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Case Report: Noninvasive Clinical Intervention of REBACIN® on Histologic Regression of High Grade Cervical Intraepithelial Neoplasia.

ABSTRACT: High-risk human papillomavirus (hrHPV) persistent infection is the major cause of cervical cancer. Clinical intervention of hrHPV-associated high-grade squamous intraepithelial lesion (HSIL) is critical to prevent cervical cancer, and current treatment is surgery (an invasive therapy). However, some patients refuse to do so for an afraid of potential adverse effects on future fertility or other concerns which creates a critical need for development of non-invasive therapeutic strategies. Here, we report for the first time the cases of non-invasive intervention with REBACIN®, a proprietary antiviral biologics, in clinical treatment of HSIL. From 12,958 visiting patients assessed for eligibility, 18 HSIL-patients with cervical intraepithelial neoplasia-grade 2, positive of both diffused overexpression of p16 and high-risk HPV were enrolled in this non-invasive clinical intervention mainly due to concerns of future fertility. REBACIN® was administered intravaginally every other day for 3 months (one-course) except during menstrual period, and were followed up for 6-36 months for the examination of high-risk HPV DNA, cervical cytology, and histopathology. After one to three course treatments, most cases (16/18) displayed both the regression from HSIL (CIN2) to normal cervical cytology and clearance of high-risk HPV infection. Further studies demonstrated REBACIN® significantly suppressed HPV16 E7 oncoprotein expression in a human cervical cancer cell line, which is consistent with previous finding that REBACIN® inhibits the growth of tumors induced by expression of E6/E7 oncogenes of either HPV16 or HPV18. This report indicates REBACIN® as a novel effective non-invasive clinical intervention for HSIL-patients as well for high-risk HPV persistent infection, providing a new clinical option for the non-invasive treatment of hrHPV-associated high-grade squamous intraepithelial lesion, which is worthy of further research on clinical validation and application.

SUBMITTER: Wang F

PROVIDER: S-EPMC8329360 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: The development of cervical cancer and its high-grade precursor lesions (Cervical Intraepithelial Neoplasia grade 2/3 [CIN2/3]) result from a persistent infection with high-risk human papillomavirus (hrHPV) types and the accumulation of (epi)genetic host cell aberrations. Epidemiological studies have demonstrated variable CIN2/3 and cancer risks between different hrHPV types. Recent genomic profiling studies revealed substantial heterogeneity in the chromosomal aberrations detected in morphologically indistinguishable CIN2/3 suggestive of varying cancer risk. The current study aimed to investigate whether CIN2/3 with different hrHPV types vary with respect to their chromosomal profiles, both in terms of the number of aberrations and chromosomal loci affected. METHODS: Chromosomal profiles were determined of 43 p16INK4a-immunopositive CIN2/3 of women with long-term hrHPV infection (? 5 years). Sixteen lesions harboured HPV16, 3 HPV18, 14 HPV31, 1 HPV33, 4 HPV45, 1 HPV51, 2 HPV52 and 2 HPV58. RESULTS: Unsupervised hierarchical clustering analysis of the chromosomal profiles revealed two major clusters, characterised by either few or multiple chromosomal aberrations, respectively. A majority of 87.5% of lesions with HPV16 were in the cluster with relatively few aberrations, whereas no such unbalanced distribution was seen for lesions harbouring other hrHPV types. Analysis of the two most prevalent types (HPV16 and HPV31) in this data set revealed a three-fold increase in the number of losses in lesions with HPV31 compared to HPV16-positive lesions. In particular, losses at chromosomes 2q, 4p, 4q, 6p, 6q, 8q & 17p and gain at 1p & 1q were significantly more frequent in HPV31-positive lesions (FDR < 0.2). CONCLUSIONS: Chromosomal aberrations in CIN2/3 are at least in part related to the hrHPV type present. The relatively low number of chromosomal aberrations observed in HPV16-positive CIN2/3 suggests that the development of these lesions is less dependent on genetic insult than those caused by other types like HPV31.

Project description:New prevention strategies are needed to detect cervical intraepithelial neoplasia (CIN). The microRNA expression analysis has already been reported as molecular biomarkers in the early detection of cervical cancer (CC) through minimally invasive samples, such as liquid biopsy, obtained through collection using liquid-based cytology (LBC). In this study, we aimed to identify molecular signatures of microRNAs in cervical precursor lesions from LBC cervical and the molecular pathways potentially associated with the CC progression. We analyzed 31 LBC cervical samples from women who underwent colposcopy. These samples were divided into two groups: the first group was composed of samples without precursor lesions of CC, considering the control group, referred to as healthy female subjects (HFS; n = 11). The second group corresponded to women diagnosed with cervical interepithelial neoplasia grade 3 (CIN 3; n = 20). We performed microRNA and gene expression profiling using the nCounter® miRNA Expression Assays (NanoString Technology) and PanCancer Pathways (NanoString Technology), respectively. A microRNA target prediction was performed by mirDIP, and molecular pathway interaction was constructed using Cytoscape. Bidirectional in silico analyses and Pearson's correlation were performed for associated the relation between genes, and miRNAs differentially expressed related cervical cancer progression were performed. We found that the expression of nine microRNAs was significantly higher, two were downregulated (miR-381-3p and miR-4531), and seven miRNAs were upregulated (miR-205-5p, miR-130a-3p, miR-3136-3p, miR-128-2-5p, let-7f-5p, miR-202-3p, and miR-323a-5p) in CIN 3 (fold change ≥ 2 and p ≤ 0.05). The miRNA expression patterns were independent of hr-HPV infection. We identified four miRNAs (miR-205-5p, miR-130a-3p, miR-4531, and miR-381-3p) that could be used as biomarkers for CIN 3 in LBC samples through multiple logistic regression analyses. We found 16 genes differentially expressed between CIN 3 and HSF samples (fold change ≥ 2 and p ≤ 0.05). We found the correlation between miR-130a-3p and CCND1(R = -0.52; p = 0.0029), miR-205-5p and EGFR (R = 0.53; p = 0.0021), and miR-4531 and SMAD2 (R = -0.54; p = 0.0016). In addition, we demonstrated the most significant pathways of the targets associated with cervical cancer progression (FDR-corrected p < 0.001). This study demonstrated that miRNA biomarkers may distinguish healthy cervix and CIN 3 and regulate important molecular pathways of carcinogenesis.

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Case Report: Noninvasive Clinical Intervention of REBACIN® on Histologic Regression of High Grade Cervical Intraepithelial Neoplasia.

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