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LINC00665 activating Wnt3a/β-catenin signaling by bond with YBX1 promotes gastric cancer proliferation and metastasis

Cancer Gene Therapy volume 30, pages 1530–1542 (2023)Cite this article

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Abstract

Long noncoding RNAs (lncRNAs) play a key role in human cancer development; nevertheless, the effect of lncRNA LINC00665 on the progression of gastric cancer (GC) still unclear. In this study, we found that LINC00665 expression is upregulated in GC than normal gastric mucosa tissues and higher LINC00665 expression is associated with a poor prognosis in GC patients. Downregulated LINC00665 inhibited GC cells proliferation, invasion, and migration in vitro. Pulmonary metastasis animal models showed that downregulated LINC00665 could reduce the lung metastasis of GC in vivo. Tumor organoids were generated from human malignant GC tissues, downregulated LINC00665 could inhibit the growth of the organoids of GC tissues. Mechanistically, downregulated LINC00665 could inhibit GC cells EMT. RNA pulldown, RIP, and RIP-seq studies found that LINC00665 can bind to the transcription factor YBX1 and form a positive feed-forward loop. The luciferase reporter and CHIP results showed that YBX1 could regulate the transcriptional activity of Wnt3a, and downregulation of LINC00665 could block the activation of Wnt/β-catenin signaling. In conclusion, our results identified a feedback loop between LINC00665 and YBX1 that activates Wnt/β-catenin signaling, and it may be a potential therapeutic approach to suppress GC progression.

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Fig. 1: LINC00665 expression is upregulated in GC tissues and associated with a poor prognosis in GC patients.
Fig. 2: LINC00665 regulates GC cell progression in vitro.
Fig. 3: LINC00665 promotes tumor formation and metastasis of gastric cancer in vivo.
Fig. 4: Downregulation of LINC00665 expression inhibits EMT and the Wnt/β-catenin pathway.
Fig. 5: LINC00665 interacts with YBX1.
Fig. 6: LIN00665 and YBX1 formed a positive feed-forward loop.
Fig. 7: YBX1 affects the transcription of Wnt3a and controls the activation of LINC00665 on the Wnt/β-catenin pathway.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files. The datasets are also available from the corresponding author on reasonable request.

References

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. Kim H, Hwang Y, Sung H, Jang J, Ahn C, Kim SG, et al. Effectiveness of gastric cancer screening on gastric cancer incidence and mortality in a community-based prospective cohort. Cancer Res Treat. 2018;50:582–9.

    Article  PubMed  Google Scholar 

  3. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66:115–32.

    Article  PubMed  Google Scholar 

  4. Zhang T, Chen H, Yin X, He Q, Man J, Yang X, et al. Changing trends of disease burden of gastric cancer in China from 1990 to 2019 and its predictions: Findings from Global Burden of Disease Study. Chin J Cancer Res. 2021;33:11–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Machlowska J, Baj J, Sitarz M, Maciejewski R, Sitarz R. Gastric cancer: epidemiology, risk factors, classification, genomic characteristics and treatment strategies. Int J Mol Sci. 2020;21:4012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Cabianca DS, Casa V, Bodega B, Xynos A, Ginelli E, Tanaka Y, et al. A long ncRNA links copy number variation to a polycomb/trithorax epigenetic switch in FSHD muscular dystrophy. Cell. 2012;149:819–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wu P, Mo Y, Peng M, Tang T, Zhong Y, Deng X, et al. Emerging role of tumor-related functional peptides encoded by lncRNA and circRNA. Mol Cancer. 2020;19:22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Liang ZX, Liu HS, Wang FW, Xiong L, Zhou C, Hu T, et al. LncRNA RPPH1 promotes colorectal cancer metastasis by interacting with TUBB3 and by promoting exosomes-mediated macrophage M2 polarization. Cell Death Dis. 2019;10:829.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wu H, Yang L, Chen LL. The diversity of long noncoding RNAs and their generation. Trends Genet. 2017;33:540–52.

    Article  CAS  PubMed  Google Scholar 

  10. Ding J, Zhao J, Huan L, Liu Y, Qiao Y, Wang Z, et al. Inflammation-induced LINC00665 increases the malignancy through activating PKR/NF-kappaB pathway in hepatocellular carcinoma. Hepatology. 2020;72:1666–81.

