Exosome-transmitted miR-30a-5p enhances cell proliferation, migration, and invasion in ovarian cancer.

BACKGROUND: Ovarian cancer (OC) causes the highest rates of mortality among women's genital tract malignancies. Micro-ribonucleic acid (miRNA), the most abundant long noncoding RNAs transmitted by exosomes, has been revealed to be a potential marker for OC since 2008. In this study, we aimed to determine the possible roles of miRNAs derived from exosomes in the early diagnosis of OC through miRNA microarray, besides, exploring the underlying mechanisms of miRNAs in the OC progression. METHODS: We isolated exosomes from high invasive OC cell line HO8910PM and its parent cell line HO8910 using transmission electron microscopy and western blot, and performed miRNA microarray to identify the exosome-transmitted miRNA from the two cell lines, respectively. The expression profile was obtained by quantitative analysis, and then the differentially expressed individuals were screened. miRNA-30a-5p, a stable miRNA in both cells of our sequencing data was set for further study. MiR-30a-5p mimics, inhibitor and their corresponding negative controls were applied in OC cells. Then the cell proliferation, migration, and invasion of different groups were analyzed via cell counting-kit 8 (CCK8), wound healing, and Transwell analyses. Besides, ZBE2 and LDH2 expressions were detected by qRT-PCR. RESULTS: Combined with the data report of miRNA microarray technology, we set miR-30a-5p as our target miRNA to analyze its molecular function in regulating proliferation, migration, and invasion in OC cells. Our results showed that the miR-30a-5p overexpression could significantly enhance the capability of proliferation, migration, and invasion of HO8910 and HO8910PM cells, whereas the miR-30a-5p inhibition showed the opposite tendency (all P < 0.05). Besides, miR-30a-5p may be involved in these oncogenic processes through the upregulation of ZEB2 and LDH2. CONCLUSION: Our results demonstrate that exosome-transmitted miRNA-30a-5p promotes the malignant behavior of OC cells, which may be served as a promising diagnostic and prognostic marker for patients with OC.

Targeting CK2-mediated phosphorylation of p53R2 sensitizes BRCA-proficient cancer cells to PARP inhibitors.

Poly[ADP-ribose] polymerase (PARP) inhibitors, which selectively kills homologous recombination (HR) repair-deficient cancer cells, are widely employed to treat cancer patients harboring BRCA1/2 mutations. However, they display limited efficacy in tumors with wild-type (WT) BRCA1/2. Thus, it is crucial to identify new druggable HR repair regulators and improve the therapeutic efficacy of PARP inhibitors via combination therapies in BRCA1/2-WT tumors. Here, we show that the depletion of ribonucleotide reductase (RNR) subunit p53R2 impairs HR repair and sensitizes BRCA1/2-WT cancer cells to PARP inhibition. We further demonstrate that the loss of p53R2 leads to a decrease of HR repair factor CtIP, as a result of dNTPs shortage-induced ubiquitination of CtIP. Moreover, we identify that casein kinase II (CK2) phosphorylates p53R2 at its ser20, which subsequently activates RNR for dNTPs production. Therefore, pharmacologic inhibition of the CK2-mediated phosphorylation of p53R2 compromises its HR repair capacity in BRCA1/2-WT cancer cells, which renders these cells susceptible to PARP inhibition in vitro and in vivo. Therefore, our study reveals a novel strategy to inhibit HR repair activity and convert BRCA1/2-proficient cancers to be susceptible to PARP inhibitors via synthetic lethal combination.

Pelvic floor dysfunction in gynecologic cancer survivors.

Pelvic floor dysfunction (PFD) is a common complication in gynecologic cancer survivors (GCS) and is now a worldwide medical and public health problem because of its great impact on the quality of life of GCS. PFD after comprehensive gynecologic cancer treatment is mainly reflected in bladder function, rectal function, sexual dysfunction and pelvic organ prolapse (POP), of which different types of gynecologic cancer correspond to different disease incidence. The prevention strategies of PFD after comprehensive gynecologic cancer treatment mainly included surgical treatment, physical therapy and behavioral guidance, etc. At present, most of them still focus on physical therapy, mostly using Pelvic Floor Muscle Training (PFMT) and multi-modal PFMT treatment of biofeedback combined with electrical stimulation, which can reduce the possibility of PFD after surgery in GCS to some extent. This article reviews the clinical manifestations, causes and current research progress of prevention and treatment methods of PFD after comprehensive treatment for GCS.

