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Detection of microRNAs seed sequences within human papillomavirus genomes

How to cite this article: Pineda-Gómez D, Garrido E, Chávez P, Salcedo M. Detection of microRNAs seed sequences within human papillomavirus genomes. Rev Med Inst Mex Seguro Soc. 2015;53 Supl 2:S140-53.



Received: October 22nd 2014

Accepted: May 15th 2015

Detection of microRNAs seed sequences within human papillomavirus genomes

David Pineda-Gómez,a Efraín Garrido,b Pedro Chávez,b Mauricio Salcedoa

aUnidad de Investigación Médica en Enfermedades Oncológicas, Hospital de Oncología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social

bDepartamento de Genética y Biología Molecular, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional

Distrito Federal, México

Communication with: Mauricio Salcedo

Telephone: (55) 5627 6900, extensión 22706


In this paper we are reporting for the first time the presence of seed sequences of human and viral microRNAs embedded within both high and low risk human papillomavirus (HPV) genomes. These seed sequences have high oncogenic potential. They were found using an in silico analysis based on the microRNA sequences added to Sanger’s database. Among these sequences, it was observed a potential fingerprint harbouring several repeated sequences of microRNA 297 (miR-297) within the LCR region of HPV types 16, 18, 33, 45 and 52. Further analyses were performed for low risk HPV types 6 and 11 and we observed that the probable fingerprint was absent in HPV11, even when we detected other repeated sequences of miR-363. According to these findings, besides the fact that we detected the presence of microRNA sequences within HPV genomes, we suggest a common putative viral mechanism of gene expression regulation shared among human virus.

Keywords: MicroRNAs, HPV.

MicroRNAs are small RNA molecules of 22 to 24 nucleotides in length that play an important role in the regulation of gene expression at the translational level.1 They exert this function through their ability to integrate into translational silencing complexes, which are dependent on interference RNA (RISC). These inhibit translation by binding to specific molecules of messenger RNA (mRNA), silencing them or sending them to degradation. Almost 10,000 microRNA sequences have been detected in a wide variety of species, but their physiological targets have only been identified and characterized in a fraction of these; however, it has been shown that some microRNAs detected in humans have targets, either related to cell cycle regulation, growth factor expression, or individual development.2

MicroRNAs have also been linked with the development of different types of cancer in humans.1 Their expression has been reported in different viruses that infect humans and develop pathologies.3 Although apparently this type of molecule is absent in the genome of the human papillomavirus (HPV), which is the main etiologic agent of cervical cancer, in this paper we report the existence microRNA seed sequences in the genome of different types of HPV, which have been previously reported in the genome of other families of viruses and in humans.


The database with microRNA sequences corresponding to version 10.0 was downloaded from the Sanger Institute website ( MicroRNA sequences were classified into families according to the similarity in their sequences, and the seed sequences of each one were selected (taking nucleotides 2-8 at the 5' end), redundancy among them was eliminated, whereby only 1253 seeds were obtained, each representative of a family (of these seeds, 280 corresponded to H. sapiens). This database was called Fam_miRNAs. Then, researchers downloaded from the website of the National Center of Biotechnology Information (NCBI) consensus sequences of the genomes of HPV types 16 and 18 (NC_001526.1 and X01505, respectively) and of different reported sequences of the entire genomes of HPV 6 (AF092932), -11 (EU918768, LZod45-11 strain), -33 (EU918766, LZcc12-33 strain), -45 (EF202164, Qv25000 strain), and -52 (X74481), all in Fasta format.  

Researchers proceeded to create a spreadsheet in Excel (part of Microsoft Office suite, Version 2003) that would detect different seeds in the genome of HPV based on the Fam_miRNAs database; the Find function was used, which requires the viral genome sequence of interest and the seeds contained in the Fam_miRNAs database to be entered into the same spreadsheet. The function generated a report, which recorded the seeds that were found and the viral region in which they were located. Based on this information, a new database was created, called miRNAs_VPH X, wherein X represented the viral type in which the detection took place. After selecting the different microRNAs seeds of H. sapiens, they were placed within a genetic map of the viral types; for this, researchers used the gene sequence of the virus loaded into Word (Microsoft Office suite, version 2003) and the Search command (located within the Editing option of the toolbar), in which the seed sequence to be located was introduced, and the program performed detection in the different viral regions. The seeds were then marked with different colors, depending on their origin (viral, other than HPV, and H. sapiens) and the copy number of each was noted, as well as noting which seeds overlapped and which were contiguous with one another.   


In order to work with genomic sequences representative of each of the HPV types, researchers performed the search for sequences in the NCBI Entrez database, and this only found seeds for types 16 and 18. Of the other viral genome sequences searched, only reports of different strains were found, of which those containing complete genomic sequences were selected.

Upon applying the Find function of Excel, variable amounts of microRNA seeds were detected, both for H. sapiens and different viruses in the different HPV types analyzed. The list of seed sequences corresponding to the viral microRNAs are found in Annex 1, while Annexes 2 and 3 list microRNA seed sequences belonging to H. sapiens detected in the HPV types. 

Repetitions of some seeds were also found in different regions of the genomes, of which the most notable was that recorded in the LCR of the seed of miR-297 in types 16, 18, 33, 45, and 52. Annex 4 shows the LCR regions of the different HPV types included in this study, indicating the position of said repetitions.