    Article  CAS  PubMed  Google Scholar 

  11. Liang Y, Song X, Li Y, Chen B, Zhao W, Wang L, et al. LncRNA BCRT1 promotes breast cancer progression by targeting miR-1303/PTBP3 axis. Mol Cancer. 2020;19:85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chang KC, Diermeier SD, Yu AT, Brine LD, Russo S, Bhatia S, et al. MaTAR25 lncRNA regulates the Tensin1 gene to impact breast cancer progression. Nat Commun. 2020;11:6438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Huang C, Leng D, Lei KC, Sun S, Zhang XD. Transcriptome analysis reveals lncRNA-mediated complex regulatory network response to DNA damage in the liver tissue of Rattus norvegicus. J Cell Physiol. 2019;234:23216–31.

    Article  CAS  PubMed  Google Scholar 

  14. Ransohoff JD, Wei Y, Khavari PA. The functions and unique features of long intergenic non-coding RNA. Nat Rev Mol Cell Biol. 2018;19:143–57.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang E, He X, Zhang C, Su J, Lu X, Si X, et al. A novel long noncoding RNA HOXC-AS3 mediates tumorigenesis of gastric cancer by binding to YBX1. Genome Biol. 2018;19:154.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Zhuo W, Liu Y, Li S, Guo D, Sun Q, Jin J, et al. Long noncoding RNA GMAN, up-regulated in gastric cancer tissues, is associated with metastasis in patients and promotes translation of ephrin A1 by competitively binding GMAN-AS. Gastroenterology. 2019;156:676–691.e11.

    Article  CAS  PubMed  Google Scholar 

  17. Chen Y, Li Z, Chen X, Zhang S. Long non-coding RNAs: from disease code to drug role. Acta Pharm Sin B. 2021;11:340–54.

    Article  CAS  PubMed  Google Scholar 

  18. Li H, Ma X, Yang D, Suo Z, Dai R, Liu C. PCAT-1 contributes to cisplatin resistance in gastric cancer through epigenetically silencing PTEN via recruiting EZH2. J Cell Biochem. 2020;121:1353–61.

    Article  CAS  PubMed  Google Scholar 

  19. Ji W, Diao Y-L, Qiu Y-R, Ge J, Cao X-C, Yu Y. LINC00665 promotes breast cancer progression through regulation of the miR-379-5p/LIN28B axis. Cell Death Dis. 2020;11:16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Cong Z, Diao Y, Xu Y, Li X, Jiang Z, Shao C, et al. Long non-coding RNA linc00665 promotes lung adenocarcinoma progression and functions as ceRNA to regulate AKR1B10-ERK signaling by sponging miR-98. Cell Death Dis. 2019;10:84.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Guo B, Wu S, Zhu X, Zhang L, Deng J, Li F, et al. Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression. EMBO J. 2020;39:e102190.

    Article  CAS  PubMed  Google Scholar 

  22. Qi H, Xiao Z, Wang Y. Long non-coding RNA LINC00665 gastric cancer tumorigenesis by regulation miR-149-3p/RNF2 axis. Onco Targets Ther. 2019;12:6981–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Conlon T, John-Schuster G, Heide D, Pfister D, Lehmann M, Hu Y, et al. Inhibition of LTβR signalling activates WNT-induced regeneration in lung. Nature. 2020;588:151–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang Y, Wang X. Targeting the Wnt/beta-catenin signaling pathway in cancer. J Hematol Oncol. 2020;13:165.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Abitbol S, Dahmani R, Coulouarn C, Ragazzon B, Mlecnik B, Senni N, et al. AXIN deficiency in human and mouse hepatocytes induces hepatocellular carcinoma in the absence of β-catenin activation. J Hepatol. 2018;68:1203–13.

    Article  CAS  PubMed  Google Scholar 

  26. Yu S, Li L, Cai H, He B, Gao Y, Li Y. Overexpression of NELFE contributes to gastric cancer progression via Wnt/β-catenin signaling-mediated activation of CSNK2B expression. J Exp Clin Cancer Res. 2021;40:1–16.

    Article  CAS  Google Scholar 

  27. Wang Z, Li Z, Ji H. Direct targeting of β-catenin in the Wnt signaling pathway: current progress and perspectives. Med Res Rev. 2021;41:2109–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Zhai W, Sun Y, Guo C, Hu G, Wang M, Zheng J, et al. LncRNA-SARCC suppresses renal cell carcinoma (RCC) progression via altering the androgen receptor(AR)/miRNA-143-3p signals. Cell Death Differentiation. 2017;24:1502–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang J, Chen C, Wang S, Zhang Y, Yin P, Gao Z, et al. Bufalin inhibits HCT116 colon cancer cells and its orthotopic xenograft tumor in mice model through genes related to apoptotic and PTEN/AKT pathways. Gastroenterol Res Pract. 2015;2015:1–11.

