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Essay, 10 pages (2500 words)

Editorial: pvt1 in cancer

Editorial on the Research Topic

The plasmacytoma variant translocation 1 (PVT1) gene is located at human chromosome 8q24, downstream of the well-known c-MYC oncogene ( 1 ). As chromosome 8q24 is a chromosomal region of genomic instability, it is not surprising that PVT1 was discovered in the context of cancer. PVT1 is now known to be dysregulated in non-cancerous diseases such as kidney disease (including diabetic nephropathy) ( 2 ), cardiac hypertrophy ( 3 ), vitiligo ( 4 ), osteoarthritis ( 5 ), and asthma ( 6 ). However, PVT1 is much better established to be dysregulated in a wide variety of cancers including plasmacytomas ( 7 , 8 ), lymphomas ( 9 , 10 ), leukemias ( 11 , 12 ), sarcomas (including osteosarcoma) ( 13 , 14 ), ovarian cancer ( 15 , 16 ), breast cancer ( 16 , 17 ), lung cancer ( 18 , 19 ), astrocytomas ( 20 ), pancreatic cancer ( 21 , 22 ), prostate cancer ( 23 26 ), cholangiocarcinoma ( 27 ), gliomas ( 28 ), medulloblastoma ( 29 ), mesothelioma ( 30 ), colorectal cancer ( 31 ), gastric cancer ( 32 ), hepatocellular carcinoma ( 33 , 34 ), thyroid cancer ( 35 ), bladder cancer ( 36 ), renal cell carcinoma ( 37 , 38 ), cervical cancer ( 39 ), esophageal cancer ( 40 ), melanoma ( 41 ), endometrial cancer ( 42 , 43 ), non-small cell lung cancer ( 44 , 45 ), and cutaneous squamous cell carcinoma ( 46 , 47 ).

PVT1 has at least 12 annotated exons: exon 1A, exon 1B, exon 1C, exon 2, exon 3A, exon 3B, exon 4A, exon 4B, exon 5, exon 6, exon 7, exon 8, and exon 9 ( 1 ). And it encodes six annotated microRNAs (miRNAs): miR-1204, miR-1205, miR-1206, miR-1207-3p, miR-1207-5p, and miR-1208 ( 48 ). PVT1 is expressed in the various organs throughout the human body. There is progressively increasing evidence that distinct PVT1 exons, and PVT1-encoded miRNAs have significant biological functions, as discussed in the well-written articles included in our Research Topic entitled “ PVT1 in Cancer.” In addition, there is evidence of alternative splicing at the PVT1 gene, resulting in at least 25 annotated PVT1 transcript variants (). As noted in several of the papers published in the Research Topic “ PVT1 in Cancer,” PVT1 induces cancer development and progression via a variety of biological mechanisms including but not limited to miRNA regulation (), and as a competing endogenous RNA (ceRNA) ().

The articles included in the Research Topic “ PVT1 in Cancer” are particularly interesting because they highlight the clinical relevance and potential clinical applications of PVT1 in cancer. For example, the article by discusses the potential prognostic applications and the potential to target PVT1 for therapeutic applications in pediatric cancers. All of the other articles discuss potential clinical applications in a variety of adult cancers. Notably, identify PVT1 as a mediator of cancer chemoresistance. Thus, targeting PVT1 may have a future role in the treatment of many highly lethal cancers such as pancreatic cancer, and neuroendocrine prostate cancer where chemoresistance is common.

Author Contributions

All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.

Funding

OO was supported by National Cancer Institute grant # U54CA221704.

Conflict of Interest

OO is a co-founder of NucleoBio, Inc., a City University of New York start-up biotechnology company.

The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

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2. Alvarez ML, DiStefano JK. Functional characterization of the plasmacytoma variant translocation 1 gene (PVT1) in diabetic nephropathy. PLoS ONE . (2011) 6: e18671. doi: 10. 1371/journal. pone. 0018671

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3. Yu YH, Hu ZY, Li MH, Li B, Wang ZM, Chen SL. Cardiac hypertrophy is positively regulated by long non-coding RNA PVT1. Int J Clin Exp Pathol . (2015) 8: 2582–9.

