid malignancies, with the majority of cases typically diagnosed at an advanced, inoperable stage. Dysregulated long noncoding RNAs (lncRNAs) play a significant role in the progression of PDAC; however, t...
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| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
January 2026
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| In: |
International journal of surgery
Year: 2026, Volume: 112, Issue: 1, Pages: 666-682 |
| ISSN: | 1743-9159 |
| DOI: | 10.1097/JS9.0000000000003596 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1097/JS9.0000000000003596 Verlag, kostenfrei, Volltext: https://journals.lww.com/international-journal-of-surgery/fulltext/2026/01000/linc00476_cooperates_with_arih2_and_suppresses.50.aspx 
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| Author Notes: | Qian Yan, PhD, Yubin Chen, MSc, Zhenchong Li, MSc, Shiye Ruan, MD, Zhongyan Zhang, MSc,Jinwei Cui, MSc, Hexian Shi, MSc, Jike Fang, MSc, Hailiang Wang, MSc, Jiayu Yang, MSc, Shanzhou Huang, PhD, Chuanzhao Zhang, PhD, Baohua Hou, PhD |
| Summary: | Background: - Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid malignancies, with the majority of cases typically diagnosed at an advanced, inoperable stage. Dysregulated long noncoding RNAs (lncRNAs) play a significant role in the progression of PDAC; however, the underlying mechanisms, especially the interactions between lncRNAs and protein modifications, remain poorly understood. - Method: - We initially screened for potential markers among pancreatic cancer-associated lncRNAs using public databases. The involvement of LINC00476 in PDAC cell proliferation, migration, and invasion was confirmed through both in vivo and in vitro experiments. To dissect the molecular mechanisms underlying LINC00476-mediated regulation of PDAC progression and metastasis, we utilized RNA pull-down assays, RNA immunoprecipitation (RIP) assays, Co-immunoprecipitation (Co-IP) assays, and rescue experiments. - Result: - Our findings identify LINC00476 as a novel lncRNA that is generally downregulated in PDAC tissues and correlates with more unfavorable clinicopathological features and poorer patient outcomes. Functionally, LINC00476 suppressed PDAC cell proliferation and invasion in vitro and inhibited lung metastasis in vivo. Mechanistically, LINC00476 directly bound vimentin (VIM) and recruited the E3 ubiquitin ligase Ariadne homolog 2 (ARIH2), promoting K29-linked polyubiquitination of VIM at Lys373 residue and subsequent proteasomal degradation. In a patient-derived xenograft (PDX) model, overexpression of ARIH2 led to a significant reduction in VIM protein levels and tumor growth (P < 0.05). - Conclusion: - Our data suggest that LINC00476 enhances VIM ubiquitination and degradation by recruiting ARIH2, highlighting the role of LINC00476 in PDAC progression and indicating that the overexpression of LINC00476 or ARIH2 may serve as a promising therapeutic strategy for PDAC. |
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| Item Description: | Gesehen am 09.03.2026 |
| Physical Description: | Online Resource |
| ISSN: | 1743-9159 |
| DOI: | 10.1097/JS9.0000000000003596 |