Hong Yang

Mitochondrial‐Derived Peptide MOTS‐c Suppresses Ovarian Cancer Progression by Attenuating USP7‐Mediated LARS1 Deubiquitination

AbstractMitochondrial‐nuclear communication plays a vital role in maintaining cellular homeostasis. MOTS‐c, a short peptide derived from the 12S rRNA of mitochondrial DNA, has been suggested as a retrograde mitochondrial signal. Although recent clinical studies have suggested a possible link between MOTS‐c and human cancer, the role of MOTS‐c in tumorigenesis has yet to be investigated. Here, MOTS‐c levels are found to be reduced in both serum and tumor tissues from ovarian cancer (OC) patients, which are associated with poor patients’ prognosis. Exogenous MOTS‐c inhibits the proliferation, migration and invasion of OC cells, and induces cell cycle arrest and apoptosis. Mechanistically, MOTS‐c interacts with LARS1 and promotes its ubiquitination and proteasomal degradation. In addition, USP7 was identified as a deubiquitinase of LARS1, and MOTS‐c can attenuates USP7‐mediated LARS1 deubiquitination by competing with USP7 for binding to LARS1. Besides, LARS1 was found to be increased and play an important oncogenic function in OC. More importantly, MOTS‐c displays a marked anti‐tumor effect on OC growth without systemic toxicity in vivo. In conclusion, this study reveals a crucial role of MOTS‐c in OC and provides a possibility for MOTS‐c as a therapeutic target for the treatment of this manlignacy.

MARCH5-mediated downregulation of ACC2 promotes fatty acid oxidation and tumor progression in ovarian cancer

Lipid metabolic reprogramming has been recognized as a hallmark of human cancer. Acetyl-CoA Carboxylases (ACCs) are key rate-limiting enzymes involved in fatty acid metabolism regulation by catalyzing the carboxylation of acetyl-CoA to malonyl-CoA. Previously, most studies focused on the role of ACC1 in fatty acid metabolism in cancer, while the function of ACC2 remains largely uncharacterized in human cancers, especially in ovarian cancer (OC). Here, we show that ACC2 was significantly downregulated in cancerous tissue of OC, and the downregulation of ACC2 is closely associated with lager tumor size, metastases and worse prognosis in OC patients. Downregulation of ACC2 promoted proliferation and metastasis of OC both in vitro and in vivo by enhancing FAO. Notably, mitochondria-associated ubiquitin ligase (MARCH5) was identified to interact with and downregulate ACC2 by ubiquitination and degradation in OC. Moreover, ACC2 downregulation-enhanced FAO contributed to the progression of OC promoted by MARCH5. In conclusion, our findings demonstrate that MARCH5-mediated downregulation of ACC2 promotes FAO and tumorigenesis in OC, suggesting MARCH5-ACC2 axis as a potent candidate for the treatment and prevention of OC.

Risk Prediction Model for Radiation-induced Dermatitis in Patients with Cervical Carcinoma Undergoing Chemoradiotherapy

Radiation-induced dermatitis (RD) is a common side-effect of therapeutic ionizing radiation that can severely affect patient quality of life. This study aimed to develop a risk prediction model for the occurrence of RD in patients with cervical carcinoma undergoing chemoradiotherapy using electronic medical records (EMRs). Using EMRs, the clinical data of patients who underwent simultaneous radiotherapy and chemotherapy at a tertiary cancer hospital between 2017 and 2022 were retrospectively collected, and the patients were divided into two groups: a training group and a validation group. A predictive model was constructed to predict the development of RD in patients who underwent concurrent radiotherapy and chemotherapy for cervical cancer. Finally, the model's efficacy was validated using a receiver operating characteristic curve. The incidence of radiation dermatitis was 89.5% (560/626) in the entire cohort, 88.6% (388/438) in the training group, and 91.5% (172/188) in the experimental group. The nomogram was established based on the following factors: age, the days between the beginning and conclusion of radiotherapy, the serum albumin after chemoradiotherapy, the use of single or multiple drugs for concurrent chemotherapy, and the total dose of afterloading radiotherapy. Internal and external verification indicated that the model had good discriminatory ability. Overall, the model achieved an area under the receiver operating characteristic curve of .66. The risk of RD in patients with cervical carcinoma undergoing chemoradiotherapy is high. A risk prediction model can be developed for RD in cervical carcinoma patients undergoing chemoradiotherapy, based on over 5 years of EMR data from a tertiary cancer hospital.

MIEF2 over-expression promotes tumor growth and metastasis through reprogramming of glucose metabolism in ovarian cancer

Abstract Background Increasing evidence has revealed the close link between mitochondrial dynamic dysfunction and cancer. MIEF2 (mitochondrial elongation factor 2) is mitochondrial outer membrane protein that functions in the regulation of mitochondrial fission. However, the expression, clinical significance and biological functions of MIEF2 are still largely unclear in human cancers, especially in ovarian cancer (OC). Methods The expression and clinical significance of MIEF2 were determined by qRT-PCR, western blot and immunohistochemistry analyses in tissues and cell lines of OC. The biological functions of MIEF2 in OC were determined by in vitro and in vivo cell growth and metastasis assays. Furthermore, the effect of MIEF2 on metabolic reprogramming of OC was determined by metabolomics and glucose metabolism analyses. Results MIEF2 expression was significantly increased in OC mainly due to the down-regulation of miR-424-5p, which predicts poor survival for patients with OC. Knockdown of MIEF2 significantly suppressed OC cell growth and metastasis both in vitro and in vivo by inhibiting G1-S cell transition, epithelial-to-mesenchymal transition (EMT) and inducing cell apoptosis, while forced expression of MIEF2 had the opposite effects. Mechanistically, mitochondrial fragmentation-suppressed cristae formation and thus glucose metabolism switch from oxidative phosphorylation to glycolysis was found to be involved in the promotion of growth and metastasis by MIEF2 in OC cells. Conclusions MIEF2 plays a critical role in the progression of OC and may serve as a valuable prognostic biomarker and therapeutic target in the treatment of this malignancy.