High uterosacral ligament suspension in radical hysterectomy: a step-by-step procedure to prevent pelvic organ prolapse.

INTRODUCTION AND HYPOTHESIS: Given the younger age of cervical cancer patients and improved postoperative survival, postoperative quality of life should be a reason for concern, particularly given the prevalence of pelvic floor dysfunction. High uterosacral ligament suspension (HUS) has been deemed the more consistently successful surgery for the treatment of mid-pelvic abnormalities. HUS intraoperatively prevents pelvic floor dysfunction effectively. METHODS: We demonstrate the steps of surgery using surgical video and photographs. The uterosacral ligament is fan shaped and connected to the fascial and extraosseous membranes on the surface of the anterior sacral foramen of the 2nd, 3rd, and 4th sacral vertebrae. Given that the uterosacral ligament was fan-shaped, the fan-shaped suture with three stitches was more compatible with the original anatomy. RESULTS: Thirty patients with HUS who underwent thorough hysterectomy had no complications, operation time 230.82 ± 43.61 min, and blood loss 62.32 ± 37.25 ml. The urinary catheter was successfully removed 1 week after the operation, and no pelvic organ prolapse, including vaginal anterior and posterior wall prolapse, or rectocele, occurred after 3 years of follow-up. CONCLUSION: The uterosacral ligament fulfills the role of supporting, pulling, and suspending the uterus. We should exploit the advantage of fully exposing the uterosacral ligament in radical hysterectomy. Performing HUS to prevent pelvic organ prolapse following radical hysterectomy is a procedure worthy of investigation and promotion.

Development of the nonreceptor tyrosine kinase FER-targeting PROTACs as a potential strategy for antagonizing ovarian cancer cell motility and invasiveness.

Aberrant overexpression of nonreceptor tyrosine kinase FER (Fps/Fes Related) has been reported in various ovarian carcinoma-derived tumor cells and is a poor prognosis factor for patient survival. It plays an essential role in tumor cell migration and invasion, acting concurrently in both kinase-dependent and -independent manners, which is not easily suppressed by conventional enzymatic inhibitors. Nevertheless, the PROteolysis-TArgeting Chimera (PROTAC) technology offers superior efficacy over traditional activity-based inhibitors by simultaneously targeting enzymatic and scaffold functions. Hence in this study, we report the development of two PROTAC compounds that promote robust FER degradation in a cereblon-dependent manner. Both PROTAC degraders outperform a Food and Drug Administration-approved drug, brigatinib, in ovarian cancer cell motility suppression. Importantly, these PROTAC compounds also degrade multiple oncogenic FER fusion proteins identified in human tumor samples. These results lay an experimental foundation to apply the PROTAC strategy to antagonize cell motility and invasiveness in ovarian and other types of cancers with aberrant expression of FER kinase and highlight PROTACs as a superior strategy for targeting proteins with multiple tumor-promoting functions.

A signature based on glycosyltransferase genes provides a promising tool for the prediction of prognosis and immunotherapy responsiveness in ovarian cancer.

