Cancers Of Reproductive System Research Articles

Anticancer Effect of Puerarin on Ovarian Cancer Progression Contributes to the Tumor Suppressor Gene Expression and Gut Microbiota Modulation.

Ovarian cancer (OC) causes more deaths than any other cancer of the female reproductive system due to its late presentation and malignant nature. Although significant progress has been made in the diagnosis and treatment of OC over the last decade, chemotherapeutic drug resistance and cancer recurrence remain serious challenges in OC management. In the field of cancer therapy, traditional Chinese herbal medicines and their active compounds have been widely reported to have favorable therapeutic effects on cancer. Recent studies have also revealed the protective effect of puerarin in cancer, but the exact role and underlying mechanism of puerarin in OC remain unclear. Here, we established in vivo and in vitro OC models to evaluate the anticancer effect of puerarin. It was found that puerarin significantly inhibited OC cell viability and proliferation and induced cell apoptosis. In OC model mice, puerarin treatment suppressed tumor formation and modulated the gut microbiome. In addition, the expression of tumor suppressor genes was activated by puerarin in vitro and in vivo. These findings add to the existing knowledge on the usefulness of herbal active ingredients for the prevention and treatment of OC and provide a new perspective regarding the therapeutic potential of puerarin in cancer.

Recent Insights into PARP and Immuno-Checkpoint Inhibitors in Epithelial Ovarian Cancer.

Ovarian cancer is one of the most common gynecologic cancers and has the highest mortality rate of any other cancer of the female reproductive system. Epithelial ovarian cancer (EOC) accounts for approximately 90% of all ovarian malignancies. The standard therapeutic strategy includes cytoreductive surgery accompanied by pre- or postoperative platinum-based chemotherapy. Nevertheless, up to 80% of the patients relapse within the following 12–18 months from the completion of the treatment and then receive first-line chemotherapy depending on platinum sensitivity. Mutations in BRCA1/2 genes are the most significant molecular aberrations in EOC and serve as prognostic and predictive biomarkers. Poly ADP-ribose polymerase (PARP) inhibitors exploit defects in the DNA repair pathway through synthetic lethality. They have also been shown to trap PARP1 and PARP2 on DNA, leading to PARP-DNA complexes. Olaparib, rucaparib, and niraparib have all obtained Food and Drug Administration (FDA) and/or the European Medicine Agency (EMA) approval for the treatment of EOC in different settings. Immune checkpoint inhibitors (ICI) have improved the survival of several cancers and are under evaluation in EOC. However, despite the success of immunotherapy in other malignancies, the use of antibodies inhibiting the immune checkpoint programmed cell death (PD-1) or its ligand (PD-L1) obtained modest results in EOC so far, with median response rates of up to 10%. As such, ICI have not yet been approved for the treatment of EOC. We herein provided a comprehensive insight into the most recent progress in synthetic lethality PARP inhibitors, along with the mechanisms of resistance. We also summarised data regarding the role of immune checkpoint inhibitors, the use of vaccination therapy, and adoptive immunotherapy in treating epithelial ovarian cancer.

Repetitive DNA Sequences in the Human Y Chromosome and Male Infertility.

The male-specific Y chromosome, which is well known for its diverse and complex repetitive sequences, has different sizes, genome structures, contents and evolutionary trajectories from other chromosomes and is of great significance for testis development and function. The large number of repetitive sequences and palindrome structure of the Y chromosome play an important role in maintaining the stability of male sex determining genes, although they can also cause non-allelic homologous recombination within the chromosome. Deletion of certain Y chromosome sequences will lead to spermatogenesis disorders and male infertility. And Y chromosome genes are also involved in the occurrence of reproductive system cancers and can increase the susceptibility of other tumors. In addition, the Y chromosome has very special value in the personal identification and parentage testing of male-related cases in forensic medicine because of its unique paternal genetic characteristics. In view of the extremely high frequency and complexity of gene rearrangements and the limitations of sequencing technology, the analysis of Y chromosome sequences and the study of Y-gene function still have many unsolved problems. This article will introduce the structure and repetitive sequence of the Y chromosome, summarize the correlation between Y chromosome various sequence deletions and male infertility for understanding the repetitive sequence of Y chromosome more systematically, in order to provide research motivation for further explore of the molecules mechanism of Y-deletion and male infertility and theoretical foundations for the transformation of basic research into applications in clinical medicine and forensic medicine.

Molecular Regulation of Androgen Receptors in Major Female Reproductive System Cancers.

