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ZNF460-mediated upregulation of APCDD1L-DT promotes cholangiocarcinoma development by inhibiting the ubiquitin-mediated degradation of DVL2

Cancer Gene Therapy volume 31, pages 1585–1597 (2024)Cite this article

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Abstract

Cholangiocarcinoma (CCA), known for its aggressive nature, poses a formidable challenge in the current medical landscape, particularly in targeted therapies. Against this backdrop, long non-coding RNAs (lncRNAs) have captured the attention of researchers. These unique RNAs are believed to play pivotal roles in various cancers, offering promising avenues for the development of more effective treatment strategies. Previous studies have substantiated the aberrant expression of the APCDD1L-DT in numerous human tumors, demonstrating its positive regulatory roles in disease progression. Nevertheless, the biological functions of APCDD1L-DT in CCA are still not fully understood. This study marks the inaugural documentation of APCDD1L-DT exhibiting aberrant expression in CCA specimen, establishing a close correlation with the TNM staging of tumor patients. Furthermore, suppressing APCDD1L-DT expression hinders both the viability and motility of tumor cells. Mechanistically, the abnormal activation of the transcription factor ZNF460 positively regulated APCDD1L-DT expression in CCA. This activation, in turn, propels the abnormal activation of the Wnt pathway, fostering tumor development by impeding the ubiquitin-mediated degradation of DVL2. Broadly speaking, this study provides auspicious perspectives for comprehending CCA and furnishes support for addressing this daunting malignancy.

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Fig. 1: The expression of APCDD1L-DT was dysregulated in CCA tissues.
Fig. 2: Silencing APCDD1L-DT suppressed the malignant biological behaviors of cholangiocarcinoma tumor cells.
Fig. 3: Suppression of APCDD1L-DT impeded CCA progression in vivo.
Fig. 4: APCDD1L-DT expression level was closely associated with Wnt signaling pathway activation.
Fig. 5: The biological function of DVL2 in CCA.
Fig. 6: The intrinsic mechanism of APCDD1L-DT in regulating the expression of DVL2.
Fig. 7: ZNF460 acted as the transcription factor for APCDD1L-DT.

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Data availability

The datasets generated during the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This work was supported by the Heilongjiang Postdoctoral Science Foundation (Grant No. LBH-Q21023) and the National Natural Science Foundation of China (Grant No. 82270599).

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  1. These authors contributed equally: Xin Gao, Xinlei Zou, Canghai Guan, Xiangjun Sha.

Authors and Affiliations

  1. Department of General Surgery, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, China

    Xin Gao, Xinlei Zou, Canghai Guan, Xiangjun Sha, Sidi Liu, Xinmiao Zhang, Chengru Yang, Xiangyu Zhong & Xingming Jiang

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Contributions

XG, XLZ, CHGm, and XJS designed and executed the experiments. SDL collected the data. XYZ and XMJ provided the experimental resources. XMZ and CRY wrote and modified the paper. All authors have read and approved the final paper.

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Correspondence to Xiangyu Zhong or Xingming Jiang.

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Gao, X., Zou, X., Guan, C. et al. ZNF460-mediated upregulation of APCDD1L-DT promotes cholangiocarcinoma development by inhibiting the ubiquitin-mediated degradation of DVL2. Cancer Gene Ther 31, 1585–1597 (2024). https://doi.org/10.1038/s41417-024-00826-z

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