Since the beginning of the 20th century when microRNAs were discovered in C. elegans, an increasing number of microRNA sequences has been reported in different organisms, and it has been shown that they are part of a mechanism for regulation of gene expression that has barely begun to be studied.7,8 Several microRNA sequences have been detected in a variety of pathogenic viruses, as in the case of the Herpesviridiae family and some members of the polyomavirus and adenovirus families.3 More recently, the presence of microRNA has been reported in the genome of human immunodeficiency virus (HIV).9 These data would suggest that viruses also possess this type of gene regulatory elements.

Although there have been several attempts to detect compatible sequences of microRNAs in the HPV genome, different strategies have failed and only cellular microRNAs have been reported found, as in the case of HPV 3110 and detection attempts in HPV + cell lines.11 After these reports, we identified compatible sequences of cellular microRNA within the HPV genomes. Unfortunately, at the time the data were not accepted for publication (V Villegas, M Salcedo, personal communication, 2011). However, recently the presence of microRNAs in HPV types 16 (six candidates, two of them located in the LCR), 38, 45, and 68 (one candidate in each) has been reported.12 With this report we demonstrate and suggest that HPV contains microRNA seed sequences shared by human microRNA sequences and those of other viruses.

This paper presents an in silico analysis that was implemented as a detection strategy for potential microRNAs conserved among different species recorded in the Sanger Institute database and different HPV genomes; for this, tools contained in two programs of Windows Office suite were used. The methodology shown is proposed as an alternative to using other programs that require a basic knowledge of programming and creating scripts, as in the case of Perl. This strategy has been successfully used to detect seeds of approximately 100 different microRNAs encoded in H. sapiens and other viruses. It was not possible to detect complete sequences of mature microRNAs or their precursors (pre-miRNAs) in any of the genomes analyzed by comparing the sequences reported in the miRBase database. Given the length of HPV genomes, we think there is the possibility that these viruses have developed the strategy of keeping in their genome only microRNA seeds that can grant them some benefit for survival, negatively regulating genes encoding tumor suppressor proteins or immune system recognition, or indirectly allowing oncogenic protein synthesis through mechanisms such as those reported by Esquela-Kerschner et al.1 Moreover, research has demonstrated the existence of alternative  intron cutting and exon splicing to generate a variety of regulatory RNAs in HPV 16, as demonstrated above,13 so we suggest that, as part of this mechanism, certain regions could be transcribed where different microRNA seeds are located, which would generate an non-coding RNA molecule that would thus allow a possible regulatory function.       

If the above is true, it is likely that these sequences were acquired as the result of the joint evolution of HPV and H. sapiens, as proposed by several authors for HPV 16 and 18,14-17 and that they may have been preserved in the viral genome as a survival strategy that includes avoidance of the immune system and cell cycle regulation. In addition, the presence of seeds derived from microRNAs of other viruses with human hosts, such as Kaposi sarcoma, Epstein-Barr virus, or cytomegalovirus, is intriguing; one could speculate that these viruses share the same pattern of infection and possible regulation of cellular functions. The low or zero oncogenic capacity of HPV 6 or 11 could be explained, at least in part, by this event, as no link could be shown between the evolution of the virus and the appearance of different races of humans.18 Moreover, science has not yet demonstrated the existence of possible recombination between different types of HPV,17 so we think the presence of human microRNA seeds in the viral genome is an event caused by their coevolution.

As for the bioinformatic analysis results, there are clear differences in the number of seeds present in the low- and high-risk types of HPV. The former shows few microRNAs seeds from other viruses, although type 11 does show a high copy number of these. The high-risk types show a higher number of seeds of this type and a smaller number of copies, which may mean that the virus requires a greater number of these seeds to induce a lesion in its host and, possibly, the development of some type of cancer in the cervix. The low number of seeds of other viruses in the low-risk types of HPV may therefore explain, at least in part, that these HPV are only capable of inducing low-grade intraepithelial lesions.  

There are seeds that overlap with each other in the different viral types (as in the case of miR-297), which are present in the LCR region of HPV 16, 18, 33, 45, and 52. This event may have the following meanings: 1) that this overlap leads to the inactivation of the seeds, so that, when the genomic region where they are located is transcribed, a messenger RNA is created encoding the viral protein and not encoding small regulatory RNAs; or, 2) that overlapping seeds may generate a microRNA unique to the virus, which can interact with multiple mRNAs that are target at once. This last event has been shown in some cases when a pre-miRNA is polycistronic, that is, it codes for two or more microRNAs in a single transcript,3 or they are grouped in tandem, as in the case of a set of microRNAs detected on chromosome 19 in the human.19 Even the length of this hypothetical HPV microRNA could possess additional binding sites to the target mRNA, which could help stabilize the microRNA-mRNA interaction and subsequent regulation. The existence of this type of molecules, and if any of these hypotheses may have some meaning for viral activity, remain to be demonstrated, using molecular techniques.   

As regards microRNA seeds present in H. sapiens, differences are also observed between types of high-risk HPV. The biggest similarities between these allow types 18 and 45 to be grouped, while types 16, 33, and 52 form another group, which is in line with the phylogenetic trees developed based on the L1 protein.20 This may be because the shared seeds are on highly conserved domains or sequences between different viral types, and the same potential for lesion induction may be reflected in the HPV belonging to the two groups.