There are three main types of cancer in the female reproductive system, specifically ovarian cancer (OVCA), endometrial cancer (EC), and cervical cancer (CC). They are common malignant tumors in women worldwide, with high morbidity and mortality. In recent years, androgen receptors (ARs) have been found to be closely related to the occurrence, progression, prognosis, and drug resistance of these three types of tumors. This paper summarizes current views on the role of AR in female reproductive system cancer, the associations between female reproductive system cancers and AR expression and polymorphisms. AR regulates the downstream target genes transcriptional activity and the expression via interacting with coactivators/corepressors and upstream/downstream regulators and through the gene transcription mechanism of “classical A/AR signaling” or “non-classical AR signaling”, involving a large number of regulatory factors and signaling pathways. ARs take part in the processes of cancer cell proliferation, migration/invasion, cancer cell stemness, and chemotherapeutic drug resistance. These findings suggest that the AR and related regulators could target the treatment of female reproductive system cancer.

Green Tea Epigallocatechin-3-Gallate Regulates Autophagy in Male and Female Reproductive Cancer.

With a rich abundance of natural polyphenols, green tea has become one of the most popular and healthiest nonalcoholic beverages being consumed worldwide. Epigallocatechin-3-gallate (EGCG) is the predominant catechin found in green tea, which has been shown to promote numerous health benefits, including metabolic regulation, antioxidant, anti-inflammatory, and anticancer. Clinical studies have also shown the inhibitory effects of EGCG on cancers of the male and female reproductive system, including ovarian, cervical, endometrial, breast, testicular, and prostate cancers. Autophagy is a natural, self-degradation process that serves important functions in both tumor suppression and tumor cell survival. Naturally derived products have the potential to be an effective and safe alternative in balancing autophagy and maintaining homeostasis during tumor development. Although EGCG has been shown to play a critical role in the suppression of multiple cancers, its role as autophagy modulator in cancers of the male and female reproductive system remains to be fully discussed. Herein, we aim to provide an overview of the current knowledge of EGCG in targeting autophagy and its related signaling mechanism in reproductive cancers. Effects of EGCG on regulating autophagy toward reproductive cancers as a single therapy or cotreatment with other chemotherapies will be reviewed and compared. Additionally, the underlying mechanisms and crosstalk of EGCG between autophagy and other cellular processes, such as reactive oxidative stress, ER stress, angiogenesis, and apoptosis, will be summarized. The present review will help to shed light on the significance of green tea as a potential therapeutic treatment for reproductive cancers through regulating autophagy.

The effect of toxic air pollutants on fertility men and women, fetus and birth rate.

Human health is affected by various factors such as air pollutants. Exposure to toxic air pollutants is impaired fertility in men and women. The purpose of this review study was investigation of the effect of toxic air pollutants on fertility and birth rate. Databases used to for searched were the PubMed, Web of Science, Springer and Science Direct (Scopus) and Google Scholar. Identify all relevant studies published 1999-2022. In this study, according to databases five hundred articles were retrieved. 33 studies were screened after review and 19 full-text articles entered into the analysis process. Finally, 11 articles were selected in this study. The literature signs a notable health effects from toxic air pollutants and increase risk of infertility in men and women and having a variety of reproductive system cancers such as prostate, bladder, ovary, kidney and uterus. According to the finding toxic air pollutants can increase the risk infertility in men and women, incidence of cancers of reproductive system and decrease the birth rate. Activities that play an important role in reducing the health effects of toxic air pollutants such as infertility in men and women and reducing the population rate of communities are improving the quality of fuel used in the home, car, industries, changing production processes in large industries, installing catalysts to reduce emissions in cars, use more public transportation, plant trees and increase green space per capita, increase public awareness about various effects of toxic air pollutants and protective measures.

Impact of a previous cancer history on the overall survival of patients with primary gastric cancer: A SEER population-based study

BackgroundThe impact of previous cancers on the survival of gastric cancer (GC) patients is still uncertain. To evaluate the impact of a prior cancer history on the overall survival of patients with primary GC. MethodsThe Surveillance, Epidemiology, and End Results (SEER) database provided data on patients diagnosed with GC as the first or second primary malignancy between 2010 and 2015 in this retrospective cohort study. Cox proportional hazards models, Kaplan-Meier curves and forest plots were utilized to analyze overall survival. Subgroup analysis was performed based on age, gender, race and prior cancer type. ResultsTotally 39,379 were eligible for this study, including 7403 (18.8%) with a previous cancer history. A previous cancer was an independent risk factor for overall survival [hazard ratio (HR) = 1.103, 95% confidence interval (CI): 1.070–1.138]. For GC patients aged 40–60 years (HR = 1.191, 95% CI: 1.084–1.308) and ≥60 years (HR = 1.093, 95% CI: 1.058–1.13) at diagnosis, a previous cancer was significantly associated with worse overall survival. GC patients with previous oral cavity and pharynx cancer (HR = 1.249, 95% CI: 1.038–1.501), respiratory system cancer (HR = 1.177, 95% CI: 1.076–1.286), female genital system cancer (HR = 1.169, 95% CI: 1.011–1.351), or lymphoma cancer (HR = 1.192, 95% CI: 1.023–1.389) had shorter overall survival than GC patients without a previous cancer. ConclusionA previous cancer adversely affected the overall survival of GC patients. Specifically, GC patients aged ≥40 years, or with oral cavity and pharynx cancer, respiratory system cancer, female genital system cancer, or lymphoma cancer had inferior overall survival. These patients should obtain more attention and get individualized treatment to improve prognosis, and clinical trial eligibility criteria could be reconsidered for particular age and cancer types.

