1887

Abstract

Chronic hepatitis C virus (HCV) infection is a leading cause of end-stage liver diseases, such as fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Several cellular entities, including paraspeckles and their related components, are involved in viral pathogenesis and cancer progression. NEAT1 lncRNA is a major component of paraspeckles that has been linked to several malignancies. In this study, analysis of the Cancer Genome Atlas (TCGA) database and validation in HCV-induced HCC tissue and serum samples showed significantly high expression of NEAT1 in patients with liver cancer. Moreover, we found that NEAT1 levels increased upon HCV infection. To further understand the mechanism of NEAT1-induced HCC progression, we selected one of its targets, miR-9–5 p, which regulates BGH3 mRNA levels. Interestingly, miR-9–5 p levels were downregulated upon HCV infection, whereas BGH3 levels were upregulated. Additionally, partial NEAT1 knockdown increased miR-9–5 p levels and decreased BGH3 levels, corroborating our initial results. BGH3 levels were also upregulated in HCV-induced HCC and TCGA tissue samples, which could be directly correlated with NEAT1 levels. As a known oncogene, BGH3 is directly linked to HCC progression mediated by NEAT1. We also found that NEAT1 levels remained upregulated in serum samples from patients treated with direct-acting antivirals (DAA), indicating that NEAT1 might be a molecular trigger that promotes HCC development. Collectively, these findings provide molecular insights into HCV-induced HCC progression via the NEAT1-miR-9-BGH3 axis.

Funding
This study was supported by the:
  • Council of Scientific & Industrial Research (Award CSIR-SRF)
    • Principle Award Recipient: SachinKumar Tripathi
  • Department of Science and Technology, India (Award JC-Bose- SB/S2/JCB-51/2013)
    • Principle Award Recipient: SaumitraDas
Loading

Article metrics loading...

/content/journal/jgv/10.1099/jgv.0.001809
2022-12-02
2024-06-17
Loading full text...

Full text loading...

