Although radiotherapy has been widely applied to treating cervical cancer in the clinic, its therapeutic efficacy is often restricted to the radioresistance of cancer cells. Retinoblastoma protein-interacting zinc finger gene 1 (RIZ1) has been suggested as a tumour suppressor gene, whereas its role in cervical cancer with or without radiotherapy has been unclear. In this study, two cervical cancer cell lines, HeLa and SiHa cells, stably transfected with RIZ1 overexpression plasmid were subjected to ionizing radiation, and their survival fractions were calculated by assessing their clonogenic abilities. Our results showed that the forced overexpression of RIZ1 significantly reduced the clonogenic survival rates of both HeLa and SiHa cells exposed to ionizing radiation. By analysing the cell apoptotic status, we found that the RIZ1-overexpressed cervical cancer cells under ionizing radiation were more vulnerable to damage, and more γ-H2AX foci were found in these cells. Furthermore, the volumes of tumour xenografts formed by the RIZ1-overexpressed cells in nude mice under ionizing radiation were smaller than those generated by the control cells. There were more morphological changes, apoptosis cells and lower expression of PCNA in RIZ1-overexpressed tumour tissues of mice after exposure to ionizing radiation. Taken together, our study demonstrates that the overexpression of RIZ1 combined with radiotherapy facilitates apoptosis and DNA damage of cervical cancer cells.

Ovarian cancer is the most lethal gynaecological cancer, and resistance of platinum‐based chemotherapy is the main reason for treatment failure. The aim of the present study was to identify candidate genes involved in ovarian cancer platinum response by analysing genes from homologous recombination and Fanconi anaemia pathways. Associations between these two functional genes were explored in the study, and we performed a random walk algorithm based on reconstructed gene‐gene network, including protein‐protein interaction and co‐expression relations. Following the random walk, all genes were ranked and GSEA analysis showed that the biological functions focused primarily on autophagy, histone modification and gluconeogenesis. Based on three types of seed nodes, the top two genes were utilized as examples. We selected a total of six candidate genes (FANCA, FANCG, POLD1, KDM1A, BLM and BRCA1) for subsequent verification. The validation results of the six candidate genes have significance in three independent ovarian cancer data sets with platinum‐resistant and platinum‐sensitive information. To explore the correlation between biomarkers and clinical prognostic factors, we performed differential analysis and multivariate clinical subgroup analysis for six candidate genes at both mRNA and protein levels. And each of the six candidate genes and their neighbouring genes with a mutation rate greater than 10% were also analysed by network construction and functional enrichment analysis. In the meanwhile, the survival analysis for platinum‐treated patients was performed in the current study. Finally, the RT‐qPCR assay was used to determine the performance of candidate genes in ovarian cancer platinum response. Taken together, this research demonstrated that comprehensive bioinformatics methods could help to understand the molecular mechanism of platinum response and provide new strategies for overcoming platinum resistance in ovarian cancer treatment.

No abstract

Ovarian cancer is the most frequent cause of death among gynecologic malignancies. A total of 80% of patients who have completed platinum-based chemotherapy suffer from relapse and develop resistance within 2 years. In the present study, we obtained patients' complete platinum (cisplatin and carboplatin) medication information from The Cancer Genome Atlas database and then divided them into two categories: resistance and sensitivity. Difference analysis was performed to screen differentially expressed genes (DEgenes) related to platinum response. Subsequently, we annotated DEgenes into the protein–protein interaction network as seed nodes and analyzed them by random walk. Finally, second-ranking protease serine 1 gene (PRSS1) was selected as a candidate gene for verification analysis. PRSS1's expression pattern was continuously studied in Oncomine and cBio Cancer Genomic Portal databases, revealing the key roles of PRSS1 in ovarian cancer formation. Hereafter, we conducted in-depth explorations on PRSS1's platinum response to ovarian cancer through tissue and cytological experiments. Quantitative real-time polymerase chain reaction and Western blot assay results indicated that PRSS1 expression levels in platinum-resistant samples (tissue/cell) were significantly higher than in samples sensitive to platinum. By cell transfection assay, we observed that knockdown of PRSS1 reduced the resistance of ovarian cancer cells to cisplatin. Meanwhile, overexpression of PRSS1 increased the resistance to cisplatin. In conclusion, we identified a novel risk gene PRSS1 related to ovarian cancer platinum response and confirmed its key roles using multiple levels of low-throughput experiments, revealing a new treatment strategy based on a novel target factor for overcoming cisplatin resistance in ovarian cancer.

Background Uterine corpus endometrial carcinoma (UCEC) ranks sixth among malignant tumors in women and the mortality is still rising. FAT2 gene has been considered to be related to the survival and prognosis of some certain diseases in previous studies, but the FAT2 mutation status in UCEC and its prognostic value has been rarely studied. Hence, the purpose of our study was to explore the role of FAT2 mutations for predicting prognosis and responsiveness to immunotherapy in patients with UCEC. Methods UCEC samples from the Cancer Genome Atlas database were analyzed. We evaluated the impact of FAT2 gene mutation status and clinicopathological characteristics on the prognosis of UCEC patients and used univariate and multivariate Cox analysis risk scores to independently predict patient overall survival (OS). Tumor mutation burden (TMB) values of the FAT2 mutant and non‐mutant groups were computed by Wilcoxon rank sum test. The correlation of FAT2 mutation and half maximal inhibitory concentration (IC50) values of various anticancer drugs was analyzed. Gene Ontology data and Gene Set Enrichment Analysis (GSEA) were employed to examine the differential expression of genes between the two groups. Finally, a single‐sample GSEA arithmetic was utilized to measure the abundance of tumor‐infiltrating immune cells in UCEC patients. Results FAT2 mutations suggested better OS ( p < 0.001) and disease‐free survival (DFS) ( p = 0.007) in UCEC. The IC50 values of 18 anticancer drugs were upregulated in FAT2 mutation patients ( p < 0.05). The TMB and microsatellite instability values of patients with FAT2 mutations were significantly higher ( p < 0.001). Next, the Kyoto Encyclopedia of Genes and Genomes functional analysis and GSEA revealed the potential mechanism of FAT2 mutation on the tumorigenesis and progression of UCEC. In addition, in reference to the UCEC microenvironment, the infiltration levels of activated CD4/CD8 T cells ( p < 0.001/ p = 0.001) and plasmacytoid dendritic cells ( p = 0.006) were upregulated in the non‐FAT2 mutation group, and Type 2 T helper cells ( p = 0.001) were downregulated in the FAT2 mutation group. Conclusions UCEC patients with FAT2 mutations have better prognosis and are more likely to respond to immunotherapy. FAT2 mutation may be a valuable predictor for prognosis and responsiveness to immunotherapy in UCEC patients.