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MiR-9, miR-21, miR-27b, and miR-34a Expression in HPV16/58/52-Infected Cervical Cancer

ABSTRACT: The aim of this study was to observe the expression of miR-9, miR-21, miR-27b, and miR-34a related with E6/E7 in HPV16-, HPV52-, and HPV58-infected cervical cancer patients and explore their possible role in cervical cancer with HPV infection. The expression levels of 4 miRNAs were detected in cervical exfoliated cells using qRT-PCR. In the current study, miR-34a expression was significantly upregulated in HPV-positive cervical cancer compared with the HPV-negative healthy population and HPV-positive CIN, but just the expression of miR-34a in HPV16 cervical cancer was statistically significant, and the expression of HPV52 and HPV58 was not statistically significant. The expression of miR-21 increased in HPV-positive cervical cancer compared with HPV-positive CIN, but only HPV16-infected cervical cancer had statistical significance compared with HPV16-infected CIN. By observing the change trend of each subtype group, we can show that the expression of miR-9 in HPV16 CIN was opposite to the other subtypes, and it was upregulated, compared with HPV58 CIN, and significantly increased. The level change of miR-27b in HPV58 cervical cancer and HPV58 CIN was opposite to the other subtypes; unlike the expression of miR-27b which was upregulated in HPV16 and HPV52 infected, it was downregulated compared with Normal. We also found that the expression of miR-34a and miR-9 was contrary to other studies. These findings indicate that the upregulated miR-21 expression may be a biomarker to distinguish between CC and CIN. miR-34a in HPV infection, especially in HPV16 infection, might be related to the occurrence and development of cervical cancer. The infection of different subtypes may play different roles in disease by activating different mechanisms; miRNAs play a very complex role in tumorigenesis and development, and there may be multiple targets in which multiple mechanisms play a role.

SUBMITTER: Liu M

PROVIDER: S-EPMC7519443 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Project description:Human T-lymphotropic virus 1 (HTLV-1) immortalizes T-cells and is the causative agent of adult T-cell leukemia/lymphoma (ATLL). HTLV-1 replication and transformation are governed by multiple interactions between viral regulatory proteins and host cell factors that remain to be fully elucidated. The present study investigated the impact of HTLV-1 infection on the expression of miR-34a, a microRNA whose expression is downregulated in many types of cancer. Results of RT-PCR assays showed that five out of six HTLV-1-positive cell lines expressed higher levels of miR-34a compared to normal PBMC or purified CD4+ T-cells. ATLL cell line ED, which did not express miR-34a, showed methylation of the miR-34a promoter. Newly infected PBMC and samples from 10 ATLL patients also showed a prominent increase in miR-34a expression compared to PBMC controls. The primary miR-34a transcript expressed in infected cell line C91PL contained binding motifs for NF-?B and p53. Pharmacological inhibition of NF-?B with Bay 11-7082 indicated that this pathway contributes to sustain miR-34a levels in infected cells. Treatment of infected cell lines with the p53 activator nutlin-3a resulted in a further increase in miR-34a levels, thus confirming it as a transcriptional target of p53. Nutlin-3a-treated cells showed downregulation of known miR-34a targets including the deacetylase SIRT1, which was accompanied by increased acetylation of p53, a substrate of SIRT1. Transfection of C91PL cells with a miR-34a mimic also led to downregulation of mRNA targets including SIRT1 as well as the pro-apoptotic factor BAX. Unlike nutlin-3a, the miR-34a mimic did not cause cell cycle arrest or reduce cell viability. On the other hand, sequestration of miR-34a with a sponge construct resulted in an increase in death of C91PL cells. These findings provide evidence for a functional role for miR-34a in fine-tuning the expression of target genes that influence the turnover of HTLV-1-infected cells.

Project description:BackgroundHuman papillomavirus genotypes 52 and 58 (HPV52/58) are frequently detected in patients with cervical intraepithelial neoplasia (CIN) and invasive cervical cancer (ICC) in East Asian countries including Japan. As with other HPV genotypes, HPV52/58 consist of multiple lineages of genetic variants harboring less than 10% differences between complete genome sequences of the same HPV genotype. However, site variations of nucleotide and amino acid sequences across the viral whole-genome have not been fully examined for HPV52/58. The aim of this study was to investigate genetic variations of HPV52/58 prevalent among Japanese women by analyzing the viral whole-genome sequences.MethodsThe entire genomic region of HPV52/58 was amplified by long-range PCR with total cellular DNA extracted from cervical exfoliated cells isolated from Japanese patients with CIN or ICC. The amplified DNA was subjected to next generation sequencing to determine the complete viral genome sequences. Phylogenetic analyses were performed with the whole-genome sequences to assign variant lineages/sublineages to the HPV52/58 isolates. The variability in amino acid sequences of viral proteins was assessed by calculating the Shannon entropy scores at individual amino acid positions of HPV proteins.ResultsAmong 52 isolates of HPV52 (CIN1, n = 20; CIN2/3, n = 21; ICC, n = 11), 50 isolates belonged to lineage B (sublineage B2) and two isolates belonged to lineage A (sublineage A1). Among 48 isolates of HPV58 (CIN1, n = 21; CIN2/3, n = 19; ICC, n = 8), 47 isolates belonged to lineage A (sublineages A1/A2/A3) and one isolate belonged to lineage C. Single nucleotide polymorphisms specific for individual variant lineages were determined throughout the viral genome based on multiple sequence alignments of the Japanese HPV52/58 isolates and reference HPV52/58 genomes. Entropy analyses revealed that the E1 protein was relatively variable among the HPV52 isolates, whereas the E7, E4, and L2 proteins showed some variations among the HPV58 isolates.ConclusionsAmong the HPV52/58-positive specimens from Japanese women with CIN/ICC, the variant distributions were strongly biased toward lineage B for HPV52 and lineage A for HPV58 across histological categories. Different patterns of amino acid variations were observed in HPV52 and HPV58 across the viral whole-genome.

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MiR-9, miR-21, miR-27b, and miR-34a Expression in HPV16/58/52-Infected Cervical Cancer

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