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ZNF582 promoter methylation predicts cervical cancer radiosensitivity and ZNF582 protein overexpression reduces radiosensitivity by cell cycle arrest in S phase.

ABSTRACT: This study aimed to investigate the relationship between ZNF582 promoter methylation (ZNF582^m) level and radiosensitivity of cervical cancer and its biological basis. This was a prospective multicenter clinical study, comprising two independent cohorts of locally advanced cervical cancer patients. Exfoliated cervical cells were collected at 0, 24, 30, 36, 48, and 64 Gy to test ZNF582^m levels. Radiotherapy response was evaluated according to RECIST Version. RT-PCR and WT were used to detect the mRNA and protein expression levels; MTT and flow cytometry were used to detect the cell viability and cell cycle, respectively. While clone formation and subcutaneous tumorigenesis in nude mice were used to detect the growth of HeLa cells with/without ZNF582 overexpression. In the first cohort, 22 cases achieved complete remission (CR) or partial response (PR), and the other 28 cases exhibited stable disease (SD). Radiotherapy reduced ZNF582^m levels among all patients. Initial lever of ZNF582^m was significantly higher in the Responder (CR + PR) group than in the SD group. Also, patients with higher initial lever ZNF582^m were more sensitive towards radiotherapy than ZNF582^m-^low patients. The second cohort confirmed the above results. The amplitude of ZNF582^m levels were related to the radiotherapeutic response; some patients of ZNF582^m-^low showed a transient increase in ZNF582^m, and present greater radiosensitivity than other ZNF582^m-^low patients. In vitro, ZNF582 protein overexpression promoted cell cycle arrest in S phase. These results suggested that higher ZNF582^m levels predicted greater radiosensitivity in clinical cervical cancer cases. Overexpressed ZNF582 conferred radioresistance by cell cycle arrest in vitro.

SUBMITTER: Wu N

PROVIDER: S-EPMC9621039 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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ZNF582 promoter methylation predicts cervical cancer radiosensitivity and ZNF582 protein overexpression reduces radiosensitivity by cell cycle arrest in S phase.

Wu Nayiyuan N Zhang Xiaoyun X Zhu Miaochen M Fang Chao C Liu Xiaoting X Wang Ying Y Li He H Liu Siye S Ting Hong H Qin Chongzhen C Liao Qianjin Q Cai JingTing J Wang Jing J

Epigenetics 20220609 12

This study aimed to investigate the relationship between ZNF582 promoter methylation (ZNF582m) level and radiosensitivity of cervical cancer and its biological basis. This was a prospective multicenter clinical study, comprising two independent cohorts of locally advanced cervical cancer patients. Exfoliated cervical cells were collected at 0, 24, 30, 36, 48, and 64 Gy to test ZNF582m levels. Radiotherapy response was evaluated according to RECIST Versi ...[more]

PMID: 35642528

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Project description:BackgroundCervical cancer screening by combined cytology and HPV test has reduced the incidence of cervical cancer, but cytological screening lacks a higher sensitivity while HPV testing possesses a lower specificity. Most patients with invasive cervical cancer are treated with radiotherapy. However, insensitivity to radiotherapy leads to poor efficacy.MethodsIllumina Methylation EPIC 850k Beadchip was used for genomic screening. We detected methylation of SEPT9 and mRNA expression in different cervical tissues by using methylation-specific PCR and qRT-PCR. Then using CCK8, migration assay, and flow cytometry to detect the biological function and irradiation resistance of SEPT9 in vitro and in vivo. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and co-immunoprecipitation (CoIP) were used to find the interacting gene with SEPT9. Immunostaining of CD206 in cervical cancer and polarization of macrophages (M2) were evaluated by immunofluorescence and WB. The Cancer Genome Atlas (TCGA) database was used for screening the potential miRNAs induced by SEPT9.ResultsHyper-methylation of SEPT9 detects cervical cancer and normal tissues, normal+CIN1 and CIN2+CIN3+cancer with high sensitivity and specificity (AUC = 0.854 and 0.797, respectively, P < 0.001). The mRNA and protein expression of SEPT9 was upregulated in cervical cancer tissues when compared to para-carcinoma tissues. SEPT9 promotes proliferation, invasion, migration, and influences the cell cycle of cervical cancer. SEPT9 interacted with HMGB1-RB axis increases irradiation resistance. Furthermore, SEPT9 mediated miR-375 via the tumor-associated macrophages (TAMs) polarization, affecting the resistance to radiotherapy in cervical cancer.ConclusionsThese findings give us the evidence that SEPT9 methylation could be a biomarker for cervical cancer diagnoses. It promotes tumorigenesis and radioresistance of cervical cancer by targeting HMGB1-RB axis and causes polarization of macrophages by mediating miR-375. We suggest SEPT9 could be a potential screening and therapeutic biomarker for cervical cancer.

Project description:BackgroundThe risk of cervical cancer progression in high-risk human papillomavirus (HR-HPV)-positive women is associated with cervical lesion severity and molecular heterogeneity. Classification systems based on p16 and Ki67 expression cumulative scores (0-3 each)-p16/Ki67 collectively known as an immunoscore [IS]-are an accurate and reproducible method for grading cervical intraepithelial neoplasia (CIN) lesions. Meanwhile, DNA methylation is an early event in the development of cervical cancer. Hence, this study evaluated the relationship among CIN, p16/Ki-67 IS, and PAX1/ZNF582 methylation.MethodsIn this study, 414 HPV-positive paraffin-embedded specimens were collected, and PAX1/ZNF582 methylation and the p16/ki67 IS were determined. A total of 43 invalid samples were excluded and 371 were included in the statistical analyses. There were 103 cervicitis, 95 CIN1, 71 CIN2, 89 CIN3, and 13 squamous cell carcinoma (SCC) cases. The association between PAX1/ZNF582 methylation and p16/Ki6 immunohistochemical staining scores was analyzed.ResultsThe ΔCp of PAX1m (PAX1 methylation) and ZNF582m (ZNF582 methylation) decreased with cervical lesion severity (Cuzick trend test, all P < 0.001). The severity of the cervical lesions and p16, Ki67, and p16/Ki67 IS showed an increasing trend (Multinomial Cochran-Armitage trend test, all P < 0.001). The prevalence of PAX1m/ZNF582m increased with an increase in the IS of p16, Ki67, and p16/Ki67 (Cochran-Armitage trend test, all P < 0.001). In cervical SCC, the IS was 5-6, and the PAX1m/ZNF582m was positive. Meanwhile, heterogeneity was observed in CIN lesions: 10 cases had an IS of 3-4 and were PAX1m/ZNF582m-positive in ≤ CIN1; 1 case had an IS of 0-2 and was PAX1m/ZNF582m-positive in CIN2/3.ConclusionsSignificant heterogeneity was observed in CIN lesions for p16 and Ki67 immunohistochemical staining scores and PAX1/ZNF582 methylation. This may help clinicians personalize the management of CIN based on the predicted short-term risk of cancer progression, minimizing the rate of missed CIN1 diagnoses and incorrect treatment of CIN2/3.

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ZNF582 promoter methylation predicts cervical cancer radiosensitivity and ZNF582 protein overexpression reduces radiosensitivity by cell cycle arrest in S phase.

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<i>ZNF582</i> promoter methylation predicts cervical cancer radiosensitivity and ZNF582 protein overexpression reduces radiosensitivity by cell cycle arrest in S phase.

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