The presence of repetitions of the miR-297 seeds in the LCR of high-risk viral types may indicate that these repeats make up a cluster that is necessary for the regulation of viral or cellular genome expression, given the particular location of these seeds (LCR). Consistent with the above, the presence of several repetitions of the miR-363 seed in the corresponding LCR of HPV 11 could reflect that the presence of repeats in this region is necessary, regardless of the specific microRNA to which they belong, and this event might point towards a possible genetic fingerprint that could identify the presence of HPV and differentiate it from other viruses that may be present in the same tissue sample.

In summary, this paper reports on a simple methodology for an in silico analysis that allowed us to detect a variety of microRNA seeds in the genome of different HPV types. This detection strategy could also be used to detect microRNA sequences conserved in genomes of other species, even those that are in the process of assembly.

In conclusion, the human papillomaviruses with high oncogenic power theoretically share compatible sequences with human and viral microRNAs, suggesting common mechanisms of viral regulation. These sequences may at least be in clusters within the LCR control region.


This paper is derived from a project approved by CONACYT sectoral funds and the IMSS project on the detection of microRNAs in the human papillomavirus.

During the creation of this work, David Pineda Gomez was a grantee of CONACyT in the Molecular Biotechnology and Biomedicine PhD program at ENCB-IPN.

Clarifying note

over two years ago we sent for publication a report on the existence of microRNAs in HPV to two different indexed journals, and both times it was rejected. However, in 2013, an article was published in the journal PLoS ONE that reported the presence of microRNAs in HPV.

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Annex 1 MicroRNA seeds present in the genomes of other viruses, detected in the genome of low- and high-risk HPV
ebv-miR-BART10 ebv-miR-BART12 ebv-miR-BART10 ebv-miR-BART10 ebv-miR-BART11-5p ebv-miR-BART10 ebv-miR-BART14
ebv-miR-BART11-5p ebv-miR-BART14 ebv-miR-BART12 ebv-miR-BART11-5p ebv-miR-BART12 ebv-miR-BART12 ebv-miR-BART17-5p
ebv-miR-BART12 ebv-miR-BART16 ebv-miR-BART15 ebv-miR-BART12 ebv-miR-BART16 ebv-miR-BART14 ebv-miR-BART20-5p
ebv-miR-BART14 ebv-miR-BART17-5p ebv-miR-BART1-5p ebv-miR-BART13 ebv-miR-BART17-5p ebv-miR-BART1-5p ebv-miR-BART3
ebv-miR-BART15 ebv-miR-BART19-5p ebv-miR-BART19-5p ebv-miR-BART14 ebv-miR-BART19-5p ebv-miR-BART3 ebv-miR-BART5
ebv-miR-BART19-5p ebv-miR-BART3 ebv-miR-BART3 ebv-miR-BART15 ebv-miR-BART2-5p ebv-miR-BART4 ebv-miR-BART6-5p
