Cancer cells are usually featured by metabolic adaptations that facilitate their growth, invasion, and metastasis. Thus, reprogramming of intracellular energy metabolism is currently one of the ...hotspots in the field of cancer research. Whereas aerobic glycolysis (known as the Warburg effect) has long been considered a dominant form of energy metabolism in cancer cells, emerging evidence indicates that other metabolic forms, especially oxidative phosphorylation (OXPHOS), may play a critical role at least in some types of cancer. Of note, women with metabolic syndromes (MetS), including obesity, hyperglycemia, dyslipidemia, and hypertension, have an increased risk of developing endometrial carcinoma (EC), suggesting a close link between metabolism and EC. Interestingly, the metabolic preferences vary among EC cell types, particularly cancer stem cells and chemotherapy-resistant cells. Currently, it is commonly accepted that glycolysis is the main energy provider in EC cells, while OXPHOS is reduced or impaired. Moreover, agents specifically targeting the glycolysis and/or OXPHOS pathways can inhibit tumor cell growth and promote chemosensitization. For example, metformin and weight control not only reduce the incidence of EC but also improve the prognosis of EC patients. In this review, we comprehensively overview the current in-depth understanding of the relationship between metabolism and EC and provide up-to-date insights into the development of novel therapies targeting energy metabolism for auxiliary treatment in combination with chemotherapy for EC, especially those resistant to conventional chemotherapy.
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•Metabolic syndromes (obesity, hyperglycemia, dyslipidemia, etc) increase the risk of EC.•The alterations involving metabolic pathways contribute to EC development and drug resistance.•Interventions for metabolic syndromes and metabolism-targeted therapies prevent and treat EC.
Poly-ADP-ribose polymerase (PARP) plays an important role in DNA damage detection and repair. PARP inhibitors (PARPi) are a novel class of targeted agents used widely in the treatment of female ...cancer patients with BRCA mutations, including younger patients. However, the impact of PARPi on ovarian function remains a considerable problem in clinical practice. In this review article, we summarize the current understanding of PARPi's effects on the function of ovary and discuss their potential underlying mechanisms, highlighting the significance of further investigation on the criterion for ovarian failure and its preventive approaches during PARPi treatment.
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•Increasing use of PARP inhibitors in female cancer patients raises an issue about their adverse impact on fertility.•Emerging evidence reveals the diverse functions of PARPs in ovarian reserve and function.•PRAP inhibitors may have bidirectional effects on ovarian function, likely in a context-dependent manner.•The approach for managing the deleterious effects of PARP inhibitors is currently lacking.
Cervical cancer is the most prevalent gynecologic malignancy, especially in women of low- and middle-income countries (LMICs). With a better understanding of the etiology and pathogenesis of cervical ...cancer, it has been well accepted that this type of cancer can be prevented and treated
early screening. Due to its higher sensitivity than cytology to identify precursor lesions of cervical cancer, detection of high-risk human papillomavirus (HR-HPV) DNA has been implemented as the primary screening approach. However, a high referral rate for colposcopy after HR-HPV DNA detection due to its low specificity in HR-HPV screening often leads to overtreatment and thus increases the healthcare burden. Emerging evidence has demonstrated that detection of host cell gene and/or HPV DNA methylation represents a promising approach for the early triage of cervical cancer in HR-HPV-positive women owing to its convenience and comparable performance to cytology, particularly in LMICs with limited healthcare resources. While numerous potential markers involving DNA methylation of host cell genes and the HPV genome have been identified thus far, it is crucial to define which genes or panels involving host and/or HPV are feasible and appropriate for large-scale screening and triage. An ideal approach for screening and triage of CIN/ICC requires high sensitivity and adequate specificity and is suitable for self-sampling and inexpensive to allow population-based screening, particularly in LMICs. In this review, we summarize the markers of host cell gene/HR-HPV DNA methylation and discuss their triage performance and feasibility for high-grade precancerous cervical intraepithelial neoplasia or worse (CIN2+ and CIN3+) in HR-HPV-positive women.