    Article  Google Scholar 

  30. Wang J, Cai H, Xia Y, Wang S, Xing L, Chen C, et al. Bufalin inhibits gastric cancer invasion and metastasis by down-regulating Wnt/ASCL2 expression. Oncotarget. 2018;9:23320–33.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Li W, Wong CC, Zhang X, Kang W, Nakatsu G, Zhao Q, et al. CAB39L elicited an anti-Warburg effect via a LKB1-AMPK-PGC1alpha axis to inhibit gastric tumorigenesis. Oncogene. 2018;37:6383–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Simion V, Zhou H, Haemmig S, Pierce JB, Mendes S, Tesmenitsky Y, et al. A macrophage-specific lncRNA regulates apoptosis and atherosclerosis by tethering HuR in the nucleus. Nat Commun. 2020;11:6135.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang X, Li L, Zhao K, Lin Q, Li H, Xue X, et al. A novel LncRNA HITT forms a regulatory loop with HIF-1alpha to modulate angiogenesis and tumor growth. Cell Death Differ. 2020;27:1431–46.

    Article  CAS  PubMed  Google Scholar 

  34. Seidlitz T, Merker SR, Rothe A, Zakrzewski F, von Neubeck C, Grützmann K, et al. Human gastric cancer modelling using organoids. Gut. 2019;68:207–17.

    Article  CAS  PubMed  Google Scholar 

  35. Wang CY, Colognori D, Sunwoo H, Wang D, Lee JT. PRC1 collaborates with SMCHD1 to fold the X-chromosome and spread Xist RNA between chromosome compartments. Nat Commun. 2019;10:2950.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Yuan L, Xu ZY, Ruan SM, Mo S, Qin JJ, Cheng XD. Long non-coding RNAs towards precision medicine in gastric cancer: early diagnosis, treatment, and drug resistance. Mol Cancer. 2020;19:96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Xu J, Ji L, Liang Y, Wan Z, Zheng W, Song X, et al. CircRNA-SORE mediates sorafenib resistance in hepatocellular carcinoma by stabilizing YBX1. Signal Transduct Target Ther. 2020;5:298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Feng M, Xie X, Han G, Zhang T, Li Y, Li Y, et al. YBX1 is required for maintaining myeloid leukemia cell survival by regulating BCL2 stability in an m6A-dependent manner. Blood. 2021;138:71–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lin Y, Zhang J, Li Y, Guo W, Chen L, Chen M, et al. CTPS1 promotes malignant progression of triple-negative breast cancer with transcriptional activation by YBX1. J Transl Med. 2022;20:17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Shi C, Yang Y, Yu J, Meng F, Zhang T, Gao Y. The long noncoding RNA LINC00473, a target of microRNA 34a, promotes tumorigenesis by inhibiting ILF2 degradation in cervical cancer. Am J Cancer Res. 2017;7:2157–68.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Zhang X, Wu J. LINC00665 promotes cell proliferation, invasion, and metastasis by activating the TGF-beta pathway in gastric cancer. Pathol Res Pract. 2021;224:153492.

    Article  CAS  PubMed  Google Scholar 

  42. Yang B, Bai Q, Chen H, Su K, Gao C. LINC00665 induces gastric cancer progression through activating Wnt signaling pathway. J Cell Biochem. 2020;121:2268–76.

    Article  CAS  PubMed  Google Scholar 

  43. Conlon GA, Murray GI. Recent advances in understanding the roles of matrix metalloproteinases in tumour invasion and metastasis. J Pathol. 2019;247:629–40.

    Article  PubMed  Google Scholar 

  44. Mittal V. Epithelial mesenchymal transition in tumor metastasis. Annu Rev Pathol. 2018;13:395–412.

    Article  CAS  PubMed  Google Scholar 

  45. Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017;36:1461–73.

    Article  CAS  PubMed  Google Scholar 

  46. Ma Y, Yang Y, Wang F, Moyer M, Wei Q, Zhang P, et al. Long non-coding RNA CCAL regulates colorectal cancer progression by activating Wnt/β-catenin signalling pathway via suppression of activator protein 2α. Gut. 2016;65:1494–504.