ebv-miR-BART4 ebv-miR-BART4 ebv-miR-BART5 ebv-miR-BART1-5p ebv-miR-BART3 ebv-miR-BART5 ebv-miR-BHRF1-1
ebv-miR-BART5 ebv-miR-BART5 ebv-miR-BART6-5p ebv-miR-BART17-5p ebv-miR-BART5 ebv-miR-BART6-5p hcmv-miR-UL148D
ebv-miR-BHRF1-1 ebv-miR-BART6-5p ebv-miR-BART9 ebv-miR-BART2-5p ebv-miR-BART6-5p hcmv-miR-UL112 hcmv-miR-US33-5p
ebv-miR-BHRF1-2 ebv-miR-BHRF1-2 hcmv-miR-US33-5p ebv-miR-BART3 hcmv-miR-UL148D hcmv-miR-US33-5p hcmv-miR-US5-1
ebv-miR-BHRF1-3 hcmv-miR-US33-5p hcmv-miR-US5-1 ebv-miR-BART4 hcmv-miR-US33-5p hcmv-miR-US5-2 hcmv-miR-US5-2
hcmv-miR-UL148D hcmv-miR-US5-2 hcmv-miR-US5-2 ebv-miR-BART5 hcmv-miR-US5-1 hiv1-miR-H1 hiv1-miR-N367
hcmv-miR-US33-5p hiv1-miR-H1 hiv1-miR-N367 hcmv-miR-UL112 hcmv-miR-US5-2 hsv1-miR-LAT hsv1-miR-H1
hcmv-miR-US5-2 hiv1-miR-N367 kshv-miR-K12-1 hcmv-miR-UL36 hiv1-miR-N367 kshv-miR-K12-1 hsv1-miR-LAT
hiv1-miR-H1 hsv1-miR-LAT kshv-miR-K12-10a hcmv-miR-US33-5p hsv1-miR-H1 kshv-miR-K12-10a kshv-miR-K12-1
hiv1-miR-N367 kshv-miR-K12-1 kshv-miR-K12-10b hcmv-miR-US5-2 hsv1-miR-LAT kshv-miR-K12-10b kshv-miR-K12-10a
hsv1-miR-H1 kshv-miR-K12-10a kshv-miR-K12-12 hsv1-miR-LAT kshv-miR-K12-1 kshv-miR-K12-2 kshv-miR-K12-10b
hsv1-miR-LAT kshv-miR-K12-4-5p kshv-miR-K12-3 kshv-miR-K12-10a kshv-miR-K12-10b kshv-miR-K12-6-5p kshv-miR-K12-2
kshv-miR-K12-1 kshv-miR-K12-6-5p kshv-miR-K12-4-5p kshv-miR-K12-10b kshv-miR-K12-2 mdv1-miR-M2 kshv-miR-K12-4-5p
kshv-miR-K12-10b kshv-miR-K12-9 kshv-miR-K12-6-5p kshv-miR-K12-5 kshv-miR-K12-5 mdv1-miR-M3 kshv-miR-K12-5
kshv-miR-K12-2 mdv1-miR-M2 kshv-miR-K12-9 kshv-miR-K12-6-5p mdv1-miR-M2 mdv2-miR-M14-5p kshv-miR-K12-6-5p
kshv-miR-K12-6-5p mdv1-miR-M3 mdv1-miR-M1 mdv1-miR-M1 mdv1-miR-M3 mdv2-miR-M16 mdv1-miR-M2
kshv-miR-K12-7 mdv2-miR-M14-5p mdv1-miR-M3 mdv1-miR-M2 mdv2-miR-M14-5p mdv2-miR-M20 mdv1-miR-M3
mdv1-miR-M1 mdv2-miR-M15 mdv2-miR-M14-5p mdv1-miR-M3 mdv2-miR-M15 mdv2-miR-M21 mdv2-miR-M15
mdv1-miR-M2 mdv2-miR-M16 mdv2-miR-M16 mdv2-miR-M14-5p mdv2-miR-M21 mdv2-miR-M26 mdv2-miR-M18-5p
mdv1-miR-M3 mdv2-miR-M20 mdv2-miR-M18-5p mdv2-miR-M15 mdv2-miR-M22 mghv-miR-M1-1 mdv2-miR-M22
mdv1-miR-M6 mdv2-miR-M22 mdv2-miR-M22 mdv2-miR-M16 mdv2-miR-M26 mghv-miR-M1-7-5p mdv2-miR-M27-5p
mdv2-miR-M14-5p mdv2-miR-M24 mdv2-miR-M25-5p mdv2-miR-M18-5p mdv2-miR-M30 mghv-miR-M1-9 mghv-miR-M1-1
mdv2-miR-M15 mghv-miR-M1-1 mghv-miR-M1-1 mdv2-miR-M21 mghv-miR-M1-1 mghv-miR-M1-2
mdv2-miR-M16 mghv-miR-M1-7-5p mghv-miR-M1-2 mdv2-miR-M22 mghv-miR-M1-2 mghv-miR-M1-9
mdv2-miR-M18-5p mghv-miR-M1-9 mghv-miR-M1-9 mdv2-miR-M25-5p mghv-miR-M1-9
mdv2-miR-M19 mdv2-miR-M26
mdv2-miR-M22 mghv-miR-M1-1
mdv2-miR-M24 mghv-miR-M1-7-5p
ebv  = Epstein-Barr virus; hcmv = human cytomegalovirus; hiv = human immunodeficiency virus; hsv = herpes simplex virus; kshv = Kaposi's sarcoma virus; mdv = Marek disease virus; mghv = murine gamma herpesvirus