Abstract 3641: Age-related changes in microenvironmental collagen affect ovarian cancer metastasis

Abstract Aging is the biggest risk factor for the development of ovarian cancer (OvCa), the deadliest cancer of the female reproductive system. Despite this, age is understudied in the OvCa field. Using a C57Bl/6 mouse model of aging, young (Y) mice ranging from 3-6 months of age and aged (A) mice ranging from 20-23 months of age were used to study the role aging has on metastasis. Fluorescently tagged C57Bl/6 syngeneic ID8trp53-/- mouse ovarian surface epithelial cancer cells were injected intraperitoneally in Y and A mice and disease progression was evaluated following 5.5 weeks. Organ-specific tumor burden was quantified with ImageJ, revealing increased tumor burden in A mice compared to their Y counterparts. These results were reproduced in the FVB mouse model using syngeneic PTENshRNA/KRASG12V oviductal epithelial cells. While in vitro assays showed no significant difference in adhesion or invasion of OvCa cells on Y vs A collagen, human cell lines showed increased invasion through Boyden invasion chambers lined with A collagen compared to Y. The relationship between tumors and aged collagen was further investigated by analysis of collagen hybridizing peptide (CHP) staining of paraffin-embedded omental tumor sections, which shows an increase of intratumoral collagen remodeling in A tumors despite no significant difference in overall collagen amount as shown by trichrome analysis of serial sections. However, second harmonic generation microscopy (SHG) and CHP fluorescence analysis of early tumor events shows increased peritumoral collagen remodeling in Y mice, showing a difference between intratumoral collagen and microenvironmental collagen. Immunohistochemical analysis of paraffin-embedded tumor sections showed similar amounts of advanced glycation end products (AGEs) and cancer-associated fibroblasts (CAFs) in Y and A tumors, suggesting intratumoral collagen is newly synthesized by CAFs whereas the collagen in the microenvironment is truly aged. To further investigate peritumoral collagen in the metastatic microenvironment, SHG was used to visualize collagen of common metastatic sites from Y and A tumor naïve C57Bl/6 mice. Distinct structural differences were shown in omental collagen in the Y vs A cohorts and validated with scanning electron microscopy (SEM). In conclusion, aging induces changes in the structure and properties of both intra- and peritumoral collagen, increasing OvCa metastatic success. Citation Format: Elizabeth Harper, Elizabeth Agadi, Emma Sheedy, Preston Carey, Paul Wilkinson, Michael Siroky, Tyvette Hilliard, Ethan Low, Annemarie Leonard, Yueying Liu, Jing Yang, M. Sharon Stack. Age-related changes in microenvironmental collagen affect ovarian cancer metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3641.

Abstract 2484: Hyperpolarized magnetic resonance spectroscopy assessment of the metabolic effects of glutaminase inhibitor therapy in an ovarian cancer model