References

  1. Cancer IAfRo Global Cancer Observatory 2022 [Available from. n.d https://gco.iarc.fr/
  2. Cho JW, Baek WK, Suh SI, Yang SH, Chang J et al. Hepatitis C virus core protein promotes cell proliferation through the upregulation of cyclin E expression levels. Liver 2001; 21:137–142 [View Article] [PubMed]
    [Google Scholar]
  3. Li Y, Boehning DF, Qian T, Popov VL, Weinman SA. Hepatitis C virus core protein increases mitochondrial ROS production by stimulation of Ca2+ uniporter activity. FASEB J 2007; 21:2474–2485 [View Article] [PubMed]
    [Google Scholar]
  4. Venturini D, Simão ANC, Barbosa DS, Lavado EL, Narciso VES et al. Increased oxidative stress, decreased total antioxidant capacity, and iron overload in untreated patients with chronic hepatitis C. Dig Dis Sci 2010; 55:1120–1127 [View Article] [PubMed]
    [Google Scholar]
  5. Sharma G, Tripathi SK, Das S. lncRNA HULC facilitates efficient loading of HCV-core protein onto lipid droplets and subsequent virus-particle release. Cell Microbiol 2019; 21:10 [View Article] [PubMed]
    [Google Scholar]
  6. Qian X, Xu C, Zhao P, Qi Z. Long non-coding RNA GAS5 inhibited hepatitis C virus replication by binding viral NS3 protein. Virology 2016; 492:155–165 [View Article] [PubMed]
    [Google Scholar]
  7. Unfried JP, Fortes P. LncRNAs in HCV infection and HCV-related liver disease. Int J Mol Sci 2020; 21:E2255 [View Article]
    [Google Scholar]
  8. Shih CH, Chuang LL, Tsai MH, Chen LH, Chuang EY et al. Hypoxia-induced MALAT1 promotes the proliferation and migration of breast cancer cells by sponging MiR-3064-5p. Front Oncol 2021; 11:658151 [View Article]
    [Google Scholar]
  9. Nishitsuji H, Ujino S, Yoshio S, Sugiyama M, Mizokami M et al. Long noncoding RNA #32 contributes to antiviral responses by controlling interferon-stimulated gene expression. Proc Natl Acad Sci 2016; 113:10388–10393 [View Article]
    [Google Scholar]
  10. Li ZQ, Gu XY, Hu JX, Ping Y, Li H et al. Hepatitis C virus core protein impairs metabolic disorder of liver cell via HOTAIR-Sirt1 signalling. Biosci Rep 2016; 36:e00336 [View Article]
    [Google Scholar]
  11. Fan J, Cheng M, Chi X, Liu X, Yang W. A human long non-coding RNA LncATV promotes virus replication through restricting RIG-I-mediated innate immunity. Front Immunol 2019; 10:1711 [View Article]
    [Google Scholar]
  12. Hu P, Wilhelm J, Gerresheim GK, Shalamova LA, Niepmann M. Lnc-ITM2C-1 and GPR55 are proviral host factors for Hepatitis C virus. Viruses 2019; 11:549 [View Article]
    [Google Scholar]
  13. Liu X, Duan X, Holmes JA, Li W, Lee SH et al. A long noncoding RNA regulates Hepatitis C virus infection through interferon alpha-inducible protein 6. Hepatology 2019; 69:1004–1019 [View Article]
    [Google Scholar]
  14. Xiong Y, Jia M, Yuan J, Zhang C, Zhu Y et al. STAT3‑regulated long non‑coding RNAs lnc‑7SK and lnc‑IGF2‑AS promote hepatitis C virus replication. Mol Med Rep 2015; 12:6738–6744 [View Article] [PubMed]
    [Google Scholar]
  15. Carnero E, Barriocanal M, Prior C, Pablo Unfried J, Segura V et al. Long noncoding RNA EGOT negatively affects the antiviral response and favors HCV replication. EMBO Rep 2016; 17:1013–1028 [View Article] [PubMed]
    [Google Scholar]
  16. Roshdy F, Farag MMS, El-Ahwany E, Mahmode O, Mousa AA et al. Long non-coding RNA HOTAIR and HOTTIP as potential biomarkers for hepatitis C virus genotype 4-induced hepatocellular carcinoma. Egypt J Med Hum Genet 2020; 21: [View Article]
    [Google Scholar]
  17. Wang Z, Fan P, Zhao Y, Zhang S, Lu J et al. NEAT1 modulates herpes simplex virus-1 replication by regulating viral gene transcription. Cell Mol Life Sci 2017; 74:1117–1131 [View Article] [PubMed]
    [Google Scholar]
  18. Zhang Q, Chen CY, Yedavalli VSRK, Jeang KT. NEAT1 long noncoding RNA and paraspeckle bodies modulate HIV-1 posttranscriptional expression. mBio 2013; 4:e00596-12 [View Article]
    [Google Scholar]
  19. Ma H, Han P, Ye W, Chen H, Zheng X et al. The long noncoding RNA NEAT1 exerts antihantaviral effects by acting as positive feedback for RIG-I signaling. J Virol 2017; 91:e02250-16 [View Article]
    [Google Scholar]
  20. Imamura K, Imamachi N, Akizuki G, Kumakura M, Kawaguchi A et al. Long noncoding RNA NEAT1-dependent SFPQ relocation from promoter region to paraspeckle mediates IL8 expression upon immune stimuli. Mol Cell 2014; 53:393–406 [View Article] [PubMed]