BACKGROUND: Ovarian cancer (OC) is the most fatal gynaecological malignancy and has a poor prognosis. Glycosylation, the biosynthetic process that depends on specific glycosyltransferases (GTs), has recently attracted increasing importance due to the vital role it plays in cancer. In this study, we aimed to determine whether OC patients could be stratified by glycosyltransferase gene profiles to better predict the prognosis and efficiency of immune checkpoint blockade therapies (ICBs). METHODS: We retrieved transcriptome data across 420 OC and 88 normal tissue samples using The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, respectively. An external validation dataset containing 185 OC samples was downloaded from the Gene Expression Omnibus (GEO) database. Knockdown and pathway prediction of B4GALT5 were conducted to investigate the function and mechanism of B4GALT5 in OC proliferation, migration and invasion. RESULTS: A total of 50 differentially expressed GT genes were identified between OC and normal ovarian tissues. Two clusters were stratified by operating consensus clustering, but no significant prognostic value was observed. By applying the least absolute shrinkage and selection operator (LASSO) Cox regression method, a 6-gene signature was built that classified OC patients in the TCGA cohort into a low- or high-risk group. Patients with high scores had a worse prognosis than those with low scores. This risk signature was further validated in an external GEO dataset. Furthermore, the risk score was an independent risk predictor, and a nomogram was created to improve the accuracy of prognostic classification. Notably, the low-risk OC patients exhibited a higher degree of antitumor immune cell infiltration and a superior response to ICBs. B4GALT5, one of six hub genes, was identified as a regulator of proliferation, migration and invasion in OC. CONCLUSION: Taken together, we established a reliable GT-gene-based signature to predict prognosis, immune status and identify OC patients who would benefit from ICBs. GT genes might be a promising biomarker for OC progression and a potential therapeutic target for OC.

Association of ERCC1 rs11615 Polymorphism with the Risk of Cervical Cancer Especially in Chinese Populations: A Meta-Analysis.

Abnormalities of the ERCC1 gene can affect DNA repair pathways, thereby having a vital effect on genomic stability. A growing amount of case-control studies have focused on making an investigation of the association between ERCC1 rs11615 polymorphism and cervical cancer susceptibility. However, the controversial results have raised concerns. To draw a more accurate conclusion, six studies were elaborately selected from the electronic databases for this meta-analysis, with 753 cervical cancer cases and 851 healthy controls. We applied pooled ORs combined with 95% CIs to test the potential associations. Significant associations were revealed in Chinese populations (T vs C: OR = 1.557 and 95%CI = 1.234-1.966; TT vs CC: OR = 3.175 and 95%CI = 1.754-5.748; TT/CT vs CC: OR = 1.512 and 95%CI = 1.126-2,031; and TT vs CT/CC: OR = 2.836 and 95%CI = 1.592-5.051). Even when the studies deviating from HWE were excluded, an increased cervical cancer susceptibility was observed in Chinese. These results disclose that there is an obvious correlation between the risk of cervical cancer and ERCC1 rs11615 polymorphism, especially in Chinese populations, and the T variant is the risky one. Also, our findings need further studies to validate.

FER-mediated phosphorylation and PIK3R2 recruitment on IRS4 promotes AKT activation and tumorigenesis in ovarian cancer cells.

Tyrosine phosphorylation, orchestrated by tyrosine kinases and phosphatases, modulates a multi-layered signaling network in a time- and space-dependent manner. Dysregulation of this post-translational modification is inevitably associated with pathological diseases. Our previous work has demonstrated that non-receptor tyrosine kinase FER is upregulated in ovarian cancer, knocking down which attenuates metastatic phenotypes. However, due to the limited number of known substrates in the ovarian cancer context, the molecular basis for its pro-proliferation activity remains enigmatic. Here, we employed mass spectrometry and biochemical approaches to identify insulin receptor substrate 4 (IRS4) as a novel substrate of FER. FER engaged its kinase domain to associate with the PH and PTB domains of IRS4. Using a proximity-based tagging system in ovarian carcinoma-derived OVCAR-5 cells, we determined that FER-mediated phosphorylation of Tyr779 enables IRS4 to recruit PIK3R2/p85ß, the regulatory subunit of PI3K, and activate the PI3K-AKT pathway. Rescuing IRS4-null ovarian tumor cells with phosphorylation-defective mutant, but not WT IRS4 delayed ovarian tumor cell proliferation both in vitro and in vivo. Overall, we revealed a kinase-substrate mode between FER and IRS4, and the pharmacological inhibition of FER kinase may be beneficial for ovarian cancer patients with PI3K-AKT hyperactivation.

Progress in Applicability of Scoring Systems Based on Nutritional and Inflammatory Parameters for Ovarian Cancer.