Abstract Introduction: Ovarian cancer accounts for more deaths than any other cancer of the female reproductive system despite advances in targeted drugs such as anti-VEGF antibody (AVA). Additionally, resistance to AVA therapy is nearly ubiquitous given the occurrence of metabolic adaptations such as a dependence on glutamine metabolism via the enzyme glutaminase. Objectives: To examine the metabolic vulnerability of AVA-resistant cancer with glutaminase inhibitor (GLSi) therapy and to test the utility of hyperpolarized magnetic resonance spectroscopy (HP-MRS) for assessing changes in lactate metabolism associated with GLSi treatment following injection of hyperpolarized [1-13C] pyruvate. Methods: We used a well-characterized SKOV3ip1 orthotopic mouse model of high-grade serous ovarian cancer with adaptive resistance to AVA (bevacizumab) treatment. Following three weeks of GLSi and bevacizumab treatment, we performed HP-MRS imaging to directly and non-invasively compare metabolic changes between the treatment groups of bevacizumab monotherapy versus a combined treatment of bevacizumab plus GLSi therapy. Upon injection of hyperpolarized [1-13C] pyruvate, we quantitatively assessed a normalized lactate ratio (nLac), defined as the 13C resonance signal of lactate divided by the sum of the pyruvate and lactate signals, sixty seconds after injection. GLSi treatment effect was subsequently compared between GLSi monotherapy, bevacizumab monotherapy and control mice receiving no therapy. This was performed via gross necropsy to assess disease burden and quantification of tumor weight and nodule number. Results: Significance analysis microarrays (SAM) of bevacizumab treated tumors from the mouse models revealed greater glutamine and glutamate abundance in all tissues suggestive of a glutamine dependence in AVA resistant tumors that could be susceptible to glutaminase inhibition. The in vivo HP-MRS provided a direct and non-invasive investigation of pyruvate metabolism of tumors in situ. Our analysis indicated that the pyruvate-to-lactate conversion was significantly reduced in vivo by GLSi treatment (0.337 vs 0.178, p=0.0002), suggestive of therapeutic efficacy of GLSi in the setting of AVA-resistant tumors. Consistent with this, we observed a statistically significant reduction in tumor weight (0.05g vs 0.62g and 0.64g, p<0.01) and tumor nodule number (n=3.3 vs n=12.8 and n=13.9, p<0.05) in mice treated with a combination of bevacizumab and GLSi compared to the control group, or GLSi monotherapy, respectively. Conclusions: Using HP-MRS in vivo, we directly monitored metabolic changes occurring after GLSi treatment. These findings are consistent with the notion of glutamine dependence being an important resistance mechanism to AVA therapy and imply potential future use of HP-MRS in monitoring therapeutic efficacy in a clinical realm. Citation Format: Deanna Glassman, Mark S. Kim, Prasanta Dutta, Charles V. Kingsley, Emine Bayraktar, Yutuan Wu, Elaine Stur, Lingegowda S. Mangala, Katherine Foster, Sanghoon Lee, Timothy A. Yap, Shannon N. Westin, Pratip Bhattacharya, Anil K. Sood. Hyperpolarized magnetic resonance spectroscopy assessment of the metabolic effects of glutaminase inhibitor therapy in an ovarian cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2484.

Abstract 1117: Investigating PD-1/PD-L1 checkpoint inhibition as a treatment for platinum-resistant ovarian cancer

Abstract Ovarian cancer is the deadliest cancer of the female reproductive system, with the majority of patients experiencing relapse on first-line platinum-based chemotherapies. Identifying potential targets for additional second-line therapies is critical for treating platinum-resistant ovarian cancer. To that end, the evolution of platinum resistance in a cell-based model of ovarian cancer was monitored via characterization of proteomic changes in cancer-derived extracellular vesicles (EVs) after progressive rounds of cisplatin treatment. The content of cancer-derived EVs was analyzed via reverse phase protein array, mass spectrometry, and Western blotting to identify pathways that could be targeted by second-line therapies. Several therapeutically relevant markers were upregulated, including phospho-EGFR (Y1068), multidrug transporter ABCE1, and PD-L1. Monoclonal antibody-based therapies (mAbs) targeting PD-1/PD-L1 have been deployed successfully as second-line treatments for a variety of cancers, but their success has yet to be translated to ovarian cancer. Current mAb-based immunotherapies suffer from several pitfalls including poor tissue penetration, a long-standing issue in ovarian cancer treatment. To offer an alternative to mAb-based immunotherapies, we developed a small interfering peptide consisting of a portion of the PD-L1 interface sequence. This lead peptide underwent several rounds of in silico optimization via molecular dynamics and modeling simulations to identify modifications that could improve affinity for PD-1 or stability in serum. When efficacy was assessed in vitro via Amplified Luminescent Proximity Homogeneous Assay screening, the modifications to the lead peptide were not shown to improve efficacy. However, serum stability studies indicated the modifications dramatically improved peptide stability, with detectable levels still quantifiable via mass spectrometry after 48 hours. The stabilized peptide, titled MN1.4, was chosen for further efficacy testing in cell-based models. A cisplatin-treated daughter line from the OVCAR8 high grade serous ovarian carcinoma cell line was created to model the effects of clinical platinum-based chemotherapy treatments on the most common ovarian cancer subtype. OVCAR8 cells were co-cultured in the presence of stimulated Jurkat T cells to measure markers of T cell activation, including IL-2, via ELISA after treatment with MN1.4 in the presence or absence of EVs derived from cisplatin-treated cells. This model allows for examination of the potential sensitization effects of first-line cisplatin treatment on PD-1/PD-L1 immunotherapy, and how cancer-derived EVs from cisplatin-treated cells can abrogate this effect. We conclude that exosomal PD-L1 may impair responses to PD-1/PD-L1 immunotherapy and should be considered when assessing the viability of this treatment option for ovarian cancer patients. Citation Format: Rachel Carter, Marissa Howard, James Erickson, Paul Russo, Alessandra Luchini, Amanda Haymond, Fatah Kashanchi, Mikell Paige, Lance Liotta. Investigating PD-1/PD-L1 checkpoint inhibition as a treatment for platinum-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1117.