    [Google Scholar]
  21. Choudhry H, Albukhari A, Morotti M, Haider S, Moralli D et al. Tumor hypoxia induces nuclear paraspeckle formation through HIF-2α dependent transcriptional activation of NEAT1 leading to cancer cell survival. Oncogene 2015; 34:4482–4490 [View Article] [PubMed]
    [Google Scholar]
  22. Hirose T, Virnicchi G, Tanigawa A, Naganuma T, Li R et al. NEAT1 long noncoding RNA regulates transcription via protein sequestration within subnuclear bodies. Mol Biol Cell 2014; 25:169–183 [View Article] [PubMed]
    [Google Scholar]
  23. Guru SC, Agarwal SK, Manickam P, Olufemi SE, Crabtree JS et al. A transcript map for the 2.8-Mb region containing the multiple endocrine neoplasia type 1 locus. Genome Res 1997; 7:725–735 [View Article] [PubMed]
    [Google Scholar]
  24. Yamazaki T, Souquere S, Chujo T, Kobelke S, Chong YS et al. Functional domains of NEAT1 architectural lncRNA induce paraspeckle assembly through phase separation. Mol Cell 2018; 70:1038–1053 [View Article]
    [Google Scholar]
  25. Yan H, Wang Z, Sun Y, Hu L, Bu P. Cytoplasmic NEAT1 suppresses AML stem cell self-renewal and leukemogenesis through inactivation of Wnt signaling. Adv Sci (Weinh) 2021; 8:e2100914 [View Article]
    [Google Scholar]
  26. Chen LL, Carmichael GG. Altered nuclear retention of mRNAs containing inverted repeats in human embryonic stem cells: functional role of a nuclear noncoding RNA. Mol Cell 2009; 35:467–478 [View Article] [PubMed]
    [Google Scholar]
  27. Beeharry Y, Goodrum G, Imperiale CJ, Pelchat M. The Hepatitis Delta virus accumulation requires paraspeckle components and affects NEAT1 level and PSP1 localization. Sci Rep 2018; 8:6031 [View Article]
    [Google Scholar]
  28. Lellahi SM, Rosenlund IA, Hedberg A, Kiær LT, Mikkola I et al. The long noncoding RNA NEAT1 and nuclear paraspeckles are up-regulated by the transcription factor HSF1 in the heat shock response. J Biol Chem 2018; 293:18965–18976 [View Article] [PubMed]
    [Google Scholar]
  29. Sun C, Li S, Zhang F, Xi Y, Wang L et al. Long non-coding RNA NEAT1 promotes non-small cell lung cancer progression through regulation of miR-377-3p-E2F3 pathway. Oncotarget 2016; 7:51784–51814 [View Article]
    [Google Scholar]
  30. Kim YS, Hwan JD, Bae S, Bae DH, Shick WA. Identification of differentially expressed genes using an annealing control primer system in stage III serous ovarian carcinoma. BMC Cancer 2010; 10:576 [View Article]
    [Google Scholar]
  31. Li Y, Li Y, Chen W, He F, Tan Z et al. NEAT expression is associated with tumor recurrence and unfavorable prognosis in colorectal cancer. Oncotarget 2015; 6:27641–27650 [View Article]
    [Google Scholar]
  32. Yuan L-Y, Zhou M, Lv H, Qin X, Zhou J et al. Involvement of NEAT1/miR-133a axis in promoting cervical cancer progression via targeting SOX4. J Cell Physiol 2019; 234:18985–18993 [View Article] [PubMed]
    [Google Scholar]
  33. Huang B, Liu C, Wu Q, Zhang J, Min Q et al. Long non-coding RNA NEAT1 facilitates pancreatic cancer progression through negative modulation of miR-506-3p. Biochem Biophys Res Commun 2017; 482:828–834 [View Article] [PubMed]
    [Google Scholar]
  34. Huang G, He X, Wei XL. lncRNA NEAT1 promotes cell proliferation and invasion by regulating miR‑365/RGS20 in oral squamous cell carcinoma. Oncol Rep 2018; 39:1948–1956 [View Article] [PubMed]
    [Google Scholar]
  35. Jiang X, Zhou Y, Sun AJ, Xue JL. NEAT1 contributes to breast cancer progression through modulating miR-448 and ZEB1. J Cell Physiol 2018; 233:8558–8566 [View Article] [PubMed]
    [Google Scholar]
  36. Park MK, Zhang L, Min K-W, Cho J-H, Yeh C-C et al. NEAT1 is essential for metabolic changes that promote breast cancer growth and metastasis. Cell Metab 2021; 33:2380–2397 [View Article] [PubMed]
    [Google Scholar]
  37. Zhen L, Yun-Hui L, Hong-Yu D, Jun M, Yi-Long Y. Long noncoding RNA NEAT1 promotes glioma pathogenesis by regulating miR-449b-5p/c-Met axis. Tumour Biol 2016; 37:673–683 [View Article]
    [Google Scholar]
  38. Zhang XN, Zhou J, Lu XJ. The long noncoding RNA NEAT1 contributes to hepatocellular carcinoma development by sponging miR-485 and enhancing the expression of the STAT3. J Cell Physiol 2018; 233:6733–6741 [View Article] [PubMed]
    [Google Scholar]
  39. Fang L, Sun J, Pan Z, Song Y, Zhong L et al. Long non-coding RNA NEAT1 promotes hepatocellular carcinoma cell proliferation through the regulation of miR-129-5p-VCP-IκB. Am J Physiol Gastrointest Liver Physiol 2017; 313:G150–G156 [View Article] [PubMed]