Annex 2 MicroRNA seeds present in the genome of H. sapiens, detected in the genome of HPV types 6, 11, 16, and 18
microRNA Position microRNA Position microRNA Position microRNA Position
hsa-miR-141 6827 hsa-miR-143 1915 hsa-miR-143 3109 hsa-miR-141 5647
hsa-miR-143 735 hsa-miR-144 5961 hsa-miR-220b 7103 hsa-miR-143 3428
hsa-miR-144 5980 hsa-miR-147 260 hsa-miR-220c 6583 hsa-miR-144 4667
hsa-miR-147 3477 hsa-miR-193b 3799 hsa-miR-223 409 hsa-miR-187 7632
hsa-miR-187 6713 hsa-miR-200a 5516 hsa-miR-27b 2670 hsa-miR-220c 1039
hsa-miR-193b 3803 hsa-miR-220b 3033 hsa-miR-297 286 hsa-miR-221 3772
hsa-miR-220b 3034 hsa-miR-220c 1323 hsa-miR-298 5240 hsa-miR-223 3237
hsa-miR-223 2842 hsa-miR-223 2841 hsa-miR-29b-1 5928 hsa-miR-23a 5764
hsa-miR-297 3133 hsa-miR-297 7370 hsa-miR-323-5p 3319 hsa-miR-24-1 4888
hsa-miR-298 5411 hsa-miR-298 6911 hsa-miR-325 4866 hsa-miR-296-5p 4531
hsa-miR-299-5p 4806 hsa-miR-29a 3983 hsa-miR-326 6473 hsa-miR-297 776
hsa-miR-29a 6409 hsa-miR-29b-1 5589 hsa-miR-331-5p 2416 hsa-miR-298 1676
hsa-miR-29b-2 1796 hsa-miR-325 6621 hsa-miR-338-5p 716 hsa-miR-299-5p 5862
hsa-miR-328 5623 hsa-miR-329 7708 hsa-miR-346 3920 hsa-miR-29b-1 961
hsa-miR-329 4282 hsa-miR-331-5p 4583 hsa-miR-376c 1098 hsa-miR-300 2414
hsa-miR-331-5p 7028 hsa-miR-339-5p 5166 hsa-miR-378 5074 hsa-miR-324-5p 893
hsa-miR-338-5p 7592 hsa-miR-340 7207 hsa-miR-382 3517 hsa-miR-325 809
hsa-miR-340 2853 hsa-miR-363 1349 hsa-miR-409-5p 6533 hsa-miR-328 3058
hsa-miR-367 698 hsa-miR-367 296 hsa-miR-410 3000 hsa-miR-329 90
hsa-miR-370 7233 hsa-miR-376c 1334 hsa-miR-411 1970 hsa-miR-337-5p 956
hsa-miR-376c 1341 hsa-miR-378 580 hsa-miR-450b-5p 2726 hsa-miR-338-5p 1304
hsa-miR-382 5845 hsa-miR-382 7498 hsa-miR-485-5p 928 hsa-miR-363 4405
hsa-miR-410 5631 hsa-miR-409-5p 7901 hsa-miR-488 5913 hsa-miR-367 1766
hsa-miR-411 617 hsa-miR-411 1374 hsa-miR-490-5p 3091 hsa-miR-376a 2872
hsa-miR-433 5215 hsa-miR-450b-5p 170 hsa-miR-493 1920 hsa-miR-376c 184
hsa-miR-450b-5p 5266 hsa-miR-452 4887 hsa-miR-495 380 hsa-miR-410 4629
hsa-miR-452 6761 hsa-miR-454 5475 hsa-miR-500 2692 hsa-miR-411 1790
hsa-miR-486-5p 3900 hsa-miR-483-5p 5281 hsa-miR-501-5p 2693 hsa-miR-412 6463
hsa-miR-488 2270 hsa-miR-486-5p 3883 hsa-miR-504 4949 hsa-miR-433 5203
hsa-miR-493 3879 hsa-miR-493 3853 hsa-miR-509-3-5p 3691 hsa-miR-450b-5p 2797
hsa-miR-494 1285 hsa-miR-494 1278 hsa-miR-512-5p 1284 hsa-miR-483-5p 934
hsa-miR-495 2802 hsa-miR-495 6216 hsa-miR-513-5p 2052 hsa-miR-486-5p 5321
hsa-miR-509-3-5p 220 hsa-miR-504 584 hsa-miR-519a 3107 hsa-miR-493 4185
hsa-miR-511 1485 hsa-miR-507 6508 hsa-miR-520d-5p 767 hsa-miR-504 5309
hsa-miR-513-5p 7041 hsa-miR-513-5p 7025 hsa-miR-521 4438 hsa-miR-508-5p 4569
hsa-miR-514 6379 hsa-miR-518a-5p 7167 hsa-miR-539 2894 hsa-miR-509-3-5p 5245
microRNA Position microRNA Position microRNA Position microRNA Position
hsa-miR-519a 108 hsa-miR-518b 7210 hsa-miR-541 2070 hsa-miR-511 4144
hsa-miR-520d-5p 1770 hsa-miR-520d-5p 1769 hsa-miR-544 2341 hsa-miR-512-5p 3459
hsa-miR-520g 1772 hsa-miR-520g 1771 hsa-miR-548a-3p 7833 hsa-miR-513-5p 3290
hsa-miR-539 2443 hsa-miR-539 2554 hsa-miR-548a-5p 1543 hsa-miR-515-5p 6492
hsa-miR-544 4651 hsa-miR-543 5495 hsa-miR-549 615 hsa-miR-517 5729
hsa-miR-548a-3p 2244 hsa-miR-548a-5p 106 hsa-miR-551a 125 hsa-miR-520d-5p 1953
hsa-miR-548a-5p 1679 hsa-miR-549 270 hsa-miR-551b 1551 hsa-miR-539 2542
hsa-miR-550 6588 hsa-miR-550 292 hsa-miR-552 994 hsa-miR-541 1680
hsa-miR-551b 1741 hsa-miR-551b 319 hsa-miR-556-5p 2668 hsa-miR-543 7758
hsa-miR-553 41 hsa-miR-553 40 hsa-miR-558 155 hsa-miR-544 5807
hsa-miR-561 7133 hsa-miR-555 6268 hsa-miR-561 304 hsa-miR-548a-3p 7401
hsa-miR-564 471 hsa-miR-561 7117 hsa-miR-567 2419 hsa-miR-548a-5p 1529