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4. Ben S, Jin Y, Santorico SA, Spritz RA. Genome-wide association of PVT1 with Vitiligo. J Invest Dermatol . (2018) 138: 1884–6. doi: 10. 1016/j. jid. 2018. 02. 025

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5. Li Y, Li S, Luo Y, Liu Y, Yu N. LncRNA PVT1 regulates chondrocyte apoptosis in osteoarthritis by acting as a sponge for miR-488-3p. DNA Cell Biol . (2017) 36: 571–80. doi: 10. 1089/dna. 2017. 3678

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13. Liu J, Li R, Liao X, Hu B, Yu J. Comprehensive investigation of the clinical significance and molecular mechanisms of plasmacytoma variant translocation 1 in sarcoma using genome-wide RNA sequencing data. J Cancer . (2019) 10: 4961–77. doi: 10. 7150/jca. 31675

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14. Zhou Q, Chen F, Zhao J, Li B, Liang Y, Pan W, et al. Long non-coding RNA PVT1 promotes osteosarcoma development by acting as a molecular sponge to regulate miR-195. Oncotarget . (2016) 7: 82620–33. doi: 10. 18632/oncotarget. 13012

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15. Chen Y, Du H, Bao L, Liu W. LncRNA PVT1 promotes ovarian cancer progression by silencing miR-214. Cancer Biol Med . (2018) 15: 238–50. doi: 10. 20892/j. issn. 2095-3941. 2017. 0174

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17. Tang J, Li Y, Sang Y, Yu B, Lv D, Zhang W, et al. LncRNA PVT1 regulates triple-negative breast cancer through KLF5/beta-catenin signaling. Oncogene . (2018) 37: 4723–34. doi: 10. 1038/s41388-018-0310-4

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18. Guo D, Wang Y, Ren K, Han X. Knockdown of LncRNA PVT1 inhibits tumorigenesis in non-small-cell lung cancer by regulating miR-497 expression. Exp Cell Res . (2018) 362: 172–9. doi: 10. 1016/j. yexcr. 2017. 11. 014

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19. Chen W, Zhu H, Yin L, Wang T, Wu J, Xu J, et al. lncRNA-PVT1 facilitates invasion through upregulation of MMP9 in nonsmall cell lung cancer cell. DNA Cell Biol . (2017) 36: 787–93. doi: 10. 1089/dna. 2017. 3725

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20. Schiffman JD, Hodgson JG, VandenBerg SR, Flaherty P, Polley MY, Yu M, et al. Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Cancer Res . (2010) 70: 512–9. doi: 10. 1158/0008-5472. CAN-09-1851

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21. Zhao L, Kong H, Sun H, Chen Z, Chen B, Zhou M. LncRNA-PVT1 promotes pancreatic cancer cells proliferation and migration through acting as a molecular sponge to regulate miR-448. J Cell Physiol . (2018) 233: 4044–55. doi: 10. 1002/jcp. 26072

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22. You L, Wang H, Yang G, Zhao F, Zhang J, Liu Z, et al. Gemcitabine exhibits a suppressive effect on pancreatic cancer cell growth by regulating processing of PVT1 to miR1207. Mol Oncol . (2018) 12: 2147–64. doi: 10. 1002/1878-0261. 12393

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23. Ilboudo A, Chouhan J, McNeil BK, Osborne JR, Ogunwobi OO. PVT1 Exon 9: a potential biomarker of aggressive prostate cancer? Int J Environ Res Public Health.(2015) 13: ijerph13010012. doi: 10. 3390/ijerph13010012

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24. Pal G, Huaman J, Levine F, Orunmuyi A, Olapade-Olaopa EO, Onagoruwa OT, et al. Long noncoding RNA from PVT1 exon 9 is overexpressed in prostate cancer and induces malignant transformation and castration resistance in prostate epithelial cells. Genes . (2019) 10: 964. doi: 10. 3390/genes10120964

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25. Orunmuyi A, Ilboudo A, Ogun O, Bach C, Adebayo S, Salako A, et al. PVT1 exons 4A, 4B, and 9 are overexpressed in aggressive prostate cancer, and PVT1 exon 4B may distinguish between indolent and aggressive prostate cancer. Cancer Res . (2017) 77 (13 Suppl.): 3507. doi: 10. 1158/1538-7445. AM2017-3507

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26. Pal G, Di L, Orunmuyi A, Olapade-Olaopa EO, Qiu W, Ogunwobi OO. Population differentiation at the PVT1 gene locus: implications for prostate cancer. G3 (Bethesda). (2020) 10: 2257–64. doi: 10. 1534/g3. 120. 401291

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33. Gou X, Zhao X, Wang Z. Long noncoding RNA PVT1 promotes hepatocellular carcinoma progression through regulating miR-214. Cancer Biomark . (2017) 20: 511–9. doi: 10. 3233/CBM-170331

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34. Lan T, Yan X, Li Z, Xu X, Mao Q, Ma W, et al. Long non-coding RNA PVT1 serves as a competing endogenous RNA for miR-186-5p to promote the tumorigenesis and metastasis of hepatocellular carcinoma. Tumour Biol . (2017) 39: 1010428317705338. doi: 10. 1177/1010428317705338

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36. Tian Z, Cao S, Li C, Xu M, Wei H, Yang H, et al. LncRNA PVT1 regulates growth, migration, and invasion of bladder cancer by miR-31/ CDK1. J Cell Physiol . (2019) 234: 4799–811. doi: 10. 1002/jcp. 27279

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