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Decoding dysregulated angiogenesis in HTLV-1 asymptomatic carriers compared to healthy individuals

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Abstract

Human T-cell lymphotropic virus type 1 (HTLV-1) is the first identified human retrovirus responsible for two significant diseases: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and adult T-cell leukemia/lymphoma (ATLL). Although the majority of infected individuals remain asymptomatic carriers, a small percentage may develop ATLL or HAM/TSP. In tumorigenesis, a crucial process is angiogenesis, which involves the formation of new blood vessels. However, the precise mechanism of HTLV-1 associated angiogenesis remains unclear. This study aims to investigate the gene regulation involved in the angiogenesis signaling pathway associated with HTLV-1 infection. The research enrolled 20 male participants, including asymptomatic carriers and healthy individuals. Blood samples were collected and screened using ELISA for HTLV-1 confirmation, and PCR was performed for both Tax and HBZ for validation. RNA extraction and cDNA synthesis were carried out, followed by RT-qPCR analysis targeting cellular genes involved in angiogenesis. Our findings indicate that gene expression related to angiogenesis was elevated in HTLV-1 ACs patients. However, the differences in gene expression of the analyzed genes, including HSP27, Paxillin, PDK1, PTEN, RAF1, SOS1, and VEGFR2 between ACs and healthy individuals were not statistically significant. This suggests that although angiogenesis-related genes may show increased expression in HTLV-1 infection, they might not be robust indicators of ATLL progression in asymptomatic carriers. The results of our study demonstrate that angiogenesis gene expression is altered in ACs of HTLV-1, indicating potential involvement of angiogenesis in the early stages before ATLL development. While we observed elevated angiogenesis gene expression in ACs, the lack of statistical significance between ACs and healthy individuals suggests that these gene markers may not be sufficient on their own to predict the development of ATLL in asymptomatic carriers.

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References

  1. Poiesz BJ, Ruscetti FW, Gazdar AF, Bunn PA, Minna JD, Gallo RC. Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphoma. Proc Natl Acad Sci USA. 1980;77(12):7415–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Poiesz BJ, Ruscetti FW, Reitz MS, Kalyanaraman VS, Gallo RC. Isolation of a new type C retrovirus (HTLV) in primary uncultured cells of a patient with Sezary T-cell leukaemia. Nature. 1981;294(5838):268–71.

    Article  CAS  PubMed  Google Scholar 

  3. Kalyanaraman VS, Sarngadharan MG, Robert-Guroff M, Miyoshi I, Golde D, Gallo RC. A new subtype of human T-cell leukemia virus (HTLV-II) associated with a T-cell variant of hairy cell leukemia. Science. 1982;218(4572):571–3.

    Article  CAS  PubMed  Google Scholar 

  4. Gallo RC. The discovery of the first human retrovirus: HTLV-1 and HTLV-2. Retrovirology. 2005;2(1):17.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Carneiro-Proietti ABF, Amaranto-Damasio M, Leal-Horiguchi C, Bastos R, Seabra-Freitas G, Borowiak D, et al. Mother-to-child transmission of human T-cell lymphotropic viruses-1/2: what we know, and what are the gaps in understanding and preventing this route of infection. J Pediat Infect Dis Soc. 2014;3(suppl_1):S24–9.

    Article  Google Scholar 

  6. Brites C, Grassi MF, Quaresma JAS, Ishak R, Vallinoto ACR. Pathogenesis of HTLV-1 infection and progression biomarkers: an overview. Braz J Infect Dis. 2021;25(3): 101594.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Goncalves DU, Proietti FA, Ribas JG, Araujo MG, Pinheiro SR, Guedes AC, Carneiro-Proietti AB. Epidemiology, treatment, and prevention of human T-cell leukemia virus type 1-associated diseases. Clin Microbiol Rev. 2010;23(3):577–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Eusebio-Ponce E, Anguita E, Paulino-Ramirez R, Candel FJ. HTLV-1 infection: an emerging risk. Pathogenesis, epidemiology, diagnosis and associated diseases. Rev Esp Quimioter. 2019;32(6):485–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Willems L, Hasegawa H, Accolla R, Bangham C, Bazarbachi A, Bertazzoni U, et al. Reducing the global burden of HTLV-1 infection: an agenda for research and action. Antiviral Res. 2017;137:41–8.