Ovarian cancer is a malignancy that seriously endangers women's health; its case fatality rate ranks first among the gynecological malignancies. The status of nutrition of ovarian cancer patients is related to their prognoses. Thus, it is important to evaluate, monitor, and improve the nutritional status of ovarian cancer patients during their treatment. Currently, there are several tools for examining malnutrition and nutritional assessment, including NRI (nutrition risk index), PG-SGA (patient-generated subjective global assessment), and NRS 2002 (nutritional risk screening 2002). In addition to malnutrition risk examination and related assessment tools, the evaluation of muscle mass, C-reactive protein, lymphocytes, and other inflammation status indicators, such as neutrophils to lymphocytes ratio, lymphocyte-to-monocyte ratio, and C-reactive protein-albumin ratio, is of great importance. The nutritional status of ovarian cancer patients undergoing surgery affects their postoperative complications and survival rates. Accurate evaluation of perioperative nutrition in ovarian cancer patients is crucial in clinical settings. An intelligent nutritional diagnosis can be developed based on the results of its systematic and comprehensive assessment, which would lay a foundation for the implementation of personalized and precise nutritional therapy.

Research Status and Progress of Nutritional Support Therapy for Ovarian Cancer.

Ovarian cancer is one of the most fatal gynecological cancers. For most ovarian cancer patients, nutritional risk or malnutrition may accompany them for life. Regular nutritional risk screening, timely nutritional assessment and necessary nutritional treatment play an extremely important role in the process of comprehensive treatment of ovarian cancer. The nutritional status and influence of ovarian cancer patients, preoperative screening and assessment of nutritional risk, preoperative and postoperative nutritional treatment indicate that nutritional treatment of ovarian cancer is one of the key factors in the treatment of cancer. We have summarized the status and progress of nutritional support therapy for ovarian cancer. We are aimed to improve the understanding of the impact of nutritional support therapy for ovarian cancer and to guide the clinical work.

NAD+ supplement potentiates tumor-killing function by rescuing defective TUB-mediated NAMPT transcription in tumor-infiltrated T cells.

Although tumor-infiltrating lymphocytes (TILs) maintain their ability to proliferate, persist, and eradicate tumors, they are frequently dysfunctional in situ. By performing both whole-genome CRISPR and metabolic inhibitor screens, we identify that nicotinamide phosphoribosyltransferase (NAMPT) is required for T cell activation. NAMPT is low in TILs, and its expression is controlled by the transcriptional factor Tubby (TUB), whose activity depends on the T cell receptor-phospholipase C gamma (TCR-PLCγ) signaling axis. The intracellular level of NAD+, whose synthesis is dependent on the NAMPT-mediated salvage pathway, is also decreased in TILs. Liquid chromatography-mass spectrometry (LC-MS) and isotopic labeling studies confirm that NAD+ depletion led to suppressed glycolysis, disrupted mitochondrial function, and dampened ATP synthesis. Excitingly, both adoptive CAR-T and anti-PD1 immune checkpoint blockade mouse models demonstrate that NAD+ supplementation enhanced the tumor-killing efficacy of T cells. Collectively, this study reveals that an impaired TCR-TUB-NAMPT-NAD+ axis leads to T cell dysfunction in the tumor microenvironment, and an over-the-counter nutrient supplement of NAD+ could boost T-cell-based immunotherapy.

TCF3 is epigenetically silenced by EZH2 and DNMT3B and functions as a tumor suppressor in endometrial cancer.

