Background: With the continuous improvement of surgery and chemotherapeutic treatments, many tumour patients increasingly achieve long-term survival and can even be completely cured. However, platinum-containing drugs, which are widely used to treat a variety of types of cancer, cause menstrual disorders and ovarian failure, which in turn lead to infertility. Thus far, gonadotropin releasing hormone (GnRH) agonist (GnRHa) and antagonist (GnRHant) are reported to act as protective agents of the ovary in chemotherapy through the inhibition of the female gonadal axis. Nevertheless, they both have disadvantages that limit their use. GnRHa causes a flare-up effect during the first week after administration, and no long-acting GnRHant agent is available. GnRHa combined with GnRHant may prevent the flare-up effect of GnRHa and rapidly inhibit the female gonadal axis. Several clinical studies with small sample sizes have reported controversial conclusions. In this strictly controlled animal study, we investigated the advantages of combination treatment with GnRHa and GnRHant. Methods: Rats aged 12 weeks were divided into six groups: Control, cisplatin (CDDP), GnRHa, GnRHant, Combination (sht, short-term) and Combination (lng, long-term) of GnRHa and GnRHant. The last four groups received Triptorelin (1 mg/kg·d, for 14 days), Cetrorelix (0.5 mg/kg·d, for 10 days), a combination of Triptorelin (1 mg/kg·d, for 10 days) and Cetrorelix (0.5 mg/kg·d, for 10 days) in the long-term group and for 3 days in the short-term group. The Control and CDDP groups received saline (1 ml/kg·d, for 10 day). Then, all groups apart from the Control group received cisplatin (1 mg/kg·d, for 10 days), and the Control group received another 10 days of saline as described above. Blood samples were collected to detect the serum levels of E2, LH and FSH. Observation of oestrous cyclicity was also performed after drug administration. Finally, bilateral ovaries were collected for histological study and follicle counting. Results: We observed a flare-up effect in rats treated with GnRHa, but not in any of the combination groups. The percentage of normal cyclicity increased from 0% in the CDDP group to 25.0%, 33.3%, 66.7% and 41.7%, in the GnRHa, GnRHant, combination (lng) and combination (sht) groups, respectively. Pretreatment with GnRHa, GnRHant and combination (lng) significantly protected the primordial follicles from destruction by preserving 57.6%, 63.4%, 87.1% and 60.4% of the follicles, respectively. Conclusions: The combination of a GnRH agonist with antagonist completely prevented the flare-up effect and enhanced the protective effect of the ovary from cisplatin-induced gonadotoxicity in rats.

Ovarian cancer stem cells (OCSCs) contribute to the poor prognosis of ovarian cancer. Involvement of the androgen receptor (AR) in the malignant behaviors of other tumors has been reported. However, whether AR associates with Nanog (a stem cell marker) and participates in OCSC functions remain unclear. In this study, we investigated the interaction of Nanog with AR and examined whether this interaction induced stem-like properties in ovarian cancer cells. AR and Nanog expression in ovarian tumors was evaluated. Using the CRISPR/Cas9 system, we constructed a Nanog green fluorescent protein (GFP) marker cell model to investigate the expression and co-localization of Nanog and AR. Then, we examined the effect of androgen on the Nanog promoter in ovarian cancer cell lines (A2780 and SKOV3). After androgen or anti-androgen treatment, cell proliferation, migration, sphere formation, colony formation and tumorigenesis were assessed in vitro and in vivo. Both AR and Nanog expression were obviously high in ovarian tumors. Our results showed that Nanog expression was correlated with AR expression. The androgen 5α-dihydrotestosterone (DHT) activated Nanog promoter transcription. Meanwhile, Nanog GFP-positive cells treated with DHT exhibited higher levels of proliferation, migration, sphere formation and colony formation. We also observed that the tumorigenesis of Nanog GFP-positive cells was significantly higher than that of the GFP-negative cells. Xenografts of Nanog GFP-positive cells showed significant differences when treated with androgen or anti-androgen drugs in vivo. The interaction of Nanog with the AR signaling axis might induce or contribute to OCSC regulation. In addition, androgen might promote stemness characteristics in ovarian cancer cells by activating the Nanog promoter. This finding merits further study because it may provide a new understanding of OCSC regulation from a hormone perspective and lead to the reevaluation of stem cell therapy for ovarian cancer.

Uterine corpus endometrial carcinoma (UCEC) is one of the most common cancer in female worldwide. PIK3CA has been proven to be a strong prognostic biomarker in UCEC. Nevertheless, current studies have not investigated what effects PIK3CA had on tumor associated neutrophils (TANss). Kaplan-Meier methods were used to compute the survival time of TCGA UCEC patients. GO and KEGG enrichment analysis unveiled relevant pathways PIK3CA affected using DEGs between PIK3CA high expression group and PIK3CA low expression group in TCGA UCEC, as well as GSEA. immune infiltration status was calculated using TIMER. We found that PIK3CA influenced a number of pathways including immune related pathways. The fraction of TANs was certainly altered by PIK3CA expression in UCEC. Our findings suggest that PIK3CA expression may play an important role in tumor immune microenvironment and could alter fraction of TANs in UCEC.