Abstract
The link between sexual dysfunction and male infertility has been well established. In addition to male infertility, male patients with couple pregnancy loss and preconception care are the ...most frequent reasons for the treatment of andrology outpatients. However, there is a paucity of information simultaneously investigating male sexual dysfunction in these males with different reproduction situations. A cross-sectional study was performed in consecutive series of 1256 participants, including 509 men with infertility, 437 couples with pregnancy loss, and 310 men for preconception care. All men completed a questionnaire on baseline demographic information, sexual behavior characteristics and validated research tools, including Premature Ejaculation Diagnostic Tool, seven-item Generalized Anxiety Disorder Scale, and International Index of Erectile Function. The prevalence of erectile dysfunction and premature ejaculation was 30.6%, 20.8% in the infertility population and 27.0%, 18.5% in pregnancy loss individuals, was much lower in preconception care men, at 9.3%, 11.9% (p < 0.05), respectively. Infertility and pregnancy loss couples were more biased toward choosing timed intercourse than preconception care couples, with rates of 19.6% in Infertility group and 17.4% in pregnancy loss groups, versus 10.0% (p < 0.05) in preconception care couples. The infertile and pregnancy loss men also reported higher rate of anxiety state than the preconception care group. The prevalence of erectile dysfunction increased gradually with the duration of infertility and the frequency of pregnancy loss, with a highest odds ratio of 7.346 (95% CI:4.329–12.467; P < 0.001) among men with ≥5 years of infertility, 6.282 (95% CI:3.446–11.453; P < 0.001) among couples ≥3 pregnancy loss when compared with preconception care group. The prevalence of erectile dysfunction, premature ejaculation and timed intercourse were comparable in pregnancy loss and infertile males, were all noticeably higher than preconception care group. There was also a trend toward a higher incidence of erectile dysfunction with longer duration of infertility or the more frequent of pregnancy loss.
Acquired resistance to therapeutic drugs has become an important issue in treating ovarian cancer. Studies have shown that the prevalent chemotherapy resistance (cisplatin, paclitaxel etc.) for ...ovarian cancer occurs partly because of decreased production of reactive oxygen species within the mitochondria of ovarian cancer cells.
Nuclear erythroid-related factor-2 (Nrf2) mainly controls the regulation of transcription of genes through the Keap1-Nrf2-ARE signaling pathway and protects cells by fighting oxidative stress and defending against harmful substances. This protective effect is reflected in the promotion of tumor cell growth and their resistance to chemotherapy drugs. Therefore, inhibition of the Nrf2 pathway may reverse drug resistance. In this review, we describe the functions of Nrf2 in drug resistance based on Nrf2-associated signaling pathways determined in previous studies.
Further studies on the relevant mechanisms of Nrf2 may help improve the outcomes of ovarian cancer therapy.
Erectile dysfunction is a common problem in males of couples experiencing pregnancy loss. Erectile dysfunction in males with couple infertile has been extensively investigated and found to be closely ...linked with semen quality impairment and psychological distress, but it is less clear if this relation exists in males of couples experiencing pregnancy loss.
A cross-sectional analysis of 437 men who attended our outpatient clinic between June 2021 and October 2021 for couple pregnancy loss. All subjects underwent a complete physical examination, palpation, inspection of the male genitalia, and semen analysis. Validated assessment tools for erectile dysfunction (the International Index of Sexual Function5 -IIEF-5) and anxiety (the seven-item Generalized Anxiety Disorder Scale- GAD-7) were used.
Among 437 men of couples with pregnancy loss, we found several relevant sperm parameters confirmed a significant correlation between IIEF-5 scores and sperm parameters, including: sperm progressive motility (r = 0.1627, p = 0.001), sperm normal morphology (r = 0.1373, p = 0.004) and sperm DNA fragmentation (r =-0.1248, p = 0.009). Males with an IIEF-5 scores range between 5-11 presented the worst results in terms of sperm progressive motility (p = 0.002), normal morphology (p = 0.001), and SDF levels (p = 0.003). GAD-7 score, as well as anxiety level, was significantly higher in those males with an IIEF-5 score between 5 and 11 (p = 0.000).
