Genetic variability, phylogeny and functional implication of the long control region in human papillomavirus type 16, 18 and 58 in Chengdu, China

Fang, Lizhen; Lin, Xiaojun; Yang, Yasi; Song, Zhilin; Ding, Xianping; Tan, Liping; Gao, Peng

doi:10.1186/s12985-020-01349-3

Cited by 10 publications

(12 citation statements)

References 46 publications

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“…FOXL1 is a member of the Forkhead box (FOX) superfamily and was reported to be dysregulated in various types of cancers [ 47 ]. PHOX2A was a transcription factor involving in cell proliferation and migration in lung cancer [ 48 ]. HOXA5 is a member of the homeobox (HOX) family and is upregulated in many types of tumors [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 99%

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The genetic variability, phylogeny and functional significance of E6, E7 and LCR in human papillomavirus type 52 isolates in Sichuan, China

Song

Cui

et al. 2021

Virol J

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Background Variations in human papillomavirus (HPV) E6 and E7 have been shown to be closely related to the persistence of the virus and the occurrence and development of cervical cancer. Long control region (LCR) of HPV has been shown multiple functions on regulating viral transcription. In recent years, there have been reports on E6/E7/LCR of HPV-16 and HPV-58, but there are few studies on HPV-52, especially for LCR. In this study, we focused on gene polymorphism of the HPV-52 E6/E7/LCR sequences, assessed the effects of variations on the immune recognition of viral E6 and E7 antigens, predicted the effect of LCR variations on transcription factor binding sites and provided more basic date for further study of E6/E7/LCR in Chengdu, China. Methods LCR/E6/E7 of the HPV-52 were amplified and sequenced to do polymorphic and phylogenetic analysis. Sequences were aligned with the reference sequence by MEGA 7.0 to identify SNP. A neighbor-joining phylogenetic tree was constructed by MEGA 7.0, followed by the secondary structure prediction of the related proteins using PSIPRED 4.0. The selection pressure of E6 and E7 coding regions were estimated by Bayes empirical Bayes analysis of PAML 4.9. The HLA class-I and II binding peptides were predicted by the Immune Epitope Database server. The B cell epitopes were predicted by ABCpred server. Transcription factor binding sites in LCR were predicted by JASPAR database. Results 50 SNP sites (6 in E6, 10 in E7, 34 in LCR) were found. From the most variable to the least variable, the nucleotide variations were LCR > E7 > E6. Two deletions were found between the nucleotide sites 7387–7391 (TTATG) and 7698–7700 (CTT) in all samples. A deletion was found between the nucleotide sites 7287–7288 (TG) in 97.56% (40/41) of the samples. The combinations of all the SNP sites and deletions resulted in 12 unique sequences. As shown in the neighbor-joining phylogenetic tree, except for one belonging to sub-lineage C2, others sequences clustered into sub-lineage B2. No positive selection was observed in E6 and E7. 8 non-synonymous amino acid substitutions (including E3Q and K93R in the E6, and T37I, S52D, Y59D, H61Y, D64N and L99R in the E7) were potential affecting multiple putative epitopes for both CD4+ and CD8+ T-cells and B-cells. A7168G was the most variable site (100%) and the binding sites for transcription factor VAX1 in LCR. In addition, the prediction results showed that LCR had the high probability binding sites for transcription factors SOX9, FOS, RAX, HOXA5, VAX1 and SRY. Conclusion This study provides basic data for understanding the relation among E6/E7/LCR mutations, lineages and carcinogenesis. Furthermore, it provides an insight into the intrinsic geographical relatedness and biological differences of the HPV-52 variants, and contributes to further research on the HPV-52 therapeutic vaccine development.

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Section: Discussionmentioning

confidence: 99%

“…PHOX2A was a transcription factor involving in cell proliferation and migration in lung cancer [48]. HOXA5 is a member of the homeobox (HOX) family and is upregulated in many types of tumors [48,49].…”

Section: Discussionmentioning

confidence: 99%

The genetic variability, phylogeny and functional significance of E6, E7 and LCR in human papillomavirus type 52 isolates in Sichuan, China

Song

Cui

et al. 2021

Virol J

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“…FOXL1 is a member of the Forkhead box (FOX) superfamily and was reported to be dysregulated in various types of cancers [47]. PHOX2A was a transcription factor involving in cell proliferation and migration in lung cancer [48]. HOXA5 is a member of the homeobox (HOX) family and is upregulated in many types of tumors [48,49].…”

Section: Discussionmentioning

confidence: 99%

The Genetic Variability, Phylogeny and Functional Significance of E6, E7 and LCR in Human Papillomavirus type 52 Isolates in Sichuan, China

