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LOXL1-AS1 inhibits JAK2 ubiquitination and promotes cholangiocarcinoma progression through JAK2/STAT3 signaling

Cancer Gene Therapy volume 31, pages 552–561 (2024)Cite this article

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Abstract

This study thoroughly investigated the role of the long non-coding RNA LOXL1-AS1 in the pathogenesis of cholangiocarcinoma (CCA). Through bioinformatics analysis and tissue samples validation, the study found that LOXL1-AS1 was significantly elevated in CCA, with its high expression closely tied to clinical pathological features and prognosis. In vitro and in vivo experiments revealed that LOXL1-AS1 was crucial in regulating CCA cell apoptosis, proliferation, migration, and invasion. Further investigations using FISH, subcellular localization experiments, RNA pull down, and RIP uncovered that LOXL1-AS1 primarily resided in the cytoplasm and influenced CCA progression by modulating the JAK2/STAT3 signaling pathway. Notably, LOXL1-AS1 might regulate the activity of JAK2 through modulating its ubiquitination and degradation. YY1 had also been found to act as an upstream transcription factor of LOXL1-AS1 to impact CCA cell malignancy. These findings shed light on the pivotal role of LOXL1-AS1 in CCA and offered potential directions for novel therapeutic strategies, providing a fresh perspective on tumor pathogenesis.

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Fig. 1: LOXL1-AS1 exhibited elevated expression in cholangiocarcinoma.
Fig. 2: LOXL1-AS1 augmented the proliferation and anti-apoptotic capabilities.
Fig. 3: LOXL1-AS1 enhanced the CCA migratory and invasive capacities.
Fig. 4: LOXL1-AS1 modulated the JAK2/STAT3 signaling pathway.
Fig. 5: LOXL1-AS1 restrained the ubiquitin-proteasomal degradation of JAK2 protein.
Fig. 6: Reversal of oncogenic effects by JAK2 inhibition following LOXL1-AS1 overexpression.
Fig. 7: Transcription factor YY1 galvanized the expression of LOXL1-AS1.

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Data availability

The data used to support the findings of this study are available from the corresponding author upon request.

References

  1. Wu MJ, Shi L, Dubrot J, Merritt J, Vijay V, Wei TY, et al. Mutant IDH inhibits IFNgamma-TET2 signaling to promote immunoevasion and tumor maintenance in cholangiocarcinoma. Cancer Discov. 2022;12:812–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Jiang XM, Li ZL, Li JL, Zheng WY, Li XH, Cui YF, Sun DJ. LncRNA CCAT1 as the unfavorable prognostic biomarker for cholangiocarcinoma. Eur Rev Med Pharm Sci. 2017;21:1242–7.

    Google Scholar 

  3. Valle JW, Kelley RK, Nervi B, Oh D-Y, Zhu AX. Biliary tract cancer. Lancet. 2021;397:428–44.

    Article  CAS  PubMed  Google Scholar 

  4. Guan CH, Liu L, Zhao YQ, Zhang XH, Liu GL, Wang HC, et al. YY1 and eIF4A4 are mediators of the cell proliferation, migration and invasion in cholangiocarcinoma promoted by circ-ZNF609 by targeting miR-432-5p to regulate LRRC1. Aging. 2021;13:25195–212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Blechacz B. Cholangiocarcinoma: Current knowledge and new developments. Gut Liver. 2017;11:13–26.

    Article  PubMed  Google Scholar 

  6. Kendall T, Verheij J, Gaudio E, Evert M, Guido M, Goeppert B, et al. Anatomical, histomorphological and molecular classification of cholangiocarcinoma. Liver Int. 2019;39:7–18.

    Article  CAS  PubMed  Google Scholar 

  7. Brindley PJ, Bachini M, Ilyas SI, Khan SA, Loukas A, Sirica AE, et al. Cholangiocarcinoma. Nat Rev Dis Prim. 2021;7:65–81.

    Article  PubMed  Google Scholar 

  8. Bertuccio P, Malvezzi M, Carioli G, Hashim D, Boffetta P, El-Serag HB, et al. Global trends in mortality from intrahepatic and extrahepatic cholangiocarcinoma. J Hepatol. 2019;71:104–14.

    Article  PubMed  Google Scholar 

  9. Mirzaei S, Gholami MH, Hushmandi K, Hshemi F, Zabolian A, Canadas I, et al. The long and short non-coding RNAs modulating EZH2 signaling in cancer. J Hematol Oncol. 2022;15:18–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Sun DS, Guan CH, Wang WN, Hu ZT, Zhao YQ, Jiang XM. LncRNA NORAD promotes proliferation, migration and angiogenesis of hepatocellular carcinoma cells through targeting miR-211-5p/FOXD1/VEGF-A axis. Microvasc Res. 2020;134:104120.