Although current evidence does not demonstrate the importance of spermatozoa in the etiology of pregnancy loss, significant correlations have been observed between impaired sperm quality and low IIEF-5 scores. Also, anxiety is more likely to occur in males with sexual dysfunction.
Testosterone plays a key role in women, but the associations of serum testosterone level with gynecological disorders risk are inconclusive in observational studies.
We leveraged public genome-wide ...association studies to analyze the effects of four testosterone related exposure factors on nine gynecological diseases. Causal estimates were calculated by inverse variance-weighted (IVW), MR-Egger and weighted median methods. The heterogeneity test was performed on the obtained data through Cochrane's Q value, and the horizontal pleiotropy test was performed on the data through MR-Egger intercept and MR-PRESSO methods. "mRnd" online analysis tool was used to evaluate the statistical power of MR estimates.
The results showed that total testosterone and bioavailable testosterone were protective factors for ovarian cancer (odds ratio (OR) = 0.885, P = 0.012; OR = 0.871, P = 0.005) and endometriosis (OR = 0.805, P = 0.020; OR = 0.842, P = 0.028) but were risk factors for endometrial cancer (OR = 1.549, P < 0.001; OR = 1.499, P < 0.001) and polycystic ovary syndrome (PCOS) (OR = 1.606, P = 0.019; OR = 1.637, P = 0.017). dehydroepiandrosterone sulfate (DHEAS) is a protective factor against endometriosis (OR = 0.840, P = 0.016) and premature ovarian failure (POF) (OR = 0.461, P = 0.046) and a risk factor for endometrial cancer (OR= 1.788, P < 0.001) and PCOS (OR= 1.970, P = 0.014). sex hormone-binding globulin (SHBG) is a protective factor against endometrial cancer (OR = 0.823, P < 0.001) and PCOS (OR = 0.715, P = 0.031).
Our analysis suggested causal associations between serum testosterone level and ovarian cancer, endometrial cancer, endometriosis, PCOS, POF.
Endometriosis (EMs) is a common gynecological disorder. Observational studies on the relationship between leukocyte telomere length (LTL) and EMs have shown conflicting results. The purpose of this ...study was to evaluate the precise causal relationship between LTL and EMs using Mendelian randomization (MR) methodology.
We employed MR to assess the causal relationship between LTL and EMs. Summary data from several large-scale genome-wide association studies (GWAS) were used for bidirectional two-sample MR analysis. Sensitivity analyses were conducted to ensure the robustness of our results. All analyses were also replicated in another completely independent EMs dataset.
Our MR analysis indicated that genetically predicted longer LTL increased the risk of EMs (IVW: discovery, OR=1.169, 95%CI: 1.059-1.290, p=0.002; validation, OR=1.302, 95%CI: 1.140-1.487, p=0.000), while EMs had no causal impact on LTL (IVW: discovery, OR=1.013, 95%CI: 1.000-1.027, p=0.056; IVW: validation, OR=1.005, 95%CI: 0.995-1.015, p=0.363). Causal estimates were supported by various calculation models (including MR-Egger, Weighted median, MR-PRESSO, and MR-RAPS). Heterogeneity and pleiotropy analyses also indicated robustness of the results.
Our findings substantiate the idea that a genetically predicted longer LTL elevates the risk of EMs, with no influence of EMs on LTL risk. This research bolsters the causal link between LTL and EMs, overcoming the constraints of earlier observational studies. It implies that LTL may potentially function as a biomarker for EMs, opening up novel possibilities for EMs prevention and treatment.