Endometrial cancer (EC) is the most common gynecological malignancy worldwide. However, the molecular mechanisms underlying EC progression are still largely unknown, and chemotherapeutic options for EC patients are currently very limited. In this study, we found that histone methyltransferase EZH2 and DNA methyltransferase DNMT3B were upregulated in EC samples from patients, and promoted EC cell proliferation as evidenced by assays of cell viability, cell cycle, colony formation. Mechanistically, we found that EZH2 promoted EC cell proliferation by epigenetically repressing TCF3, a direct transcriptional activator of CCKN1A (p21WAF1/Cip1), in vitro and in vivo. In addition, we found that DNMT3B specifically methylated the TCF3 promoter, repressing TCF3 expression and accelerating EC cell proliferation independently of EZH2. Importantly, elevated expression of EZH2 or DNMT3B in EC patients inversely correlated with expression of TCF3 and p21, and was associated with shorter overall survival. We show that combined treatment with GSK126 and 5-Aza-2d treatment wit synergistically inhibited methyltransferase activity of EZH2 and DNMT3B, resulting in a profound block of EC cell proliferation as well as EC tumor progression in cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) mouse models. These findings reveal that TCF3 functions as a tumor suppressor epigenetically silenced by EZH2 and DNMT3B in EC, and support the notion that targeting the EZH2/DNMT3B/TCF3/p21 axis may be a novel and effective therapeutic strategy for treatment of EC.

Identification of an immune signature to predict poor clinical outcome in cervical cancer.

Aim: To explore tumor immune microenvironment and identify immune prognostic-related circRNAs in cervical cancer. Materials & methods: RNA-seq in combination with bioinformatics were performed to establish a prognostic risk model and a circRNAs-miRNAs-CXCL8 network. Results: High-risk group correlated with poor survival outcome, and had lower PD-1 immunogenicity. Additionally, CXCL8 could distinguish normal tissue, low- and high-risk tumor tissues, the expression of which showed an increasing trend among the three groups. RNA-seq and bioinformatics indicated that circRNAs like hsa_circ_0025721 might upregulate CXCL8 through sponging miRNAs including hsa-miR-4428. Conclusion: We constructed an immune risk model related with CD8 T cells to predict the cervical cancer patients' prognosis and explored the abnormal expression mechanism of CXCL8 through the ceRNA mechanism.

OPCML Methylation and the Risk of Ovarian Cancer: A Meta and Bioinformatics Analysis.

Background: The association of opioid binding protein cell adhesion molecule-like (OPCML) gene methylation with ovarian cancer risk remains unclear. Methods: We identified eligible studies by searching the PubMed, Web of Science, ScienceDirect, and Wanfang databases. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to determine the association of OPCML methylation with ovarian cancer risk. Meta-regression and subgroup analysis were used to assess the sources of heterogeneity. Additionally, we analyzed the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets to validate our findings. Results: Our study included 476 ovarian cancer patients and 385 controls from eight eligible studies. The pooled OR was 33.47 (95% CI = 12.43-90.16) in the cancer group vs. the control group under the random-effects model. The association was still significant in subgroups according to sample type, control type, methods, and sample sizes (all P < 0.05). Sensitivity analysis showed that the finding was robust. No publication bias was observed in Begg's (P = 0.458) and Egger's tests (P = 0.261). We further found that OPCML methylation was related to III/IV (OR = 4.20, 95% CI = 1.59-11.14) and poorly differentiated grade (OR = 4.37; 95% CI = 1.14-16.78). Based on GSE146552 and GSE155760, we validated that three CpG sites (cg16639665, cg23236270, cg15964611) in OPCML promoter region were significantly higher in cancer tissues compared to normal tissues. However, we did not observe the associations of OPCML methylation with clinicopathological parameters and overall survival based on TCGA ovarian cancer data. Conclusion: Our findings support that OPCML methylation is associated with an increased risk of ovarian cancer.

Characteristics and clinical trial results of agonistic anti-CD40 antibodies in the treatment of malignancies.

Cluster of differentiation 40 (CD40) mediates many immune activities. Preclinical studies have shown that activation of CD40 can evoke massive antineoplastic effects in several tumour models in vivo, providing a rationale for using CD40 agonists in cancer immunotherapy. To date, several potential agonistic antibodies that target CD40 have been investigated in clinical trials. Early clinical trials have shown that the adverse events associated with agonists of CD40 thus far have been largely transient and clinically controllable, including storms of cytokine release, hepatotoxicity and thromboembolic events. An antitumour effect of targeting CD40 for monotherapy or combination therapy has been observed in some tumours. However, these antitumour effects have been moderate. The present review aimed to provide updated details of the clinical results of these agonists, and offer information to further investigate the strategies of combining CD40 activation with chemotherapy, radiotherapy, targeted therapy and immunomodulators. Furthermore, biomarkers should be identified for monitoring and predicting responses and informing resistance mechanisms.

