Determination of secondary and tertiary structures of cervical cancer lncRNA diagnostic and siRNA therapeutic biomarkers

https://doi.org/10.22146/ijbiotech.28508

Arli Aditya Parikesit(1*), Didik Huswo Utomo(2), Nihayatul Karimah(3)

(1) Bioinformatics Department, Indonesia International Institute for Life Sciences
(2) Bioinformatics Department, Indonesia International Institute for Life Sciences
(3) Bioinformatics Department, Indonesia International Institute for Life Sciences
(*) Corresponding Author

Abstract


Cervical cancer is one of the primary causes of mortality in women due to human papilloma virus (HPV) infection. The fingerprint of an HPV infection could be detected using a long non-coding RNA (lncRNA) biomarker, enabling it to be utilized in molecular diagnostics. The primary structure or sequences of RNA should be annotated within conventional bioinformatics tools. Therefore, this study aimed to determine the fine-grained 2D and 3D structures of lncRNA PVT1 and its respective siRNA inhibitors. lncRNA PVT1 sequences from Homo sapiens, Mus musculus, and Rattus norvegicus were retrieved from Genbank (NCBI). Prediction of the 2D structure and analysis of the interactions of the lncRNA and siRNA were performed using the Vienna RNA package. The 3D structure of the RNA was computed using the SimRNA and ModeRNA software programs. The results showed that lncRNA PVT1 from H. sapiens and M. musculus had a conserved region. However, the lncRNA from both H. sapiens and M. musculus showed a low conserved region, and the 2D structure could not be determined; thus, the annotation and 2D model focused only on H. sapiens. Both of their lncRNA PVT1 also had a short half-life in the cell. Based on the 3D modeling pipeline, the 3D model of lncRNA PVT1 showed the stability and possible function as molecules, while the PVT1 siRNA-lncRNA interaction analysis revealed that the molecules could bind well. Based on these findings, the structures of both lncRNA PVT1 and its siRNA have the potential to be utilized as biomarkers.


Keywords


biomarker; cervical cancer; HPV; lncRNA; transcriptomics

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Parikesit et al.


References

Bernhart SH, Hofacker IL, Will S, Gruber AR, Stadler PF. 2008. RNAalifold: improved consensus structure prediction for RNA alignments. BMC bioinformatics. 9:474. doi:10.1186/1471-2105-9-474.

Chang JT-C, Kuo T-F, Chen Y-J, Chiu C-C, Lu Y-C, Li H-F, Shen C-R, Cheng A-J. 2010. Highly potent and specific siRNAs against E6 or E7 genes of HPV16- or HPV18-infected cervical cancers. Cancer gene therapy. 17:827–36. doi:10.1038/cgt.2010.38.

Chen M, Manley JL. 2009. Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches. Nature reviews Molecular cell biology. 10:741–54. doi:10.1038/nrm2777.

De Villiers EM, Fauquet C, Broker TR, Bernard HU, Zur Hausen H. 2004. Classification of papillomaviruses.

Ding F, Lavender CA, Weeks KM, Dokholyan NV. 2012. Three-dimensional RNA structure refinement by hydroxyl radical probing. Nat Methods. 9:603–608. doi:10.1038/nmeth.1976.

Dong Z, Chen Y. 2013. Transcriptomics: advances and approaches. Science China Life sciences. 56:960–7. doi:10.1007/s11427-013-4557-2.

Flamm C, Hofacker IL, Stadler PF, Wolfinger T, Wolfinger MT. 2002. Barrier Trees of Degenerate Landscapes. Zeitschrift für Physikalische Chemie. 216:155. doi:10.1524/zpch.2002.216.2.155.

Gibb EA, Brown CJ, Lam WL. 2011. The functional role of long non-coding RNA in human carcinomas. Molecular cancer. 10:38. doi:10.1186/1476-4598-10-38.

Gruber AR, Bernhart SH, Lorenz R. 2015. The ViennaRNA web services. Methods in molecular biology (Clifton, NJ). 1269:307–26. doi:10.1007/978-1-4939-2291-8_19.

Gruber AR, Lorenz R, Bernhart SH, Neuböck R, Hofacker IL. 2008. The Vienna RNA websuite. Nucleic acids research. 36. doi:10.1093/nar/gkn188.

zur Hausen H. 2009a. The search for infectious causes of human cancers: where and why (Nobel lecture). Angewandte Chemie (International ed in English). 48:5798–808. doi:10.1002/anie.200901917.

zur Hausen H. 2009b. Papillomaviruses in the causation of human cancers - a brief historical account. Virology. 384:260–5. doi:10.1016/j.virol.2008.11.046.

Hofacker IL, Fekete M, Stadler PF. 2002. Secondary structure prediction for aligned RNA sequences. Journal of Molecular Biology. 319:1059–1066. doi:10.1016/S0022-2836(02)00308-X.

Iden M, Fye S, Li K, Chowdhury T, Ramchandran R, Rader JS. 2016. The lncRNA PVT1 Contributes to the Cervical Cancer Phenotype and Associates with Poor Patient Prognosis. Mallick B, editor. PLOS ONE. 11:e0156274. doi:10.1371/journal.pone.0156274.

Jiang M, Milner J. 2002. Selective silencing of viral gene expression in HPV-positive human cervical carcinoma cells treated with siRNA, a primer of RNA interference. Oncogene. 21:6041–6048. doi:10.1038/sj.onc.1205878.

Lorenz R, Bernhart SH, zu Siederdissen C, Tafer H, Flamm C, Stadler PF, Hofacker IL. 2011. ViennaRNA Package 2.0. Algorithms for Molecular Biology. 6:26. doi:10.1186/1748-7188-6-26.