Prevalence of pain symptoms among U.S. adult cancer survivors.

12062 Background: Pain symptoms are common in cancer survivors. The life expectancy of US cancer survivors continues to raise. To date, the comprehensive pattern of pain symptoms in US cancer survivors by cancer history remains unknown. Methods: Data on pain symptoms and correlates were derived from a nationally representative sample of cancer survivors (n = 55,716, weighted population = 17,352,886) in the 1997-2018 National Health Interview Survey. Individuals who answered “yes” to the questions “During the past three months, did you have headache/facial/neck/low back pain/low back pain radiating to the leg” were considered as having pain symptoms at respective anatomical regions. The US national prevalence of pain overall and by anatomical regions were estimated. Correlates of pain symptoms were examined using multivariable logistic regression. Results: The prevalence of overall pain symptoms was persistently high (48.5%, 95% CI: 48.0-49.0) in cancer survivors from 1997-2018 ( P for trend =.58), driven by low back (37.6%, 95% CI: 37.1-38.0) and neck pain (20.9%, 95% CI: 20.5-21.3), and was leading in survivors of bone (63.1%, 95% CI: 57.9-68.4), soft tissue (58.1%, 95% CI: 50.6-65.6), and brain (58.2%, 95% CI: 52.3-64.0) cancers. Considerable pain symptoms were reported by survivors of commonly diagnosed cancers: lung (48.5%), breast (46.7%), colon (52.2%) and prostate (38.4%) cancers. The prevalence of pain is higher in females (52.9%) than males (42.6%) across all anatomical regions (OR, 1.50 [95% CI, 1.38-1.63]), particularly headache (19.8% vs. 8.6%) and facial pain (8.6% vs. 3.9%). Of note, females with reproductive system cancers, cervical (66.3%), uterine (60.0%) and ovarian (59.4%) cancers, have a higher prevalence in all types of pain than those with other cancers. Cancer survivors aged ≥65 years were less likely to report pain symptoms than younger survivors (OR, 0.71 [95% CI, 0.64-0.79]). Despite no racial disparity in the prevalence of overall pain, Non-Hispanic Blacks (18.6%, 95% CI: 17.2-20.0) and Hispanics (21.2%, 95% CI: 19.5-22.9) were more likely to report headache than Non-Hispanic Whites (14.4%, 95% CI: 14.0-14.8). A higher prevalence of pain symptoms was consistently observed in cancer survivors with low income, smoking history, low physical activity levels, diabetes, and cardiovascular diseases (all P <.05). Age at cancer diagnosis ( P for trend <.001), but not the time since, affected pain symptoms. Cancer survivors diagnosed at age 0-14 (53.0%, 95% CI: 49.1-56.9) and 15-39 years (58.6%, 95% CI: 57.5-59.7) had a significantly higher prevalence of pain across all anatomical regions than those at ≥40 years (45.5%, 95% CI: 44.9-46.1). Conclusions: Half of US cancer survivors experienced pain symptoms, driven by low back and neck pain. Higher prevalence of pain was noted in cancer survivors with younger age, female sex, low income and suboptimal lifestyle behaviors, calling for adequate pain management in cancer survivorship.

Mangosteen Inhibits Growth and Survival of Cervical Cancer Cells.

Cervical cancer is the most common cancer of the female reproductive system. Late-stage cervical cancer treatment has been largely unsuccessful, and urgent anti-cancer therapy is needed. Mangosteen, a tropical fruit, has been studied and found to be rich in xanthones, known anti-cancer compounds. This study was designed to investigate the effect of mangosteen extract (ME) on SiHa cervical cancer cells and to explore the underlying molecular mechanisms. Clonogenic survival assay, Quick Cell Proliferation Assay, terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining, and caspase-3 activity kits were used to investigate the in vitro role of ME treatment in SiHa cervical cancer cell growth. We further investigated the possible molecular mechanisms using RT-PCR. Statistical analysis was done with unpaired two-tailed Student's t-test and significance at p-value <0.05; each experiment was repeated three times. Our study found that the growth and proliferation of SiHa cervical cancer cells was inhibited by ME. ME also induced apoptosis in SiHa cervical cancer cells. The anti-proliferative effect of ME on cervical cancer cells was associated with statistically significant (p<0.05) down-regulation of the pro-proliferative molecules cyclin B, cyclin D and cyclin E. The pro-apoptotic effect of ME was associated with statistically significant (p<0.05) down-regulation of the anti-apoptotic molecules flice-like inhibitory protein (FLIP) and survivin. ME impedes the growth and survival of SiHa cervical cancer cells by down-regulating cyclin B, cyclin D, cyclin E as well as FLIP and survivin. ME may be a promising strategy for targeted cancer immunotherapy development.