    Article  CAS  PubMed  Google Scholar 

  47. Wang H, Wu M, Lu Y, He K, Cai X, Yu X, et al. LncRNA MIR4435-2HG targets desmoplakin and promotes growth and metastasis of gastric cancer by activating Wnt/β-catenin signaling. Aging. 2019;11:6657–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. MacDonald BT, Tamai K, He X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17:9–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mo D, Fang H, Niu K, Liu J, Wu M, Li S, et al. Human helicase RECQL4 drives cisplatin resistance in gastric cancer by activating an AKT-YB1-MDR1 signaling pathway. Cancer Res. 2016;76:3057–66.

    Article  CAS  PubMed  Google Scholar 

  50. Wu Y, Yamada S, Izumi H, Li Z, Shimajiri S, Wang KY, et al. Strong YB-1 expression is associated with liver metastasis progression and predicts shorter disease-free survival in advanced gastric cancer. J Surg Oncol. 2012;105:724–30.

    Article  CAS  PubMed  Google Scholar 

  51. Byrne AT, Alferez DG, Amant F, Annibali D, Arribas J, Biankin AV, et al. Interrogating open issues in cancer precision medicine with patient-derived xenografts. Nat Rev Cancer. 2017;17:254–68.

    Article  CAS  PubMed  Google Scholar 

  52. Steele NG, Chakrabarti J, Wang J, Biesiada J, Holokai L, Chang J, et al. An organoid-based preclinical model of human gastric cancer. Cell Mol Gastroenterol Hepatol. 2019;7:161–84.

    Article  PubMed  Google Scholar 

  53. Sato T, Stange DE, Ferrante M, Vries RG, Van Es JH, Van den Brink S, et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology. 2011;141:1762–72.

    Article  CAS  PubMed  Google Scholar 

  54. Dekkers JF, van Vliet EJ, Sachs N, Rosenbluth JM, Kopper O, Rebel HG, et al. Long-term culture, genetic manipulation and xenotransplantation of human normal and breast cancer organoids. Nat Protoc. 2021;16:1936–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Bleijs M, van de Wetering M, Clevers H, Drost J. Xenograft and organoid model systems in cancer research. EMBO J. 2019;38:e101654.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge the GEO and TCGA databases, Kaplan–Meier Plotter database for providing their platforms and contributors for uploading their meaningful datasets.

Funding

This work was supported by the National Nature Science Foundation of China (81973625), the foundation of National Key Research and Development Program of China (2019YFC1316000), the foundation of Shanghai key medical specialty construction project (ZK2019B18), the foundation of within the budget of Shanghai University of Traditional Chinese Medicine (2019LK037), and the foundation of clinical specialized disease Construction Project of Shanghai Putuo District Municipal Health Comission (2019tszb01).

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  1. These authors contributed equally: Jie Wang, Dongxiao Shen, Shichao Li.

Authors and Affiliations

  1. Department Surgery, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 200062, Shanghai, China

    Jie Wang, Dongxiao Shen, Qingsong Zuo, Peihao Yin, Chao Chen & Teng Chen

  2. Interventional Cancer Institute of Chinese Integrative Medicine, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, 200062, Shanghai, China

    Jie Wang, Qiuying Li, Peihao Yin, Chao Chen & Teng Chen

  3. Shanghai Putuo Central School of Clinical Medicine, Anhui Medical University, 230022, Anhui, China

    Jie Wang, Jiahao Lu, Donghao Tang, Yuejiao Feng, Peihao Yin, Chao Chen & Teng Chen

  4. The Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, 646000, Luzhou, China

    Shichao Li

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Contributions

TC and CC conceived or designed the experiments; JW, DXS, and CSL performed the experiments and write the manuscript; QYL performed part of the animal experiments; JHL, DHT, and YJF performed part of the cell and molecular and biology experiments; QSZ and PHY performed part of the clinical patients collect and data analysis. All authors read and approved the final manuscript.

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Correspondence to Chao Chen or Teng Chen.

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The authors declare no competing interests.

Ethical approval

Human samples used in this study was obtained with informed consent and was approved by the Ethics Committee of Putuo Hospital, Shanghai University of Traditional Chinese Medicine (PTEC-A-2020-5(S)-1). All the animal studies were performed strictly in accordance with the Animal Care Guidelines approved by the Animal Care Committee of East China Normal University.

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Wang, J., Shen, D., Li, S. et al. LINC00665 activating Wnt3a/β-catenin signaling by bond with YBX1 promotes gastric cancer proliferation and metastasis. Cancer Gene Ther 30, 1530–1542 (2023). https://doi.org/10.1038/s41417-023-00657-4

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