Cisplatin‐based chemotherapy is the standard treatment for metastatic ovarian cancer (OC). However, chemoresistance continues to pose significant clinical challenges. Recent research has highlighted the baculoviral inhibitor of the apoptosis protein repeat‐containing 5 (BIRC5) as a member of the inhibitor of the apoptosis protein (IAP) family. Notably, BIRC5, which has robust anti‐apoptotic capabilities, is overexpressed in numerous cancers. Its dysfunction has been linked to challenges in cancer treatment. Yet, the role of BIRC5 in the chemoresistance of OC remains elusive. In our present study, we observed an upregulation of BIRC5 in cisplatin‐resistant cell lines. This upregulation was associated with enhanced chemoresistance, which was diminished when the expression of BIRC5 was silenced. Intriguingly, BIRC5 exhibited a high number of N6‐methyladenosine (m⁶A) binding sites. The modification of m⁶A was found to enhance the expression of BIRC5 by recognizing and binding to the 3′‐UTR of mRNA. Additionally, the insulin‐like growth factor 2 mRNA‐binding protein 1 (IGF2BP1) was shown to stabilize BIRC5 mRNA, synergizing with METTL3 and intensifying chemoresistance. Supporting these in vitro findings, our in vivo experiments revealed that tumors were significantly smaller in size and volume when BIRC5 was silenced. This reduction was notably counteracted by co‐silencing BIRC5 and overexpressing IGF2BP1. Our results underscored the pivotal role of BIRC5 in chemoresistance. The regulation of its expression and the stability of its mRNA were influenced by m⁶A modifications involving both METTL3 and IGF2BP1. These insights presented BIRC5 as a promising potential therapeutic target for addressing cisplatin resistance in OC.

Deregulation of matrix metalloproteinases (MMPs) contributes considerably to cancers, psychiatric disorders, macular degeneration and bone diseases. The use of humans in the development of MMPs as prognostic biomarkers and therapeutic targets is complicated by many factors, while primate models can be useful alternatives for this purpose. Here, we performed genome-enabled identification of putative MMPs across primate species, and comprehensively investigated the genes. Phylogenetic topology of the MMP family showed each type formulates a distinct clade, and was further clustered to classes, largely agreeing with classification based on biochemical properties and domain organization. Across primates, the excess of candidate sites of positive selection was detected for MMP-19, in addition to 1-3 sites in MMP-8, MMP-10 and MMP-26. MMP-26 showed Ka/Ks value above 1 between human and chimpanzee copies. We observed two copies of MMP-19 in the old-world monkey genomes, suggesting gene duplication at the early stage of or prior to the emergence of the lineage. Furin-activatable MMPs demonstrate the most variable properties regarding Domain organization and gene structure. During human aging, MMP-11 showed gradually decreased expression in testis, so as MMP-2, MMP-14, MMP15 and MMP-28 in ovary, while MMP-7 and MMP-21 showed elevated expression, implying their distinct roles in different reproductive organs. Co-expression clusters were formed among human MMPs both within and across classes, and expression correlation was observed in MMP genes across primates. Our results illuminate the utilization of MMPs for the discovery of prognostic biomarkers and therapeutic targets for aging-related diseases and carry new messages on MMP classification.

Background: In this study we aimed to identify a prognostic signature in BRCA1/2 mutations to predict disease progression and the efficiency of chemotherapy ovarian cancer (OV), the second most common cause of death from gynecologic cancer in women worldwide. Methods: Univariate Cox proportional-hazards and multivariate Cox regression analyses were used to identifying prognostic factors from data obtained from The Cancer Genome Atlas (TCGA) database. The area under the curve of the receiver operating characteristic curve was assessed, and the sensitivity and specificity of the prediction model were determined. Results: A signature consisting of two long noncoding RNAs(lncRNAs), Z98885.2 and AC011601.1, was selected as the basis for classifying patients into high and low-risk groups (median survival: 7.2 years vs. 2.3 years). The three-year overall survival (OS) rates for the high- and low-risk group were approximately 38 and 100%, respectively. Chemotherapy treatment survival rates indicated that the high-risk group had significantly lower OS rates with adjuvant chemotherapy than the low-risk group. The one-, three-, and five-year OS were 100, 40, and 15% respectively in the high-risk group. The survival rate of the high-risk group declined rapidly after 2 years of OV chemotherapy treatment. Multivariate Cox regression associated with other traditional clinical factors showed that the 2-lncRNA model could be used as an independent OV prognostic factor. Analyses of data from the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) indicated that these signatures are pivotal to cancer development. Conclusion: In conclusion, Z98885.2 and AC011601.1 comprise a novel prognostic signature for OV patients with BRCA1/2 mutations, and can be used to predict prognosis and the efficiency of chemotherapy.