CRABP2 accelerates epithelial mesenchymal transition in serous ovarian cancer cells by promoting TRIM16 methylation via upregulating EZH2 expression

AbstractRecently, it was covered that cellular retinoic acid‐binding protein 2 (CRABP2) is upregulated in ovarian cancer and participates in tumor progression, however, the specific mechanism remains to be explored. The pcDNA‐CRABP2 or si‐CRABP2 was transfected into SKOV3 and OVCAR3 ovarian cancer cells, respectively, and we observed that overexpression of CRABP2 inhibited cell apoptosis, promoted cell invasion and expression of epithelial mesenchymal transition (EMT) marker proteins, and transfection of si‐CRABP2 had the opposite effect. Furthermore, we predicted that EZH2 interacted with CRABP2, and overexpression of CRABP2 promoted EZH2 expression, knockdown of CRABP2 inhibited EZH2 expression, and co‐immunoprecipitation assay confirmed their binding relationship. The SKOV3 and OVCAR3 cells were then incubated with pcDNA‐CRABP2 alone together with si‐EZH2, and we found that si‐EZH2 reversed the effect of pcDNA‐CRABP2 on promotion of EZH2 expression, cell invasion and EMT maker protein levels. Next, we found that EZH2 could bind to DNMT1, and overexpression of EZH2 inhibited TRIM16 expression and knockdown of EZH2 promoted TRIM16 expression. Moreover, the promoter of TRIM16 contains the CpG island, and ChIP assay observed enriched DNMT1 on the promoter of TRIM16, and overexpression of EZH2 increased the promoter methylation level of TRIM16 and knockdown of EZH2 suppressed the methylation. The SKOV3 cells were incubated with si‐EZH2 alone or combined with si‐TRIM16, and we found that si‐TRIM16 reversed the effect of si‐EZH2. In vivo studies showed that knockdown of CRABP2 inhibited tumor volume and weight, suppressed the expression of EZH2 and EMT related proteins vimentin and snail, and increased the expression of TRIM16 and E‐cadherin.

Age‐specific prevalence and genotype distribution of human papillomavirus in women from Northwest China

AbstractBackgroundHuman papillomavirus (HPV) is the leading cause of cervical cancer with more than 200 genotypes. Different genotypes have different potentials in causing premalignant lesions and cervical cancers. In this study, we investigated the age‐specific prevalence and genotype distribution of HPV genotypes in Northwest China.Materials and MethodsWe recruited 145,918 unvaccinated women from Northwest China for population‐based HPV DNA screening test during June 2015 to December 2020. And a lab‐based test was performed for each volunteer by flow fluorescent technology to identify the genotypes of HPV.ResultsThe overall infection rate of HPV was 22.97%. With the participants divided into 12 groups according to age, a bimodal curve of infection rate was obtained. And the two peaks appeared in the younger than 20 group and 61–65 group, respectively. The five most common HPV genotypes included HPV 16, 58, 52, 53 and 61 in all participants, which were in descending order of frequency. Among women younger than 25 years old, HPV 6 and 11 were more common and even higher than some genotypes mentioned above. Among women older than 65 years old, HPV 18 and 66 were more common than or as high as the six most common genotypes in all populations. Additionally, the distribution of single and multiple infections in each age group was also different.ConclusionThe baseline prevalence and genotype distribution of HPV in Northwest China was uncovered for the first time. Age was related to the epidemiology of different HPV genotypes. All the results would be of great significance for future healthcare services.

Molecular evidence of a clonal relationship of synchronous/multifocal gastric‐type lesions of the female genital tract

Abstract Synchronous/multifocal gastric‐type lesions (SMGLs) of the female genital tract are heterogeneous diseases that are rare and challenging to diagnose. The core issue is distinguishing between multiple primaries and multifocal metastases from a single lesion. This is vital for staging, prognosis, and treatment decisions, especially when metastases mimic primary and early lesions at the relevant sites. Traditional morphological diagnosis often faces a paradoxical situation on this key issue and cannot quantitatively evaluate the correlations among multiple foci. Here, six cases of SMGL were collected, two of which exhibited pagetoid dissemination within the genital tract, with all lesions being noninvasive. A total of 24 samples were subjected to whole‐exome sequencing. By inference based on overlapping genetic variations, base substitution mutation patterns, composition and similarity of COSMIC signatures, clonality indices, and the construction of evolutionary trees, it was inferred that the multiple foci in each patient were clonally related, indicating that all cases were metastatic. The follow‐up duration ranged from 7 to 62 months (median: 24.5 months). Four patients died of disease (median survival time: 24.5 months, range: 8–47 months), including one patient who had no invasive lesions at initial diagnosis; two patients experienced recurrences at 17 and 40 months, respectively. These results imply that even if all foci exhibit the appearance of in situ or premalignant changes histologically, they may actually be aggressive. Hence, for SMGLs, before opting for conservative treatment, comprehensive clinical assessment, appropriate surgical extent, adequate sampling, and careful microscopic examination are crucial. Clonal analysis should also be conducted where necessary to avoid undertreatment due to understaging. The study further explored the genomic traits of SMGLs involving more than two sites. © 2025 The Pathological Society of Great Britain and Ireland.