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Abstract Background Cervical cancer is the fourth most common cancer in women. N6-dimethyladenosine (m6A) mRNA methylation is closely associated with cervical cancer. Methods Using TCGA database, we studied the expression and mutation of m6A-related genes in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and obtained genetic characteristics based on an m6A risk model and prognostic value of m6A. We studied the effects of the m6A risk score on immune features and genomic changes of patients with CESC, evaluated the sensitivity of patients with CESC to different small-molecule drugs based on the m6A risk score, and established a clinical prediction model. Results Ten m6A-related genes were differentially expressed between CESC and normal tissues. High-risk patients had a low overall survival (OS) and significantly low immune scores but showed no significantly altered stromal scores. The tumor mutation burden (TMB) and tumor neoantigen levels significantly differed between the high- and low-risk groups. In the high-risk group, copy number variation (CNV) changes mainly led to gene amplification, while in the low-risk group, CNV changes primarily manifested as gene copy number deletions. ZC3H13 expression was low in CESC tissues. ZC3H13 knockdown promoted CESC cell proliferation, migration, and invasion, reducing the RNA methylation levels. Rapamycin suppressed the CESC cell proliferation, migration, and invasion abilities, increasing the m6A levels. Conclusion m6A mRNA methylation is closely related to the occurrence, development, immune invasion, drug sensitivity, and prognosis of cervical cancer. The prognostic m6A feature model of m6A signature genes can accurately predict the OS of patients with CESC. Drugs targeting factors regulating m6A mRNA methylation might offer a good prospect for treating cervical cancer.

Abstract Background The preservation of fertility and integrity of the reproductive organs has increasingly been of concern to most women with adenomyosis. Adenomyomectomy is conservative surgery that is now widely applied; however, relapse is a serious problem after the operation. Postoperative treatment, such as gonadotropin-releasing hormone agonist (GnRHa) has been suggested to result in reducing the rate of disease recurrence. However, there is still a lack of evidence from randomized clinical trials examining the efficacy of GnRHa in decreasing the postoperative recurrence rate. Method/design Relapse after conservative surgery combined with triptorelin acetate versus conservative surgery only in women with focal adenomyosis is a multicenter, prospective, randomized controlled trial. The primary outcome is relapse assessed using a visual analogue scale (VRS) and numeric rating scale (NRS), pictorial blood loss assessment chart (PBAC) score, and the size of the uterus and the lesion as measured by two/three-dimensional color doppler ultrasonography (2D/3D-CDUS) or magnetic resonance imaging (MRI). The secondary outcomes include quality of life, clinical pregnancy, ovarian reserve, adverse events, assessment by the Short Form (36) Health Survey and Female Sexual Function index, serum follicle-stimulating hormone, estradiol levels, and anti-Muellerian hormone and so on. All these indexes are measured at 3, 6, 12, 18, 24, 30, and 36 months after conservative surgery. Discussion The result of this large, multicenter randomized trial will provide evidence for one of the strategies of long-term management in focal adenomyosis after conservative operation. Trial registration Chinese Clinical Trial Registry: ChiCTR1800014340 . Registered on 6 January 2018.

Abstract Background Tumor necrosis factor-α (TNF-α) immunotherapy controls the progression of human cervical cancer. Here, we explored the detailed molecular mechanisms played by melatonin in human cervical cancer (HeLa cells) death in the presence of TNF-α injury, with a particular attention to the mitochondrial homeostasis. Methods HeLa cells were incubated with TNFα and then cell death was determined via MTT assay, TUNEL staining, caspase ELISA assay and western blotting. Mitochondrial function was detected via analyzing mitochondrial membrane potential using JC-1 staining, mitochondrial oxidative stress using flow cytometry and mitochondrial apoptosis using western blotting. Results Our data exhibited that treatment with HeLa cells using melatonin in the presence of TNF-α further triggered cancer cell cellular death. Molecular investigation demonstrated that melatonin enhanced the caspase-9 mitochondrion death, repressed mitochondrial potential, increased ROS production, augmented mPTP opening rate and elevated cyt-c expression in the nucleus. Moreover, melatonin application further suppressed mitochondrial ATP generation via reducing the expression of mitochondrial respiratory complex. Mechanistically, melatonin augmented the response of HeLa cells to TNF-α-mediated cancer death via repressing mitophagy. TNF-α treatment activated mitophagy via elevating Parkin expression and excessive mitophagy blocked mitochondrial apoptosis, ultimately alleviating the lethal action of TNF-α on HeLa cell. However, melatonin supplementation could prevent TNF-α-mediated mitophagy activation via inhibiting Parkin in a CaMKII-dependent manner. Interestingly, reactivation of CaMKII abolished the melatonin-mediated mitophagy arrest and HeLa cell death. Conclusions Overall, our data highlight that melatonin enhances TNF-α-induced human cervical cancer HeLa cells mitochondrial apoptosis via inactivating the CaMKII/Parkin/mitophagy axis.