IGF2BP3‑stabilized SIX4 promotes the proliferation, migration, invasion and tube formation of ovarian cancer cells.

The mortality rate of ovarian cancer (OC) is the highest among the different types of female reproductive system cancers. SIX homeobox 4 (SIX4), a member of the homeobox family, subfamily SIX, fulfills an important role in metastasis and angiogenesis in a variety of types of cancer. The aim of the present study was to investigate both the effects and the underlying mechanism of SIX4 on angiogenesis in OC. The Gene Expression Profiling Interactive Analysis and Encyclopedia of RNA Interactomes databases were employed to predict the expression levels of SIX4 in OC tissues, and its association with the overall survival (OS) rate of patients with OC. The expression levels of SIX4 in OC cell lines were detected by reverse transcription-quantitative PCR (RT-qPCR) and western blot analysis. Following silencing of SIX4, the proliferation, invasion, migration and angiogenesis of OC cells were investigated via Cell Counting Kit-8, colony formation, wound healing, Transwell and tube formation assays. Subsequently, the levels of insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) in OC cell lines were detected by RT-qPCR and western blot analysis. The ability of IGF2BP3 to bind to SIX4 mRNA was detected via an RNA immunoprecipitation assay, and the stability of SIX4 mRNA was assessed by RT-qPCR following Actinomycin D treatment. Finally, the effects of transfection of sh-SIX4 and overexpression of IGF2BP3 simultaneously were examined to further delineate the mechanism involved. It was revealed that SIX4 was highly expressed in OC tissues and cells, and its expression was associated with low OS rates in patients with OC. SIX4 knockdown with short hairpin RNA inhibited the proliferation, migration and invasion of cells, as well as angiogenesis. In addition, IGF2BP3 overexpression led to an improvement in the stability of SIX4 mRNA. Overexpression of IGF2BP3 also reversed the inhibitory effect of SIX4 interference on the malignant phenotypes of OC cells. Taken together, the results of the present study demonstrated that IGF2BP3-stabilized SIX4 promoted the proliferation, metastasis and angiogenesis of SKOV3 cells.

TCOF1 is Identified to be an Unfavorable Biomarker and is Associated with Molecular Classification in Endometrial Cancer

Background: Endometrial cancer (EC) is one of the most common gynecologic cancers of the female reproductive system. Its incidence and mortality are currently increasing. Patients with early-stage EC have a much better prognosis than those with late-stage EC. Therefore, early detection, diagnosis, and treatment are critical to improving the outcome for EC patients. The proposition of molecular classification promotes the individualization for diagnosis and treatment of EC. TCOF1 has been identified as an oncogenic gene in several tumors but has been seldom studied in EC. Methods: TCGA and immunohistochemistry (IHC) experiments were performed to verify the protein level of TCOF1 expressed in endometrial cancer while its prognostic ability in EC patients was assessed by the TCGA database. Linked Omics database, Web Gestalt gene enrichment, and string database were applied to analyze the possible biological functions of TCOF1 in EC. Mutation types of TCOF1 in EC and its mutation frequency were explored in c-BIOPORTAL. The Relationship between molecules was detected by utilizing the GEPIA database. Results: TCOF1 is up-regulated in endometrial cancer compared to para cancer and it was positively correlated with poor prognosis of patients. TCOF1 is mutated in endometrial cancer and is closely associated with microsatellite instability (MSI), this being one type of molecular classification in EC. Conclusions: TCOF1 may function as a potential biomarker and is associated with molecular classification in endometrial cancer.