    Article  PubMed  Google Scholar 

  11. Kim J, Piao H-L, Kim B-J, Yao F, Han Z, Wang Y, et al. Long noncoding RNA MALAT1 suppresses breast cancer metastasis. Nat Genet. 2018;50:1705–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Amodio N, Stamato MA, Juli G, Morelli E, Fulciniti M, Manzoni M, et al. Drugging the lncRNA MALAT1 via LNA gapmeR ASO inhibits gene expression of proteasome subunits and triggers anti-multiple myeloma activity. Leukemia. 2018;32:1948–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang G, Li H, Hou Y. LncRNA MAGI2-AS3 inhibits tumor progression and angiogenesis by regulating ACY1 via interacting with transcription factor HEY1 in clear cell renal cell carcinoma. Cancer Gene Ther. 2022;29:585–96.

    Article  CAS  PubMed  Google Scholar 

  14. Wang Z, He J, Bach D, Huang Y, Li Z, Liu H, et al. Induction of m(6)A methylation in adipocyte exosomal LncRNAs mediates myeloma drug resistance. J Exp Clin Cancer Res. 2022;41:4–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Najafi S, Ghafouri-Fard S, Hussen BM, Jamal HH, Taheri M, Hallajnejad M. Oncogenic roles of small nucleolar RNA host gene 7 (SNHG7) long noncoding RNA in human cancers and potentials. Front Cell Dev Biol. 2022;9:809345.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zhang P, Zhao F, Jia K, Liu XL. The LOXL1 antisense RNA 1 (LOXL1-AS1)/microRNA-423-5p (miR-423-5p)/ectodermal-neural cortex 1 (ENC1) axis promotes cervical cancer through the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. Bioengineered. 2022;13:2567–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Xie N, Fei XQ, Liu SL, Liao J, Li YJ. LncRNA LOXL1-AS1 promotes invasion and proliferation of non-small-cell lung cancer through targeting miR-324-3p. Am J Transl Res. 2019;11:6403–12.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Bai TL, Liu YB, Li BH. LncRNA LOXL1-AS1/miR-let-7a-5p/EGFR-related pathway regulates the doxorubicin resistance of prostate cancer DU-145 cells. IUBMB Life. 2019;71:1537–51.

    Article  CAS  PubMed  Google Scholar 

  19. Yi BL, Li H, Cai H, Lou X, Yu MJ, Li Z. LOXL1-AS1 communicating with TIAR modulates vasculogenic mimicry in glioma via regulation of the miR-374b-5p/MMP14 axis. J Cell Mol Med. 2022;26:475–90.

    Article  CAS  PubMed  Google Scholar 

  20. Liu CN, Zhang HY. Serum lncRNA LOXL1-AS1 is a diagnostic and prognostic marker for epithelial ovarian cancer. J Gene Med. 2020;22:e3233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Yang J, He W, Gu L, Zhu L, Liang T, Liang X, et al. CircFOXP1 alleviates brain injury after acute ischemic stroke by regulating STAT3/apoptotic signaling. Transl Res. 2023;257:15–29.

    Article  CAS  PubMed  Google Scholar 

  22. Nie XH, Qiu S, Xing Y, Xu J, Lu B, Zhao SF, et al. Paeoniflorin regulates NEDD4L/STAT3 pathway to induce ferroptosis in human glioma cells. J Oncol. 2022;2022:6093216.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Hu X, Li J, Fu M, Zhao X, Wang W. The JAK/STAT signaling pathway: from bench to clinic. Signal Transduct Target Ther. 2021;6:402–34.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Li X, Wang X, Liu YS, Wang XD, Zhou J, Zhou H. Downregulation of miR-3568 protects against ischemia/reperfusion-induced cardiac dysfunction in rats and apoptosis in H9C2 cardiomyocytes through targeting TRIM62. Front Pharm. 2020;11:17–27.

    Article  Google Scholar 

  25. Kanno H, Matsumoto S, Yoshizumi T, Nakahara K, Kubo A, Murata H, et al. Role of SOCS and VHL proteins in neuronal differentiation and development. Int J Mol Sci. 2023;24:3880–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang J, Zhang Y, Song H, Yin H, Jiang T, Xu Y, et al. The circular RNA circSPARC enhances the migration and proliferation of colorectal cancer by regulating the JAK/STAT pathway. Mol Cancer. 2021;20:81–100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Mcgrath NA, Fu J, Gu SZ, Xie C. Targeting cancer stem cells in cholangiocarcinoma (review). Int J Oncol. 2020;57:397–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dongre A, Weinberg RA. New insights into the mechanisms of epithelial-mesenchymal transition and implications for cancer. Nat Rev Mol Cell Biol. 2019;20:69–84.