    Article  CAS  PubMed  Google Scholar 

  10. Bangham CRM, Human T. Cell leukemia virus type 1: persistence and pathogenesis. Annu Rev Immunol. 2018;36:43–71.

    Article  CAS  PubMed  Google Scholar 

  11. Saito MJF. Association between HTLV-1 genotypes and risk of HAM/TSP. Front Microbiol. 2019;10:1101.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Iwanaga M, Watanabe T, Utsunomiya A, Okayama A, Uchimaru K, Koh KR, et al. Human T-cell leukemia virus type I (HTLV-1) proviral load and disease progression in asymptomatic HTLV-1 carriers: a nationwide prospective study in Japan. Blood. 2010;116(8):1211–9.

    Article  CAS  PubMed  Google Scholar 

  13. Bangham CRM, Matsuoka M. Human T-cell leukaemia virus type 1: parasitism and pathogenesis. Philos Trans R Soc Lond B Biol Sci. 2017;372(1732):20160272.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zhang Y, Wang H, Oliveira RHM, Zhao C, Popel AS. Systems biology of angiogenesis signaling: computational models and omics. WIREs Mech Dis. 2022;14(4): e1550.

    Article  CAS  PubMed  Google Scholar 

  15. Logsdon EA, Finley SD, Popel AS, Mac GF. A systems biology view of blood vessel growth and remodelling. J Cell Mol Med. 2014;18(8):1491–508.

    Article  PubMed  Google Scholar 

  16. Flegg JA, Menon SN, Byrne HM, McElwain DLS. A current perspective on wound healing and tumour-induced angiogenesis. Bull Math Biol. 2020;82(2):23.

    Article  PubMed  Google Scholar 

  17. Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148(3):399–408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Liu ZL, Chen HH, Zheng LL, Sun LP, Shi L. Angiogenic signaling pathways and anti-angiogenic therapy for cancer. Signal Transduct Target Ther. 2023;8(1):198.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Larionova I, Kazakova E, Gerashchenko T, Kzhyshkowska J. New angiogenic regulators produced by TAMs: perspective for targeting tumor angiogenesis. Cancers (Basel). 2021;13(13):3253.

    Article  CAS  PubMed  Google Scholar 

  20. Aspritoiu VM, Stoica I, Bleotu C, Diaconu CC. Epigenetic regulation of angiogenesis in development and tumors progression: potential implications for cancer treatment. Front Cell Dev Biol. 2021;9: 689962.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Mukwaya A, Jensen L, Lagali N. Relapse of pathological angiogenesis: functional role of the basement membrane and potential treatment strategies. Exp Mol Med. 2021;53(2):189–201.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. El-Sabban ME, Merhi RA, Haidar HA, Arnulf B, Khoury H, Basbous J, et al. Human T-cell lymphotropic virus type 1-transformed cells induce angiogenesis and establish functional gap junctions with endothelial cells. Blood. 2002;99(9):3383–9.

    Article  CAS  PubMed  Google Scholar 

  23. Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004;56(4):549–80.

    Article  CAS  PubMed  Google Scholar 

  24. Shimizu Y, Yamanashi H, Miyata J, Takada M, Noguchi Y, Honda Y, et al. VEGF polymorphism rs3025039 and human T-Cell Leukemia Virus 1 (HTLV-1) infection among older Japanese individuals: a cross-sectional study. Bioengineering. 2022;9(10):527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Schwab JD, Kühlwein SD, Ikonomi N, Kühl M, Kestler HAJC. Concepts in Boolean network modeling: What do they all mean? Comput Struct Biotechnol J. 2020;18:571–82.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Parmer T, Rocha LM, Radicchi F. Influence maximization in Boolean networks. Nat Commun. 2022;13(1):3457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Weinstein N, Mendoza L, Gitler I, Klapp J. A network model to explore the effect of the micro-environment on endothelial cell behavior during angiogenesis. Front Physiol. 2017;8:960.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Bauer AL, Jackson TL, Jiang Y, Rohlf T. Receptor cross-talk in angiogenesis: mapping environmental cues to cell phenotype using a stochastic, Boolean signaling network model. J Theor Biol. 2010;264(3):838–46.