hsa-miR-566 4774 hsa-miR-567 3278 hsa-miR-568 15 hsa-miR-550 416
hsa-miR-567 3279 hsa-miR-569 6194 hsa-miR-569 807 hsa-miR-552 3783
hsa-miR-569 6210 hsa-miR-570 2480 hsa-miR-575 6494 hsa-miR-553 47
hsa-miR-570 2784 hsa-miR-578 7331 hsa-miR-579 7825 hsa-miR-556-5p 2034
hsa-miR-576-5p 1993 hsa-miR-579 1486 hsa-miR-581 7290 hsa-miR-561 1174
hsa-miR-581 3473 hsa-miR-582-5p 1824 hsa-miR-582-5p 6751 hsa-miR-564 944
hsa-miR-582-5p 1825 hsa-miR-583 24 hsa-miR-584 3217 hsa-miR-567 1845
hsa-miR-583 3240 hsa-miR-586 1580 hsa-miR-585 28 hsa-miR-570 1196
hsa-miR-584 6374 hsa-miR-592 418 hsa-miR-586 2476 hsa-miR-577 4366
hsa-miR-586 2952 hsa-miR-596 4649 hsa-miR-587 476 hsa-miR-579 2432
hsa-miR-587 5936 hsa-miR-597 419 hsa-miR-592 2783 hsa-miR-584 7225
hsa-miR-592 419 hsa-miR-600 5097 hsa-miR-595 739 hsa-miR-586 2703
hsa-miR-596 288 hsa-miR-602 1216 hsa-miR-599 7302 hsa-miR-595 788
hsa-miR-597 420 hsa-miR-607 1812 hsa-miR-603 1412 hsa-miR-600 225
hsa-miR-598 3517 hsa-miR-608 1348 hsa-miR-605 7556 hsa-miR-602 5442
hsa-miR-599 4734 hsa-miR-611 7181 hsa-miR-606 7624 hsa-miR-606 6845
hsa-miR-609 4233 hsa-miR-612 779 hsa-miR-607 6500 hsa-miR-609 7356
hsa-miR-614 3468 hsa-miR-615-5p 5319 hsa-miR-608 1357 hsa-miR-611 1018
hsa-miR-620 4186 hsa-miR-620 4346 hsa-miR-609 1397 hsa-miR-612 496
hsa-miR-622 5618 hsa-miR-622 5599 hsa-miR-611 2732 hsa-miR-619 3560
hsa-miR-624 6792 hsa-miR-624 2896 hsa-miR-614 7677 hsa-miR-624 3432
hsa-miR-625 6578 hsa-miR-625 2317 hsa-miR-620 567 hsa-miR-630 6482
hsa-miR-626 1483 hsa-miR-627 5208 hsa-miR-626 1742 hsa-miR-631 3559
hsa-miR-629 3804 hsa-miR-629 3800 hsa-miR-632 3919 hsa-miR-632 6322
hsa-miR-632 6922 hsa-miR-630 3950 hsa-miR-633 2018 hsa-miR-634 2365
hsa-miR-634 3538 hsa-miR-632 6442 hsa-miR-635 3438 hsa-miR-640 919
microRNA Position microRNA Position microRNA Position microRNA Position
hsa-miR-637 4617 hsa-miR-636 4687 hsa-miR-636 7205 hsa-miR-641 181
hsa-miR-639 507 hsa-miR-637 4661 hsa-miR-641 451 hsa-miR-642 6488
hsa-miR-641 386 hsa-miR-641 2172 hsa-miR-643 7208 hsa-miR-643 1842
hsa-miR-642 6959 hsa-miR-643 7333 hsa-miR-647 5646 hsa-miR-646 849
hsa-miR-644 3478 hsa-miR-644 261 hsa-miR-650 6867 hsa-miR-649 194
hsa-miR-647 2222 hsa-miR-647 2221 hsa-miR-653 7167 hsa-miR-650 1184
hsa-miR-649 6583 hsa-miR-649 4157 hsa-miR-655 4065 hsa-miR-652 105
hsa-miR-653 366 hsa-miR-654-5p 6235 hsa-miR-656 3225 hsa-miR-654-5p 4466
hsa-miR-654-5p 6098 hsa-miR-655 4907 hsa-miR-665 6864 hsa-miR-655 1695
hsa-miR-655 3870 hsa-miR-656 3193 hsa-miR-765 660 hsa-miR-656 1709
hsa-miR-656 3221 hsa-miR-656 3193 hsa-miR-766 6931 hsa-miR-660 4867
hsa-miR-657 5119 hsa-miR-671-5p 2150 hsa-miR-768-5p 6831 hsa-miR-770-5p 6625
hsa-miR-660 1052 hsa-miR-765 6859 hsa-miR-802 3601 hsa-miR-802 7327
hsa-miR-675 7789 hsa-miR-768-5p 6074 hsa-miR-873 5746 hsa-miR-871 346
hsa-miR-768-5p 4584 hsa-miR-770-5p 5039 hsa-miR-874 2440 hsa-miR-873 543
hsa-miR-770-5p 1821 hsa-miR-871 2705 hsa-miR-885-5p 711 hsa-miR-877 4563
hsa-miR-802 2524 hsa-miR-872 5111 hsa-miR-886-5p 490 hsa-miR-886-5p 1043
hsa-miR-871 2706 hsa-miR-874 7683 hsa-miR-891a 3359 hsa-miR-889 1005
hsa-miR-872 5121 hsa-miR-875-5p 6291 hsa-miR-891b 7883 hsa-miR-891a 2504
hsa-miR-877 4992 hsa-miR-889 3977 hsa-miR-921 322 hsa-miR-92a-1 7831
hsa-miR-885-5p 7048 hsa-miR-890 4226 hsa-miR-922 1287 hsa-miR-935 5838
hsa-miR-889 3664 hsa-miR-892a 2909 hsa-miR-934 3828 hsa-miR-939 1211
hsa-miR-891a 130 hsa-miR-92a-2 3796 hsa-miR-935 209 hsa-miR-941 5001
hsa-miR-892b 4628 hsa-miR-935 5387 hsa-miR-936 4515 hsa-miR-943 3814
hsa-miR-921 3737 hsa-miR-936 364 hsa-miR-940 4305 hsa-miR-944 6595
hsa-miR-92a-1 4590 hsa-miR-938 7605 hsa-miR-944 3381
hsa-miR-92a-2 6575 hsa-miR-940 1036
hsa-miR-92b 7199 hsa-miR-944 6675
hsa-miR-935 4857
hsa-miR-938 6335
hsa-miR-940 1037