Cervical cancer (CC) has poor prognosis and high mortality rate for its metastasis during the disease progression. Epithelial-mesenchymal transition (EMT) and anoikis are initial and pivotal steps ...during the metastatic process. Although higher levels of Nrf2 are associated with aggressive tumor behaviors in cervical cancer, the detailed mechanism of Nrf2 in cervical cancer metastasis, especially EMT and anoikis, remains unclear.
Immunohistochemistry (IHC) was used to examine Nrf2 expression in CC. Wound healing assay and transwell analysis were used to evaluate the migration ability of CC cells. Western blot, qTR-PCR and immunofluorescent staining were used to verify the expression level of Nrf2, the EMT associated markers and anoikis associated proteins. Flow cytometry assays and cell counting were used to detect the apoptosis of cervical cancer cells. The lung and lymph node metastatic mouse model were established for studies in vivo. The interaction between Nrf2 and Snail1 was confirmed by rescue-of-function assay.
When compared with cervical cancer patients without lymph node metastasis, Nrf2 was highly expressed in patients with lymph node metastasis. And Nrf2 was proved to enhance the migration ability of HeLa and SiHa cells. In addition, Nrf2 was positively correlated with EMT processes and negatively associated with anoikis in cervical cancer. In vivo, a xenograft assay also showed that Nrf2 facilitated both pulmonary and lymphatic distant metastasis of cervical cancer. Rescue-of-function assay further revealed the mechanism that Nrf2 impacted the metastasis of CC through Snail1.
Our fundings established Nrf2 plays a crucial role in the metastasis of cervical cancer by enhancing EMT and resistance to anoikis by promoting the expression of Snail1, with potential value as a therapeutic candidate.
High-risk Human papillomaviruses (HPVs) types are associated with more than 90% of premalignant and malignant squamous lesions of the uterine cervix. The E6 oncoprotein of high-risk HPVs is a key ...determinant in cell transformation because it induces the degradation of the host pro-apoptotic tumor suppressor p53. E6 recruits the intracellular ubiquitin ligase E6AP and subsequently induces proteasome-dependent p53 degradation. Neither E6 nor E6AP alone interact with p53; however, the precise mechanism of the functional regulation of the E6/E6AP/p53 complex is unclear. Here, we showed that the high-risk HPV E6 proteins are ubiquitinated during E6/E6AP/p53 complex assembly and degraded by the proteasome system. Increasing p53 expression enhanced E6/E6AP/p53 assembly and facilitated E6 ubiquitination and degradation. The dominant negative mutant of p53 R175H, which does not efficiently bind E6, decreased E6 ubiquitination and increased stability. Furthermore, we showed that the ubiquitin ligase E6AP is essential for E6 ubiquitination, and downregulation of E6AP expression increased E6 stability. We also showed that p53 R175H inhibited E6-mediated p53 degradation. Consistently, the host deubiquitinating enzyme USP15 removed ubiquitin chains from E6 proteins and inhibited E6-mediated p53 degradation. Crucially, ectopic expression of either p53 R175H or USP15 promoted p53-triggered apoptosis in human cervical cancer cells. Considering the importance of ubiquitinated E6 on p53 degradation, the disruption of E6 ubiquitination represents an attractive pharmacological intervention against HPV-positive human cervical cancer.
Virtually 100% of cervical cancers are linked to HPV infection. Commercial HPV vaccines are estimated to prevent up to 90% of HPV-associated cancers, while they do not eliminate persistent HPV infections and have no effect on the progression to malignancy. Hence, the development of novel therapeutic interventions against HPV is urgently required. The HPV oncoprotein E6 binds to the intracellular E3 ubiquitin ligase E6AP and p53 resulting in the degradation of p53. In this study, we demonstrate that HPV E6 is ubiquitinated by E6AP in presence of p53. Crucially, ubiquitination of E6 is important for p53 degradation and blockage of E6 ubiquitination negatively interferes with E6-mediated p53 degradation and enhances the apoptotic effects of p53 and the cytotoxicity of DNA damage in HPV-positive cervical cancer cells. Importantly, our data suggest that the HPV oncogene E6 might be an optimal pharmacologic.
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