Prognosis prediction signature of seven immune genes based on HPV status in cervical cancer.

Cervical cancer (CC) has a high incidence and mortality rate, with a low 5-year survival rate, and human papillomavirus (HPV) is one of its carcinogenic risks. However, little evidence exists on the impact of HPV infection on the survival of patients with CC. In the present study, the CC cohort and immune genes were downloaded from the TCGA database and the ImmPort database, respectively. Subsequently, the Gene Set Enrichment Analysis was performed and found that HPV status was involved in multiple immune signaling pathways, which revealed that HPV infection might play critical roles in the immune response. Then seven prognostic immune genes were identified according to HPV status in CC. Using the seven immune genes, we established an immune risk score (IRS) signature and the Kaplan-Meier curve showed that high IRS was significantly correlated with poor prognosis of CC in both the training sets (HR = 2.32, 95% CI = 1.66-3.33; AUC = 0.712) and the validation sets (HR = 1.38, 95% CI = 1.02-1.85 and AUC = 0.583 in TCGA-HNSCC; HR = 2.58, 95% CI = 1.364-4.893, AUC = 0.676 in GSE44001). A nomogram of IRS combined with clinical features was established, and further analyses demonstrated that the power of the nomogram to predict the prognosis of CC was more reliable than that of a single independent factor. In conclusion, this study provided a more comprehensive understanding of the correlation between HPV and immune mechanisms as well as a novel signature that can effectively predict the prognosis of CC patients.

Identification of Potential Prognostic Long Non-Coding RNA Biomarkers for Predicting Recurrence in Patients with Cervical Cancer.

BACKGROUND: Cervical cancer (CC) is one of the most common malignant tumors in women, and its treatment is often accompanied by high recurrence. We aimed to identify the long non-coding RNAs (lncRNAs) associated with CC recurrence. METHODS: We downloaded lncRNAs expression data of CC patients from The Cancer Genome Atlas (TCGA) dataset and used Cox regression models to analyze the lncRNAs relationship with CC recurrence. The significantly associated lncRNAs were utilized to construct a recurrence risk score (RRS) model. Bioinformatics analyses were used to assess the potential role of the critical lncRNAs in CC recurrence. The effect of critical lncRNAs on CC phenotype was determined by in vitro experiments. RESULTS: Using Cox regression analysis, four lncRNAs, ie, HCG11, CASC15, LINC00189, and LINC00905, were markedly associated with worse recurrence-free survival (RFS) of CC, whereas three lncRNAs, including HULC, LINC00173, and MIR22HG, were the opposite. After constructing the RRS model, Kaplan-Meier analysis revealed that patients with high RRS had significantly increased risk of recurrence. Among the 20 types of tumors in the TCGA database which all had adjacent normal tissues, MIR22HG and HCG11were significantly downregulated in 18 and 10 types of tumors including CC, respectively. Increased MIR22HG was significantly relevant to decreased risks of recurrence among the subgroups of age at diagnosis < 45 (Hazard Ratio (HR) = 0.26), stage I/II (HR = 0.33), T stage I/II (HR = 0.30), chemotherapy (HR = 0.18), and molecular therapy (HR = 0.16). Functionally, elevated MIR22HG expression could suppress CC cell proliferation, migration and invasion. CONCLUSION: MIR22HG has a fundamental role in CC recurrence and could be served as a potential prognostic biomarker.

Integrated Microfluidic Device for Accurate Extracellular Vesicle Quantification and Protein Markers Analysis Directly from Human Whole Blood.