MiRNA‐Based Cancer Classifier from TCGA Expression Profiles

IntroductionThe Cancer Genome Atlas (TCGA) is a comprehensive multi‐omics database of 33 different cancers, providing a wealth of clinical information and molecular datasets for biomarker discovery (Peng &amp; Croce, 2016) and genomic pipeline development (Hutter &amp; Zenklusen, 2018). MicroRNAs (miRNAs) are small non‐coding regulatory RNAs that are excellent classificatory tissue markers due to their abundance and cell‐type and disease‐stage specificity (Gustafson et al., 2016); miRNA expression data are available from all 33 cancer types in the TCGA.Objectives and HypothesisThe primary objective of this study is to design and validate a miRNA‐based classifier. We hypothesize that our machine learning algorithm will identify a set of miRNA biomarkers that can discriminate between the 33 types of cancer listed in the TCGA.MethodsWe compiled and preprocessed miRNA expression profiles for the 33 different cancers in TCGA. After preprocessing to remove duplicates, batch effects and technical outliers, unsupervised hierarchical clustering of miRNA expression profiles showed distinct separation of ovarian serous cystadenocarcinoma, glioblastoma multiforme and low‐grade glioma, and testicular germ cell tumors from other cancer types (Figure 1). We observed certain cancer types with reproductive system origin had grouped together and apart from other cancer types during unsupervised clustering. Based on these observations and prior knowledge of tumor anatomy and pathology, we created a hierarchical classifier wherein each cancer type is systematically discriminated from the remaining cancer types, until each cancer is identifiable through process of elimination. At each step, a feature selection algorithm developed in our lab identified miRNA biomarkers that can classify these cancers based on organ system and subsequently, the specific cancer.ResultsAfter data preprocessing and filtering at the 90th percentile of expression, the data set included 8287 samples and 617 miRNAs. Feature selection analysis for classifier design effectively separates reproductive cancers from others.ConclusionWe have developed a miRNA‐based classifier for of ovarian serous cystadenocarcinoma and testicular germ cell tumors, both under reproductive system cancers. We will continue to expand the classifier for all 33 cancers in TCGA and finalize through validation with unlabeled samples. The resultant classifier for multiple cancers has clinical potential for sample diagnosis, but also provides insight into cancer diversity and pathogenesis across organ systems and subtypes.Gustafson, D., Tyryshkin, K., &amp; Renwick, N. (2016). microRNA‐guided diagnostics in clinical samples. Best Pract Res Clin Endocrinol Metab, 30(5), 563‐575. https://doi.org/10.1016/j.beem.2016.07.002Hutter, C., &amp; Zenklusen, J. C. (2018). The Cancer Genome Atlas: Creating Lasting Value beyond Its Data. Cell, 173(2), 283‐285. https://doi.org/10.1016/j.cell.2018.03.042Peng, Y., &amp; Croce, C. M. (2016). The role of MicroRNAs in human cancer. Signal Transduction and Targeted Therapy, 1(1), 15004. https://doi.org/10.1038/sigtrans.2015.4

Absence of Toll-like receptor 5 confers survival in mice bearing ovarian tumors treated with anti-PD-L1

Abstract Ovarian cancer accounts for more deaths than any other cancer of the female reproductive system. Patients bearing ovarian tumors infiltrated with high frequencies of T cells associate with a greater survival probability. However, therapeutic strategies targeting T cells in ovarian cancers are largely ineffective. We have observed in our models of late-stage murine ovarian cancer that in the absence of Toll-Like Receptor 5 (TLR5) signaling, anti-PD-L1 therapy promotes significant survival and subsequent protection against tumor rechallenge. Ovarian tumors from rechallenged TLR5KO mice exhibited significantly higher frequency/number of both CD4 and CD8 effector memory T cell subsets and greater numbers of antigen experienced T cells. Thus, in the absence of TLR5 signaling, T cells are better able to mount/maintain a response to ovarian tumors after inhibitory receptor blockade. Furthermore, protection against tumor progression in TLR5KO mice corresponds with a significant increase in tumor infiltrating cross presenting and IL-12 producing Dendritic cells (DCs) which could account for the differences in T cell infiltrates. We hypothesize that TLR5 signaling functionally alters DCs to become more suppressive in the tumor microenvironment, impacting T cell differentiation and anti-tumor activity, thereby reducing survival during ovarian tumor progression with aPD-L1 therapy. Clinical implications are already present, as roughly 7.5% of the general population harbor a TLR5 SNP that diminishes TLR5 signaling and is associated with increased long-term survival for ovarian cancer patients. Therefore, patients who express the TLR5 SNP may immediately benefit from anti-PDL1 therapy and those without the SNP, TLR5 antagonism. Supported by NIH/NCI 1R01CA253285 UVA CIC Collaborative Grant

Characterizing the Contribution of Adrenergic Signaling to Olaparib Resistance in Ovarian Cancer Cells

According to the American Cancer Society, ovarian cancer is the deadliest cancer of the female reproductive system. Moreover, a significant number of ovarian cancer patients are clinically depressed or lack social support at the time of their diagnosis. Mounting data support an association between chronic stress and depression with sustained sympathetic nervous system activation (SNS). Furthermore, there is strong evidence supporting a relationship between prolonged SNS activation and cancer progression. In addition, work from our group and others has shown that psychological states such as chronic stress or depression accelerate the growth of existing tumors and promote chemoresistance. Also, recent data from our lab shows that exposure to norepinephrine (NE) leads to double‐stranded DNA breaks in epithelial ovarian cancer cells (EOC) in a β‐adrenergic receptor‐dependent manner. Interestingly, when EOC were co‐exposed to NE and cisplatin (a DNA damaging agent used in ovarian cancer therapy), we observed fewer double‐stranded DNA breaks than with either treatment alone. These data suggest that stress hormones could influence EOC responses to chemotherapeutic agents. Here, we sought to determine the contribution of adrenergic signaling to Olaparib (an FDA‐approved PARP inhibitor) resistance in EOC. We first determined the EOC viability after exposure to Olaparib. Here, we exposed ES‐2 ovarian cancer cells to serial dilutions of Olaparib and calculated their viability after 48 hrs, 72 hrs, 96 hrs, and 120 hrs. Following each experiment, we calculated the IC50 for each timepoint. Our preliminary data suggest an IC50 of 19µM at 48 hrs, 28.5 µM at 72 hrs, 14.5 µM at 96 hrs, and 8 µM at 120 hrs. Currently, we are performing additional experiments to expand these preliminary data to other EOC lines and further determine the contribution of NE to Olaparib resistance in EOC.