    Article  CAS  PubMed  Google Scholar 

  29. Jafari Nivlouei S, Soltani M, Carvalho J, Travasso R, Salimpour MR, Shirani E. Multiscale modeling of tumor growth and angiogenesis: evaluation of tumor-targeted therapy. PLoS Comput Biol. 2021;17(6): e1009081.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhong M, Li N, Qiu X, Ye Y, Chen H, Hua J, et al. TIPE regulates VEGFR2 expression and promotes angiogenesis in colorectal cancer. Int J Biol Sci. 2020;16(2):272–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zimna A, Kurpisz M. Hypoxia-Inducible Factor-1 in physiological and pathophysiological angiogenesis: applications and therapies. Biomed Res Int. 2015;2015: 549412.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Khosravi Shahi P, Soria Lovelle A, Perez MG. Tumoral angiogenesis and breast cancer. Clin Transl Oncol. 2009;11(3):138–42.

    Article  CAS  PubMed  Google Scholar 

  33. Lampros M, Vlachos N, Voulgaris S, Alexiou GA. The role of Hsp27 in chemotherapy resistance. Biomedicines. 2022;10(4):897.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Evans IM, Britton G, Zachary IC. Vascular endothelial growth factor induces heat shock protein (HSP) 27 serine 82 phosphorylation and endothelial tubulogenesis via protein kinase D and independent of p38 kinase. Cell Signal. 2008;20(7):1375–84.

    Article  CAS  PubMed  Google Scholar 

  35. Lim SO, Park SG, Yoo JH, Park YM, Kim HJ, Jang KT, et al. Expression of heat shock proteins (HSP27, HSP60, HSP70, HSP90, GRP78, GRP94) in hepatitis B virus-related hepatocellular carcinomas and dysplastic nodules. World J Gastroenterol. 2005;11(14):2072–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wainberg Z, Oliveira M, Lerner S, Tao Y, Brenner BG. Modulation of stress protein (hsp27 and hsp70) expression in CD4+ lymphocytic cells following acute infection with human immunodeficiency virus type-1. Virology. 1997;233(2):364–73.

    Article  CAS  PubMed  Google Scholar 

  37. Wartenberg M, Donmez F, Ling FC, Acker H, Hescheler J, Sauer H. Tumor-induced angiogenesis studied in confrontation cultures of multicellular tumor spheroids and embryoid bodies grown from pluripotent embryonic stem cells. FASEB J. 2001;15(6):995–1005.

    CAS  PubMed  Google Scholar 

  38. German AE, Mammoto T, Jiang E, Ingber DE, Mammoto A. Paxillin controls endothelial cell migration and tumor angiogenesis by altering neuropilin 2 expression. J Cell Sci. 2014;127(8):1672–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nogalski MT, Chan G, Stevenson EV, Gray S, Yurochko AD. Human cytomegalovirus-regulated paxillin in monocytes links cellular pathogenic motility to the process of viral entry. J Virol. 2011;85(3):1360–9.

    Article  CAS  PubMed  Google Scholar 

  40. Chen M-J, Wu D-W, Shen C-J, Cheng Y-M, Wu C-C, Lee H. Hepatitis B virus X protein promotes tumor invasion and poor prognosis in hepatocellular carcinoma via phosphorylation of paxillin at Serine 178 by activation of the c-Jun NH2-terminal kinase. Am J Cancer Res. 2020;10(1):275.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Yang WJ, Yan JB, Zhang L, Zhao F, Mei ZM, Yang YN, et al. Paxillin promotes the migration and angiogenesis of HUVECs and affects angiogenesis in the mouse cornea. Exp Ther Med. 2020;20(2):901–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li C, Lin C, Cong X, Jiang Y. PDK1-WNK1 signaling is affected by HBx and involved in the viability and metastasis of hepatic cells. Oncol Lett. 2018;15(4):5940–6.