    [Google Scholar]
  40. Li ZQ, Gu XY, Hu JX, Ping Y, Li H et al. Hepatitis C virus core protein impairs metabolic disorder of liver cell via HOTAIR-Sirt1 signalling. Biosci Rep 2016; 36:e00336 [View Article]
    [Google Scholar]
  41. Thankachan S, Bhardwaj BK, Venkatesh T, Suresh PS. Long non-coding RNA NEAT1 as an emerging biomarker in breast and gynecologic cancers: a systematic overview. Reprod Sci 2021; 28:2436–2447 [View Article]
    [Google Scholar]
  42. Xu X, Zou H, Luo L, Wang X, Wang G. MicroRNA-9 exerts antitumor effects on hepatocellular carcinoma progression by targeting HMGA2. FEBS Open Bio 2019; 9:1784–1797 [View Article] [PubMed]
    [Google Scholar]
  43. Wang J, Wang B, Ren H, Chen W. miR-9-5p inhibits pancreatic cancer cell proliferation, invasion and glutamine metabolism by targeting GOT1. Biochem Biophys Res Commun 2019; 509:241–248 [View Article] [PubMed]
    [Google Scholar]
  44. Han B, Cai H, Chen Y, Hu B, Luo H et al. The role of TGFBI (βig-H3) in gastrointestinal tract tumorigenesis. Mol Cancer 2015; 14:64 [View Article]
    [Google Scholar]
  45. Ma C, Rong Y, Radiloff DR, Datto MB, Centeno B et al. Extracellular matrix protein betaig-h3/TGFBI promotes metastasis of colon cancer by enhancing cell extravasation. Genes Dev 2008; 22:308–321 [View Article] [PubMed]
    [Google Scholar]
  46. Harouaka D, Engle RE, Wollenberg K, Diaz G, Tice AB et al. Diminished viral replication and compartmentalization of hepatitis C virus in hepatocellular carcinoma tissue. Proc Natl Acad Sci 2016; 113:1375–1380 [View Article]
    [Google Scholar]
  47. Dash S, Aydin Y, Widmer KE, Nayak L. Hepatocellular carcinoma mechanisms associated with chronic HCV infection and the impact of direct-acting antiviral treatment. J Hepatocell Carcinoma 2020; 7:45–76 [View Article]
    [Google Scholar]
  48. Kanwal F, Kramer JR, Ilyas J, Duan Z, El-Serag HB. HCV genotype 3 is associated with an increased risk of cirrhosis and hepatocellular cancer in a national sample of U.S. Veterans with HCV. Hepatology 2014; 60:98–105 [View Article]
    [Google Scholar]
  49. Park HK, Lee SS, Im CB, Im C, Cha RR et al. Hepatitis C virus genotype affects survival in patients with hepatocellular carcinoma. BMC Cancer 2019; 19:822 [View Article]
    [Google Scholar]
  50. Gu J, Zhang B, An R, Qian W, Han L et al. Molecular interactions of the long noncoding RNA NEAT1 in cancer. Cancers 2022; 14:4009 [View Article]
    [Google Scholar]
  51. Chai C-Y, Tai IC, Zhou R, Song J, Zhang C et al. MicroRNA-9-5p inhibits proliferation and induces apoptosis of human hypertrophic scar fibroblasts through targeting peroxisome proliferator-activated receptor β. Biol Open 2020; 9:12 [View Article] [PubMed]
    [Google Scholar]
  52. López-Urrutia E, Bustamante Montes LP, Ladrón de Guevara Cervantes D, Pérez-Plasencia C, Campos-Parra AD. Crosstalk between long non-coding RNAs, micro-RNAs and mRNAs: deciphering molecular mechanisms of master regulators in cancer. Front Oncol 2019; 9:669 [View Article]
    [Google Scholar]
  53. Entezari M, Taheriazam A, Orouei S, Fallah S, Sanaei A et al. LncRNA-miRNA axis in tumor progression and therapy response: an emphasis on molecular interactions and therapeutic interventions. Biomed Pharmacother 2022; 154:113609 [View Article]
    [Google Scholar]
  54. Luna-Cuadros MA, Chen H-W, Hanif H, Ali MJ, Khan MM et al. Risk of hepatocellular carcinoma after hepatitis C virus cure. World J Gastroenterol 2022; 28:96–107 [View Article] [PubMed]
    [Google Scholar]
  55. Perez S, Kaspi A, Domovitz T, Davidovich A, Lavi-Itzkovitz A et al. Hepatitis C virus leaves an epigenetic signature post cure of infection by direct-acting antivirals. PLoS Genet 2019; 15:e1008181 [View Article]
    [Google Scholar]
  56. Hamdane N, Jühling F, Crouchet E, El Saghire H, Thumann C et al. HCV-induced epigenetic changes associated with liver cancer risk persist after sustained virologic response. Gastroenterology 2019; 156:2313–2329 [View Article]
    [Google Scholar]
http://instance.metastore.ingenta.com/content/journal/jgv/10.1099/jgv.0.001809
Loading
/content/journal/jgv/10.1099/jgv.0.001809
Loading

Data & Media loading...

Supplements

Supplementary material 1

PDF
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error