Annex 3 MicroRNA seeds present in the genome of H. sapiens, detected in the genome of HPV types 33, 45, and 52
microRNA Position microRNA Position microRNA Position
hsa-miR-143 7701 hsa-miR-124 3587 hsa-miR-143 192
hsa-miR-144 2197 hsa-miR-141 5642 hsa-miR-144 2191
hsa-miR-187 6532 hsa-miR-143 1456 hsa-miR-187 209
hsa-miR-193b 4363 hsa-miR-144 2232 hsa-miR-220b 6877
hsa-miR-221 3665 hsa-miR-185 360 hsa-miR-221 3701
hsa-miR-222 1593 hsa-miR-187 3434 hsa-miR-222 2487
hsa-miR-223 414 hsa-miR-220b 5648 hsa-miR-223 287
hsa-miR-297 3652 hsa-miR-221 3736 hsa-miR-297 3680
hsa-miR-298 4735 hsa-miR-223 6078 hsa-miR-298 1593
hsa-miR-302a 7031 hsa-miR-24-1 4526 hsa-miR-29a 5097
hsa-miR-323-5p 3313 hsa-miR-27b 806 hsa-miR-29b-1 911
hsa-miR-328 5430 hsa-miR-297 778 hsa-miR-29b-2 7646
hsa-miR-329 5331 hsa-miR-298 1634 hsa-miR-300 227
hsa-miR-331-5p 3212 hsa-miR-29b-1 961 hsa-miR-323-5p 3307
hsa-miR-338-5p 5235 hsa-miR-302a 7517 hsa-miR-325 4500
hsa-miR-340 71 hsa-miR-326 4610 hsa-miR-329 3430
hsa-miR-376a 946 hsa-miR-329 1896 hsa-miR-331-5p 3740
hsa-miR-378 5046 hsa-miR-331-5p 5521 hsa-miR-338-5p 2997
hsa-miR-382 3472 hsa-miR-338-5p 1304 hsa-miR-370 5258
hsa-miR-410 3846 hsa-miR-367 1758 hsa-miR-376c 2200
hsa-miR-421 778 hsa-miR-370 7075 hsa-miR-378 5479
hsa-miR-452 1887 hsa-miR-411 6709 hsa-miR-379 1301
hsa-miR-485-5p 6401 hsa-miR-421 4928 hsa-miR-382 821
hsa-miR-486-5p 5639 hsa-miR-450b-5p 2755 hsa-miR-409-5p 7907
hsa-miR-490-5p 6043 hsa-miR-452 6372 hsa-miR-410 1954
hsa-miR-493 3225 hsa-miR-490-5p 4803 hsa-miR-433 1949
hsa-miR-494 1761 hsa-miR-491-5p 1416 hsa-miR-452 4094
hsa-miR-495 374 hsa-miR-492 2321 hsa-miR-453 7585
hsa-miR-500 2686 hsa-miR-493 1393 hsa-miR-483-5p 1304
hsa-miR-501-5p 2687 hsa-miR-494 1796 hsa-miR-486-5p 5685
hsa-miR-504 4993 hsa-miR-495 3606 hsa-miR-488 5907
hsa-miR-505 1795 hsa-miR-501-5p 5024 hsa-miR-490-5p 6272
hsa-miR-509-3-5p 6743 hsa-miR-509-3-5p 6769 hsa-miR-492 2280
hsa-miR-512-5p 1296 hsa-miR-510 1352 hsa-miR-493 3854
hsa-miR-514 5501 hsa-miR-514 1065 hsa-miR-494 1488
hsa-miR-517 2576 hsa-miR-516b 4428 hsa-miR-495 940
hsa-miR-518a-5p 3273 hsa-miR-517 5099 hsa-miR-500 2680
hsa-miR-518c 4743 hsa-miR-518a-5p 204 hsa-miR-501-5p 2681
microRNA Position microRNA Position microRNA Position
hsa-miR-520d-5p 2134 hsa-miR-519a 88 hsa-miR-504 131
hsa-miR-520g 1158 hsa-miR-520d-5p 1911 hsa-miR-508-5p 3476
hsa-miR-539 2465 hsa-miR-520g 4334 hsa-miR-513-5p 7707
hsa-miR-548a-3p 2815 hsa-miR-539 2500 hsa-miR-518a-5p 3264
hsa-miR-548a-5p 2038 hsa-miR-548a-3p 7665 hsa-miR-520d-5p 2872
hsa-miR-549 168 hsa-miR-548a-5p 2073 hsa-miR-539 1924
hsa-miR-553 59 hsa-miR-549 3162 hsa-miR-541 1597
hsa-miR-556-5p 1255 hsa-miR-550 413 hsa-miR-544 4297
hsa-miR-561 1139 hsa-miR-552 1150 hsa-miR-548a-3p 3793
hsa-miR-564 1008 hsa-miR-553 44 hsa-miR-548a-5p 1327
hsa-miR-567 7195 hsa-miR-561 1174 hsa-miR-552 4442
hsa-miR-568 1566 hsa-miR-564 533 hsa-miR-553 43
hsa-miR-570 4792 hsa-miR-567 779 hsa-miR-554 4812
hsa-miR-574-5p 2863 hsa-miR-568 394 hsa-miR-555 6158
hsa-miR-580 6664 hsa-miR-570 1196 hsa-miR-560 6600
hsa-miR-582-5p 2185 hsa-miR-579 2390 hsa-miR-561 1124
hsa-miR-583 1491 hsa-miR-582-5p 6734 hsa-miR-564 5218
hsa-miR-584 1769 hsa-miR-584 7171 hsa-miR-567 3681