Extracellular vesicles (EVs) have the potential to be utilized as disease-specific biomarkers. Although strategies for on-chip isolation and detection of EVs have recently been developed, they need preprocessing of clinical samples and are not accurate enough for disease diagnosis just judging by EVs concentration. Here, we designed an integrated microfluidic device named a plasma separation and EV detection (PS-ED) chip for plasma separation, quantification, and high-throughput protein analysis of EVs directly from clinical whole blood samples. The device included two modules (PS and ED module): the PS module was a six-loop microchannel for rapid separation of plasma from clinical whole blood samples under inertial force; the amount of EVs in the separated plasma kept the same value as in the initial blood samples. The module reduced the mechanical damage to the blood cells and thus reduced the interference of debris or cellular contents from damaged cells during EVs detection; the ED module contained four S-channels for quantification and high-throughput protein analysis of EVs; a wide detection range from 2.5 × 102 to 2.5 × 108 particles/µL with a detection limit of 95 particles/µL was obtained. Through simultanously monitoring three proteins (CD81, CD24, and EpCAM) of EVs, the cancer type can be accurately confirmed. Furthermore, clinical blood sample analysis verified that the proposed device could be used for accurate diagnosis and therapy monitoring of ovarian cancer.

Protein tyrosine phosphatase receptor type R (PTPRR) antagonizes the Wnt signaling pathway in ovarian cancer by dephosphorylating and inactivating ß-catenin.

Despite a lack of mutations, accumulating evidence supports an important role for the Wnt/ß-catenin pathway in ovarian tumorigenesis. However, the molecular mechanism that contributes to the aberrant activation of the Wnt signaling cascade in ovarian cancer has not been fully elucidated. Here, we found that protein tyrosine phosphatase receptor type R (PTPRR) suppressed the activation of the Wnt/ß-catenin pathway in ovarian cancer. We performed an shRNA-based biochemical screen, which identified PTPRR as being responsible for tyrosine dephosphorylation of ß-catenin on Tyr-142, a key site controlling the transcriptional activity of ß-catenin. Of note, PTPRR was down-regulated in ovarian cancers, and ectopic PTPRR re-expression delayed ovarian cancer cell growth both in vitro and in vivo Using a proximity-based tagging system and RNA-Seq analysis, we identified a signaling nexus that includes PTPRR, α-catenin, ß-catenin, E-cadherin, and AT-rich interaction domain 3C (ARID3C) in ovarian cancer. Immunohistochemistry staining of human samples further suggested that PTPRR expression is inversely correlated with disease prognosis. Collectively, our findings indicate that PTPRR functions as a tumor suppressor in ovarian cancer by dephosphorylating and inactivating ß-catenin. These results suggest that PTPRR expression might have utility as a prognostic marker for predicting overall survival.

Telomere length in cervical exfoliated cells, interaction with HPV genotype, and cervical cancer occurrence among high-risk HPV-positive women.

BACKGROUND: Although high-risk human papillomavirus (HR-HPV) infection is recognized as the main cause of cervical cancer, only a minority of HPV-infected women develop this malignancy. Increasing evidence suggests that alterations of telomere length might be implicated in carcinogenesis. However, the association between cervical cancer and telomere length remains unknown. METHODS: This case-control study included 591 cervical cancer patients and 373 cancer-free controls, all of whom were infected with HR-HPV. Relative telomere length (RTL) in cervical cancer exfoliated cells was measured by quantitative PCR. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression analysis. RESULTS: HPV16, 18, 52, and 58 were common in both case and control groups. The proportion of HPV16 infection tended to increase across the quartiles of RTL (Ptrend  < 0.001). There was no statistically significant association of RTL with tumor differentiation, histological type, and FIGO stage. After adjustment for age and HPV types, the lowest quartile of RTL presented a 49% lower risk (OR = 0.51, 95% CI: 0.35, 0.76; P < 0.001) than those with the highest quartile of RTL. There was also a dose-response relationship of shorter RTL on lower risk of cervical cancer (Ptrend  < 0.001). CONCLUSION: Shortened telomere length in cervical exfoliated cells was related to the lower risk of cervical cancer among HR-HPV-positive women, which might help to improve cervical cancer screening and surveillance. Further prospective studies with large sample should be designed to validate our preliminary findings, and evaluate the potential efficacy of telomere length for cervical cancer screening.