Song

Deng

et al. 2020

Preprint

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Background: Variations in human papillomavirus (HPV) E6 and E7 have been shown to be closely related to the persistence of the virus and the occurrence and development of cervical cancer. Long control region (LCR) of HPV has been shown multiple functions on regulating viral transcription. In recent years, there have been reports on E6/E7/LCR of HPV-16 and HPV-58, but there are few studies on HPV-52, especially for LCR. In this study, we focused on gene polymorphism of the HPV-52 E6/E7/LCR sequences, assessed the effects of variations on the immune recognition of viral E6 and E7 antigens, predicted the effect of LCR variations on transcription factor binding sites and provided more basic date for further study of E6/E7/LCR in Chengdu, China. Methods: LCR/E6/E7 of the HPV-52 were amplified and sequenced to do polymorphic and phylogenetic analysis. Sequences were aligned with the reference sequence by MEGA 7.0 to identify SNP. A neighbor-joining phylogenetic tree was constructed by MEGA 7.0, followed by the secondary structure prediction of the related proteins using PSIPRED 4.0. The selection pressure of E6 and E7 coding regions were estimated by Bayes empirical Bayes analysis of PAML 4.9. The HLA class-I and II binding peptides were predicted by the Immune Epitope Database (IEDB) server. The B cell epitopes were predicted by ABCpred server. Transcription factor binding sites in LCR were predicted by JASPAR database. Results: 50 SNP sites (6 in E6, 10 in E7, 34 in LCR) were found. From the most variable to the least variable, the nucleotide variations were LCR>E7> E6. Two deletions were found between the nucleotide sites 7387 to 7391 (TTATG) and 7698 to 7700 (CTT) in all samples. A deletion was found between the nucleotide sites 7287 to 7288 (TG) in 97.56% (40/41) of the samples. The combinations of all the SNP sites and deletions resulted in 12 unique sequences. As shown in the neighbor-joining phylogenetic tree, except for one belonging to sub-lineage C2, others sequences clustered into sub-lineage B2. No positive selection was observed in E6 and E7. 8 non-synonymous amino acid substitutions (including E3Q and K93R in the E6, and T37I, S52D, Y59D, H61Y, D64N and L99R in the E7) were potential affecting multiple putative epitopes for both CD4+ and CD8+ T-cells and B-cells. A7168G was the most variable site (100%) and the binding sites for transcription factor VAX1 in LCR. In addition, the prediction results showed that LCR had the high probability binding sites for transcription factors SOX9, FOS, RAX, HOXA5, VAX1 and SRY. Conclusion: This study provides basic data for understanding the relation among E6/E7/LCR mutations, lineages and carcinogenesis. Furthermore, it provides an insight into the intrinsic geographical relatedness and biological differences of the HPV-52 variants, and contributes to further research on the HPV-52 therapeutic vaccine development.

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“…Nowadays, the sequence analysis of LCR is widely used for the classification of HPV16 DNA into the four major phylogenetic branches (Refs [135][136][137][138][139][140]. Specific intratypic nucleotide polymorphisms have been associated with A4 sub-lineage (A7729C and G7841A), B lineage (G7488A, C7688A, C7763T, C7785T and G7833T), C lineage (A7484C, C7488A, C7668T, C7688A, C7763T, C7785T, G7825A, G7833T, A7836C and G7838G) and D lineage (A7484C, G7488A, C7668T, C7688A, A7728T, T7742G, C7763T and C7785T) (Ref.…”

Section: Long Control Regionmentioning

confidence: 99%

Genetic variability of the HPV16 early genes and LCR. Present and future perspectives

Bletsa¹,

Zagouri

Amoutzias

et al. 2021

Expert Rev. Mol. Med.

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Human papillomavirus 16 (HPV16) infection is the aetiologic factor for the development of cervical dysplasia and is regarded as highly carcinogen, because it is implicated in more than 50% of cervical cancer cases, worldwide. The tumourigenic potential of HPV16 has triggered the extensive sequence analysis of viral genome in order to identify nucleotide variations and amino acid substitutions that influence viral oncogenicity and subsequently the initiation and progression of cervical cancer. Nowadays, specific mutations of HPV16 DNA have been associated with an increased risk of high-grade squamous intraepithelial lesions and invasive cervical cancer (ICC) development, including E6 : Q14H, H78Y, L83V, Ε7 : N29S, S63F, E2 : H35Q, P219S, T310K, E5 : I65V, whereas highly conserved regions of viral DNA have been extensively characterised. In addition, numerous novel HPV16 mutations are observed among the studied populations from various geographic regions, hence advocating that different HPV16 strains seem to emerge with different tumourigenic capacities. The present review focuses on the variability of the early genes and the long control region, emphasising on the association of specific mutations with the development of severe dysplasia. Finally, it evaluates whether specific regions of HPV16 DNA are able to serve as valuable biomarkers for cervical cancer risk.

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Genetic variability, phylogeny and functional implication of the long control region in human papillomavirus type 16, 18 and 58 in Chengdu, China

Cited by 10 publications

References 46 publications

The genetic variability, phylogeny and functional significance of E6, E7 and LCR in human papillomavirus type 52 isolates in Sichuan, China

The genetic variability, phylogeny and functional significance of E6, E7 and LCR in human papillomavirus type 52 isolates in Sichuan, China

The Genetic Variability, Phylogeny and Functional Significance of E6, E7 and LCR in Human Papillomavirus type 52 Isolates in Sichuan, China

Genetic variability of the HPV16 early genes and LCR. Present and future perspectives

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