Dynamic changes in the tumor microenvironment under the effect of estradiol as a diagnostic tool and target for targeted cancer therapy

Activation of the estrogen receptor-α (ER-α) signaling pathway is a significant factor in the initiation of carcinogenesis in various types of tumors due to the genomic and non-genomic effects of estradiol in cancer cells. However, data on the expression of ER-α and aromatase on stromal and immune cells in the tumor microenvironment (TME) point to an additional mechanism by which estrogens increase tumor malignancy. There is growing evidence that TME can affect tumor immunity by increasing the immune response or reducing immunoreactivity.The important role of estrogen and the estrogen receptor signaling pathway in the response of the tumor microenvironment in cancer of various localizations, not only classical hormone-dependent cancers, has been proven. However, the clinical effectiveness of blocking the effect of estrogen on tumor growth has been primarily shown in cancer of the female reproductive system. At the same time, data on the significant role of TME in the development of endocrinotherapy resistance in breast cancer treatment are of great interest.Despite the possibilities of standard therapy, a more in-depth study on the role of various TME components in cancer evolution, creation of a micrometastatic niche, as well as in the response to therapy may result in development of new strategies for cancer treatment. It is also necessary to study the possibilities of overcoming the immunosuppressive effect of the estrogen receptor signaling pathway on TME in order to increase the survival rates in patients with hormone-dependent cancers, particularly, breast cancer.

Medical image diagnosis of prostate tumor based on PSP-Net+VGG16 deep learning network

Background and objectiveProstate cancer is the most common cancer of the male reproductive system. With the development of medical imaging technology, magnetic resonance images (MRI) have been used in the diagnosis and treatment of prostate cancer because of its clarity and non-invasiveness. Prostate MRI segmentation and diagnosis experience problems such as low tissue boundary contrast. The traditional segmentation method of manually drawing the contour boundary of the tissue cannot meet the clinical real-time requirements. How to quickly and accurately segment the prostate tumor has become an important research topic. MethodsThis paper proposes a prostate tumor diagnosis based on the deep learning network PSP-Net+VGG16. The deep convolutional neural network segmentation method based on the PSP-Net constructs a atrous convolution residual structure model extraction network. First, the three-dimensional prostate MRI is converted to two-dimensional image slices, and then the slice input of the two-dimensional image is trained based on the PSP-Net neural network; and the VGG16 network is used to analyze the region of interest and classify prostate cancer and normal prostate. ResultsAccording to the experimental results, the segmentation method based on the deep learning network PSP-Net is used to identify the data set samples. The segmentation accuracy is close to the Dice similarity coefficient and Hausdorff distance, and even exceeds the traditional prostate image segmentation method. The Dice index reached 91.3%, and the technique is superior in speed of processing. The predicted tumor markers are very close to the actual markers manually by clinicians; the classification accuracy and recognition rates of prostate MRI based on VGG16 are as high as 87.95% and 87.33%, and the accuracy rate and recall rate of the network model are relatively balanced. The area under curve index is also higher than other models, with good generalization ability. ConclusionExperiments show that prostate cancer diagnosis based on the deep learning network PSP-Net+VGG16 is superior in accuracy and processing time compared to other algorithms, and can be well applied to clinical prostate tumor diagnosis.

The prognostic and clinicopathological significance of desmoglein 2 in human cancers: a systematic review and meta-analysis.

ObjectiveThe survival and clinicopathological significance of desmoglein 2 (DSG2) in various cancers is controversial. Thus, we performed this systematic review and meta-analysis to explore the preliminary prognostic value of DSG2.MethodsEligible studies were identified from databases including PubMed, the Cochrane Library, Embase, Web of Science and Scopus. Hand searches were also conducted in relevant bibliographies. We then extracted and pooled hazard ratio (HR) of overall survival (OS) and odds ratio (OR) of clinicopathological features.ResultsA total of 11 eligible studies containing 1,488 patients were included. Our results demonstrated that in non-small cell lung cancer (NSCLC), high DSG2 expression is associated with poor OS. However, in digestive system cancer and female reproductive system cancer, there were no statistically significant associations between OS and DSG2.ConclusionsBased on the findings of this study, high DSG2 expression is associated with worse prognosis in patients with NSCLC, and thus DSG2 expression could be a biomarker for prognosis in NSCLC.