    Article  CAS  PubMed  Google Scholar 

  29. Yang T, Liang L, Wang MD, Shen F. FGFR inhibitors for advanced cholangiocarcinoma. Lancet Oncol. 2020;21:610–2.

    Article  PubMed  Google Scholar 

  30. Rizvi S, Khan SA, Hallemeier CL, Kelley RK, Gores GJ. Cholangiocarcinoma-evolving concepts and therapeutic strategies. Nat Rev Clin Oncol. 2018;15:95–111.

    Article  CAS  PubMed  Google Scholar 

  31. Zhang W, Wu Q, Liu Y, Wang X, Ma C, Zhu W. LncRNA HOTAIR promotes chemoresistance by facilitating epithelial to mesenchymal transition through miR-29b/PTEN/PI3K signaling in cervical cancer. Cells Tissues Organs. 2022;211:16–29.

    Article  CAS  PubMed  Google Scholar 

  32. Zheng Y, Qi F, Li L, Yu B, Cheng Y, Ge M, et al. LncNAP1L6 activates MMP pathway by stabilizing the m6A-modified NAP1L2 to promote malignant progression in prostate cancer. Cancer Gene Ther. 2023;30:209–18.

    Article  CAS  PubMed  Google Scholar 

  33. Wang J, Huang TJ, Mei Y, Luo FF, Xie DH, Peng LX, et al. Novel long noncoding RNA LINC02820 augments TNF signaling pathway to remodel cytoskeleton and potentiate metastasis in esophageal squamous cell carcinoma. Cancer Gene Ther. 2023;30:375–87.

    Article  CAS  PubMed  Google Scholar 

  34. Lin Z, Song J, Gao Y, Huang S, Dou R, Zhong P, et al. Hypoxia-induced HIF-1 alpha/lncRNA-PMAN inhibits ferroptosis by promoting the cytoplasmic translocation of ELAVL1 in peritoneal dissemination from gastric cancer. Redox Biol. 2022;52:102312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Winkle M, El-Daly SM, Fabbri M, Calin GA. Noncoding RNA therapeutics-challenges and potential solutions. Nat Rev Drug Discov. 2021;20:629–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Goudarzi M, Berg K, Pieper LM, Schier AF. Individual long non-coding RNAs have no overt functions in zebrafish embryogenesis, viability and fertility. Elife. 2019;8:e40815.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Guo T, Peng SA, Liu DF, Li YY. Long non-coding RNA LOXL1-AS1 facilitates colorectal cancer progression via regulating miR-1224-5p/miR-761/HK2 Axis. Biochem Genet. 2022;60:2416–33.

    Article  CAS  PubMed  Google Scholar 

  38. Yu W, Dai Y. lncRNA LOXL1-AS1 promotes liver cancer cell proliferation and migration by regulating the miR-377-3p/NFIB axis. Oncol Lett. 2021;22:624–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Li HL, Chu J, Jia JL, Sheng JX, Zhao X, Xing YR, et al. LncRNA LOXL1-AS1 promotes esophageal squamous cell carcinoma progression by targeting DESC1. J Cancer. 2021;12:530–8.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Liu SJ, Dang HX, Lim DA, Feng FY, Maher CA. Long noncoding RNAs in cancer metastasis. Nat Rev Cancer. 2021;21:446–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by grants from Heilongjiang Postdoctoral Science Foundation (LBH-Q21023), National Natural Science Foundation of Heilongjiang Province (LH2020H058).

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  1. These authors contributed equally: Shaobo Yu, Xin Gao, Sidi Liu, Xiangjun Sha.

Authors and Affiliations

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

    Shaobo Yu, Xin Gao, Sidi Liu, Xiangjun Sha, Siyuan Zhang, Xinmiao Zhang, Dongsheng Sun & Xingming Jiang

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Contributions

SBY, XG, and SDL designed and executed the experiments. XJS collected the data. DSS and XMJ. provided the experimental resources. SYZ and XMZ wrote and modified the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Dongsheng Sun or Xingming Jiang.

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Yu, S., Gao, X., Liu, S. et al. LOXL1-AS1 inhibits JAK2 ubiquitination and promotes cholangiocarcinoma progression through JAK2/STAT3 signaling. Cancer Gene Ther 31, 552–561 (2024). https://doi.org/10.1038/s41417-024-00726-2

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