hsa-miR-587 5579 hsa-miR-586 2505 hsa-miR-568 408
hsa-miR-591 105 hsa-miR-591 5360 hsa-miR-569 456
hsa-miR-592 774 hsa-miR-592 6048 hsa-miR-570 356
hsa-miR-599 436 hsa-miR-595 788 hsa-miR-574-5p 1212
hsa-miR-605 4689 hsa-miR-600 809 hsa-miR-582-5p 7414
hsa-miR-606 814 hsa-miR-601 4375 hsa-miR-584 7388
hsa-miR-607 2009 hsa-miR-606 7553 hsa-miR-586 759
hsa-miR-608 1365 hsa-miR-609 5822 hsa-miR-587 5625
hsa-miR-609 3972 hsa-miR-611 2761 hsa-miR-592 7178
hsa-miR-624 4324 hsa-miR-612 493 hsa-miR-596 5256
hsa-miR-628-5p 3375 hsa-miR-622 3978 hsa-miR-598 548
hsa-miR-630 3279 hsa-miR-624 3390 hsa-miR-602 3538
hsa-miR-633 7646 hsa-miR-632 6320 hsa-miR-605 4845
hsa-miR-634 2288 hsa-miR-633 3788 hsa-miR-607 1022
hsa-miR-641 6685 hsa-miR-634 1660 hsa-miR-608 1350
hsa-miR-644 3049 hsa-miR-640 4532 hsa-miR-609 4413
hsa-miR-648 2864 hsa-miR-641 1527 hsa-miR-612 1150
hsa-miR-649 737 hsa-miR-642 4727 hsa-miR-620 2159
hsa-miR-653 6691 hsa-miR-646 849 hsa-miR-622 5303
hsa-miR-655 1460 hsa-miR-649 3875 hsa-miR-627 4603
microRNA Position microRNA Position microRNA Position
hsa-miR-656 1476 hsa-miR-650 1184 hsa-miR-628-5p 7700
hsa-miR-658 1167 hsa-miR-652 102 hsa-miR-632 1108
hsa-miR-758 3707 hsa-miR-655 383 hsa-miR-633 3633
hsa-miR-766 4724 hsa-miR-656 338 hsa-miR-641 449
hsa-miR-768-5p 525 hsa-miR-660 4859 hsa-miR-644 5649
hsa-miR-802 5993 hsa-miR-662 3565 hsa-miR-650 2979
hsa-miR-871 1378 hsa-miR-758 524 hsa-miR-651 3936
hsa-miR-873 6435 hsa-miR-802 1493 hsa-miR-655 1612
hsa-miR-876-5p 5849 hsa-miR-871 5053 hsa-miR-656 481
hsa-miR-877 1667 hsa-miR-877 4555 hsa-miR-660 2620
hsa-miR-890 6073 hsa-miR-885-5p 3713 hsa-miR-662 5369
hsa-miR-891a 219 hsa-miR-886-5p 1043 hsa-miR-758 719
hsa-miR-892a 300 hsa-miR-889 1005 hsa-miR-768-5p 2165
hsa-miR-892b 4417 hsa-miR-891a 125 hsa-miR-802 1329
hsa-miR-921 5614 hsa-miR-891b 2885 hsa-miR-871 1366
hsa-miR-922 994 hsa-miR-921 3791 hsa-miR-873 2560
hsa-miR-92a-2 1367 hsa-miR-922 442 hsa-miR-877 1390
hsa-miR-940 4556 hsa-miR-92a-1 7820 hsa-miR-885-5p 5489
hsa-miR-943 3710 hsa-miR-92a-2 1415 hsa-miR-888 2359
hsa-miR-934 7089 hsa-miR-889 2344
hsa-miR-936 813 hsa-miR-892a 5670
hsa-miR-939 1211 hsa-miR-921 1838
hsa-miR-943 6159 hsa-miR-922 1284
hsa-miR-944 6530 hsa-miR-92a-2 1352
hsa-miR-933 6601
hsa-miR-936 2488
hsa-miR-940 7066
hsa-miR-944 6571

Annex 4 LCR region of different HPV types, showing the position of the different microRNA seeds detected. The position where region L1 ends is shown with red letters, and the position where region E6 begins is shown with green letters. The light gray boxes indicate the position of seeds corresponding to other viruses, while the blue boxes show the positions of seeds corresponding to microRNAs detected in H. sapiens. The miR-297 seed is repeated five times, three of which overlap with other seeds. Because of this overlap, some of the names of the seeds are listed below the corresponding genomic sequence.

Conflict of interest statement: The authors have completed and submitted the form translated into Spanish for the declaration of potential conflicts of interest of the International Committee of Medical Journal Editors, and none were reported in relation to this article.

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