Lu H, He Y, Lin L, Qi Z, Ma L, Li L, Su Y. 2016. Long non-coding RNA MALAT1 modulates radiosensitivity of HR-HPV+ cervical cancer via sponging miR-145. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 37:1683–91. doi:10.1007/s13277-015-3946-5.

Magnus M, Boniecki MJ, Dawson W, Bujnicki JM. 2016. SimRNAweb: a web server for RNA 3D structure modeling with optional restraints. Nucleic Acids Research. 44:gkw279. doi:10.1093/nar/gkw279.

Muckstein U, Tafer H, Hackermuller J, Bernhart SH, Stadler PF, Hofacker IL. 2006. Thermodynamics of RNA-RNA binding. Bioinformatics. 22:1177–1182. doi:10.1093/bioinformatics/btl024.

Parikesit AA, Anurogo D. 2016a. Prediksi struktur 2-dimensi non-coding {RNA} dari biomarker kanker payudara triple-negative dengan {Vienna RNA} package [The 2-Dimensional Structure Prediction of Triple-Negative Breast Cancer (TNBC) Biomarker non-coding RNA with Vienna RNA Package]. Chimica et Natura Acta. 4:27. doi:10.24198/cna.v4.n1.10445.

Parikesit AA, Anurogo D. 2016b. The 2-Dimensional Structure Prediction of Triple-Negative Breast Cancer (TNBC) Biomarker non-coding RNA with Vienna RNA Package. Jurnal Kimia. doi:10.17632/jcmyx924yy.1.

Parikesit AA, Anurogo D, Parikesit AA. 2016. Bioinformatics Approach towards Transcriptomics of Filaggrin. Journal of Agromedicine and Medical Sciences. 2:8 – 16.

Parikesit AA, Nurdiansyah R. 2018. Generating Two-Dimensional Repertoire of siRNA Linc-ROR and siRNA mRNA ARF6 from the lincRNA-RoR/miR-145/ARF6 expression Pathway that involved in the progression of Triple Negative Breast Cancer. IOP Conference Series: Materials Science and Engineering. 299:012059. doi:10.1088/1757-899X/299/1/012059.

Parikesit AAP. 2017. Research Data of the “The Discovery of Secondary and Tertiary Structure of Cervical Cancer lncRNA biomarker.” Indonesia International Institute for Life Sciences.

Qian K. 2013. Bioinformatics analysis of HPV associated host microRNA functions and identification of viral microRNA. University of Helsinki.

Qian K, Pietilä T, Rönty M, Michon F, Frilander MJ, Ritari J, Tarkkanen J, Paulín L, Auvinen P, Auvinen E. 2013. Identification and Validation of Human Papillomavirus Encoded microRNAs. Ho PL, editor. PLoS ONE. 8:e70202. doi:10.1371/journal.pone.0070202.

Rother M, Rother K, Puton T, Bujnicki JM. 2011. ModeRNA: a tool for comparative modeling of RNA 3D structure. Nucleic acids research. 39:4007–22. doi:10.1093/nar/gkq1320.

Smit S, Rother K, Heringa J, Knight R. 2008. From knotted to nested RNA structures: A variety of computational methods for pseudoknot removal. RNA. 14:410–416. doi:10.1261/rna.881308.

Tafer H, Ameres SL, Obernosterer G, Gebeshuber CA, Schroeder R, Martinez J, Hofacker IL. 2008. The impact of target site accessibility on the design of effective siRNAs. Nature biotechnology. 26:578–83. doi:10.1038/nbt1404.

Tambunan USF, Parikesit AA. 2012. HPV Bioinformatics: In Silico Detection, Drug Design and Prevention Agent Development. In: Rajkumar R, editor. Topics on Cervical Cancer with an Advocacy for Prevention. Rijeka, Croatia: Intech Publishing. p. 237–252.

TBI. 2016. Vienna RNA Package Web Version 2.0.

Wang Y, Liu J, Huang BO, Xu Y-M, Li J, Huang L-F, Lin J, Zhang J, Min Q-H, Yang W-M, et al. 2015. Mechanism of alternative splicing and its regulation. Biomedical reports. 3:152–158. doi:10.3892/br.2014.407.

Wang Z, Gerstein M, Snyder M. 2009. RNA-Seq: a revolutionary tool for transcriptomics. Nature Reviews Genetics. 10:57–63. doi:10.1038/nrg2484.

WHO. 2007. The World Health Organization’s fight against cancer: strategies that prevent, cure and care. WHO.

WHO. 2017. WHO | Cancer Key Facts. WHO.

Wolfinger MT, Svrcek-Seiler WA, Flamm C, Hofacker IL, Stadler PF. 2004. Efficient computation of RNA folding dynamics. Journal of Physics A: Mathematical and General. 37:4731–4741. doi:10.1088/0305-4470/37/17/005.

Yang L, Yi K, Wang H, Zhao Y, Xi M. 2016. Comprehensive analysis of lncRNAs microarray profile and mRNA – lncRNA co-expression in oncogenic HPV-positive cervical cancer cell lines. Oncotarget. 5:1–13. doi:10.18632/oncotarget.10232.

Yoshinouchi M, Yamada T, Kizaki M, Fen J, Koseki T, Ikeda Y, Nishihara T, Yamato K. 2003. In vitro and in vivo growth suppression of human papillomavirus 16-positive cervical cancer cells by e6 siRNA. Molecular Therapy. 8:762–768. doi:10.1016/j.ymthe.2003.08.004.



DOI: https://doi.org/10.22146/ijbiotech.28508

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