    PubMed  PubMed Central  Google Scholar 

  43. Lian S, Shao Y, Liu H, He J, Lu W, Zhang Y, et al. PDK1 induces JunB, EMT, cell migration and invasion in human gallbladder cancer. Oncotarget. 2015;6(30):29076–86.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Jiang BH, Liu LZ. PI3K/PTEN signaling in angiogenesis and tumorigenesis. Adv Cancer Res. 2009;102:19–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wen S, Stolarov J, Myers MP, Su JD, Wigler MH, Tonks NK, Durden DL. PTEN controls tumor-induced angiogenesis. Proc Natl Acad Sci. 2001;98(8):4622–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tian T, Nan K-J, Wang S-H, Liang X, Lu C-X, Guo H, et al. PTEN regulates angiogenesis and VEGF expression through phosphatase-dependent and-independent mechanisms in HepG2 cells. Carcinogenesis. 2010;31(7):1211–9.

    Article  PubMed  Google Scholar 

  47. Asami Y, Kakeya H, Komi Y, Kojima S, Nishikawa K, Beebe K, et al. Azaspirene, a fungal product, inhibits angiogenesis by blocking Raf-1 activation. Cancer Sci. 2008;99(9):1853–8.

    Article  CAS  PubMed  Google Scholar 

  48. Meng F, Ding J, Liu N, Zhang J, Shao X, Shen H, et al. Inhibition of gastric cancer angiogenesis by vector-based RNA interference for Raf-1. Cancer Biol Ther. 2005;4(1):113–7.

    Article  CAS  PubMed  Google Scholar 

  49. Hagan S, Al-Mulla F, Mallon E, Oien K, Ferrier R, Gusterson B, et al. Reduction of Raf-1 kinase inhibitor protein expression correlates with breast cancer metastasis. Clin Cancer Res. 2005;11(20):7392–7.

    Article  CAS  PubMed  Google Scholar 

  50. Mitsuda Y, Morita K, Kashiwazaki G, Taniguchi J, Bando T, Obara M, et al. RUNX1 positively regulates the ErbB2/HER2 signaling pathway through modulating SOS1 expression in gastric cancer cells. Sci Rep. 2018;8(1):6423.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Xing F, Zhao D, Wu S-Y, Tyagi A, Wu K, Sharma S, et al. Epigenetic and posttranscriptional modulation of SOS1 can promote breast cancer metastasis through obesity-activated c-met signaling in african-American women. Can Res. 2021;81(11):3008–21.

    Article  CAS  Google Scholar 

  52. Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002;2(10):795–803.

    Article  CAS  PubMed  Google Scholar 

  53. Kopparapu PK, Boorjian SA, Robinson BD, Downes M, Gudas LJ, Mongan NP, Persson JL. Expression of VEGF and its receptors VEGFR1/VEGFR2 is associated with invasiveness of bladder cancer. Anticancer Res. 2013;33(6):2381–90.

    CAS  PubMed  Google Scholar 

  54. Yan JD, Liu Y, Zhang ZY, Liu GY, Xu JH, Liu LY, Hu YM. Expression and prognostic significance of VEGFR-2 in breast cancer. Pathol Res Pract. 2015;211(7):539–43.

    Article  CAS  PubMed  Google Scholar 

  55. Toro AU, Shukla SK, Bansal P. Emerging role of MicroRNA-based theranostics in hepatocellular carcinoma. Mol Biol Rep. 2023;50(9):7681–91.

    Article  CAS  PubMed  Google Scholar 

  56. Toro AU, Shukla SK, Bansal P. Micronome revealed miR-205-5p as key regulator of VEGFA during cancer related angiogenesis in hepatocellular carcinoma. Mol Biotechnol. 2023;65(7):1178–86.

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was supported by Alborz University of Medical Sciences (Grant ID: 99-4275).

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Correspondence to Sayed-Hamidreza Mozhgani or Mojtaba Hedayatyaghoobi.

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This study was approved by Alborz University of Medical Sciences Ethics committee (IR.ABZUMS.REC.1400.056).

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Letafati, A., Mozhgani, SH., Marjani, A. et al. Decoding dysregulated angiogenesis in HTLV-1 asymptomatic carriers compared to healthy individuals. Med Oncol 40, 317 (2023). https://doi.org/10.1007/s12032-023-02177-5

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