Surgical approaches to congenital diaphragmatic hernia.

Surgical repair of the diaphragm is essential for survival in congenital diaphragmatic hernia (CDH). There are many considerations surrounding the operation - why the operation matters, optimal timing of repair and its relation to extracorporeal life support (ECLS) use, minimally invasive versus open approaches, and strategies for reconstruction. Surgery is both affected by, and affects, the physiology of these infants and is an important factor in determining long-term outcomes. Here we discuss the evidence and provide insight surrounding this complex decision making, technical pearls, and outcomes in repair of CDH.

ATM, BLM, and CDH1 gene co-mutations in a high-grade endometrial stromal sarcoma patient with multiple abdominal cavity metastases: a case report and literature review.

BACKGROUND: High-grade endometrial stromal sarcoma (HG-ESS) is a rare malignant tumor with poor prognosis. To overcome the limitations of current treatment for advanced patients, the intervention of targeted drug therapy is urgently needed. CASE PRESENTATION: A 74-year-old married woman who presented with abdominal distension and lower abdominal pain was admitted to Hebei General Hospital. After surgery, immunohistochemical staining revealed a malignant tumor which was consistent with HG-ESS. Tumor recurrence occurred 2 months after surgery. Then the patient underwent chemotherapy with two courses but responded poorly. Subsequently we observed ATM, BLM, and CDH1 co-mutations by Next Generation Sequencing (NGS). Then the patient received pamiparib, which resulted in a 10-month progression-free survival (PFS) and is now stable with the administration of sintilimab in combination with pamiparib and anlotinib. CONCLUSIONS: Due to the successful use of poly ADP-ribose polymerase inhibitor (PARPi) on HG-ESS, we suggest that the selection of effective targeted drugs combined with anti- programmed death-1 (PD-1) drug therapy based on genetic testing may become a new option for the treatment of homologous repair deficient (HR-deficient) HG-ESS.

Congenital diaphragmatic hernia-associated pulmonary hypertension.

Congenital diaphragmatic hernia (CDH) is characterized by a developmental insult which compromises cardiopulmonary embryology and results in a diaphragmatic defect, allowing abdominal organs to herniate into the hemithorax. Among the significant pathophysiologic components of this condition is pulmonary hypertension (PH), alongside pulmonary hypoplasia and cardiac dysfunction. Fetal pulmonary vascular development coincides with lung development, with the pulmonary vasculature evolving alongside lung maturation. However, in CDH, this embryologic development is impaired which, in conjunction with external compression, stifle pulmonary vascular maturation, leading to reduced lung density, increased muscularization of the pulmonary vasculature, abnormal vascular responsiveness, and altered molecular signaling, all contributing to pulmonary arterial hypertension. Understanding CDH-associated PH (CDH-PH) is crucial for development of novel approaches and effective management due to its significant impact on morbidity and mortality. Antenatal and postnatal diagnostic methods aid in CDH risk stratification and, specifically, pulmonary hypertension, including fetal imaging and gas exchange assessments. Management strategies include lung protective ventilation, fluid optimization, pharmacotherapies including pulmonary vasodilators and hemodynamic support, and extracorporeal life support (ECLS) for refractory cases. Longitudinal re-evaluation is an important consideration due to the complexity and dynamic nature of CDH cardiopulmonary physiology. Emerging therapies such as fetal endoscopic tracheal occlusion and pharmacological interventions targeting key CDH pathophysiological mechanisms show promise but require further investigation. The complexity of CDH-PH underscores the importance of a multidisciplinary approach for optimal patient care and improved outcomes.

Long-term follow-up in congenital diaphragmatic hernia.

With improvements in initial care for patients with congenital diaphragmatic hernia (CDH), the number of CDH patients with severe disease who are surviving to discharge has increased. This growing population of patients faces a unique set of long-term challenges, multisystem adverse outcomes, and post-intervention complications requiring specialized multidisciplinary follow-up. Early identification and intervention are essential to mitigate the potential morbidity associated with these challenges. This manuscript outlines a general framework for long-term follow-up for the CDH patient, including cardiopulmonary, gastrointestinal, neurodevelopmental, surgical, and quality of life outcomes.

Elevating PLK1 overcomes BETi resistance in prostate cancer via triggering BRD4 phosphorylation-dependent degradation in mitosis.

Bromodomain-containing protein 4 (BRD4) has emerged as a promising therapeutic target in prostate cancer (PCa). Understanding the mechanisms of BRD4 stability could enhance the clinical response to BRD4-targeted therapy. In this study, we report that BRD4 protein levels are significantly decreased during mitosis in a PLK1-dependent manner. Mechanistically, we show that BRD4 is primarily phosphorylated at T1186 by the CDK1/cyclin B complex, recruiting PLK1 to phosphorylate BRD4 at S24/S1100, which are recognized by the APC/CCdh1 complex for proteasome pathway degradation. We find that PLK1 overexpression lowers SPOP mutation-stabilized BRD4, consequently rendering PCa cells re-sensitized to BRD4 inhibitors. Intriguingly, we report that sequential treatment of docetaxel and JQ1 resulted in significant inhibition of PCa. Collectively, the results support that PLK1-phosphorylated BRD4 triggers its degradation at M phase. Sequential treatment of docetaxel and JQ1 overcomes BRD4 accumulation-associated bromodomain and extra-terminal inhibitor (BETi) resistance, which may shed light on the development of strategies to treat PCa.

The role of ECLS in the management of congenital diaphragmatic hernia.

In the complex arena of Congenital Diaphragmatic Hernia (CDH) management, Extracorporeal Life Support (ECLS) provides a strategic window for stabilization and surgical correction, during which time marginal gains in patient stability can tip the scales towards survival. In modern neonatal ECLS, the focus is increasingly on minimizing survivor morbidity, which calls for considerable multidisciplinary expertise to enhance patient outcomes. This review will delve into the most up-to-date literature on the management of CDH in the context of ECLS, providing a comprehensive synthesis of current insights.

Racial Inequalities in the Initial Management of Congenital Diaphragmatic Hernia in the Houston Area.

INTRODUCTION: Congenital diaphragmatic hernia (CDH) is readily prenatally diagnosed and associated with significant perinatal morbidity and mortality. Delivery at facilities with adequate resources for neonatal resuscitation, such as Children's Surgery Verification (CSV) centers, is recommended; however, disparities have been clinically noted. We aimed to characterize locoregional care of CDH and the impact of race and ethnicity. METHODS: We conducted a population-based study using the Texas Inpatient Public Use Data File to identify infants <1 y-old with CDH based on international classification of diseases 9/10 codes (2013-2021). Only initial birth admissions in the Houston region were included. Data was analyzed using descriptive statistics and chi-squared analysis. RESULTS: We identified 257 newborns with CDH. While births were noted across 29 facilities, the majority were at the 2 CSV centers in Houston. There was no significant difference in illness severity, prematurity or insurance status by race. Black and 'other' patients were less likely to deliver at CSV facilities (Black 32% versus 'Other' 48% versus White 70% versus Asian 81%; P < 0.01), receive ECMO (Black 6% versus 'Other' 5% versus White 19% versus Asian 29%; P < 0.01) or undergo a CDH repair (Black 26% versus 'Other' 33% versus White 51% versus Asian 71%; P < 0.01) on their index admission and had lower average daily costs (Black $10,292 [$3219-25,021] versus 'Other' $9106 [$3617-15,672] versus White $12,906 [$9038-18,550] versus Asian $12,896 [$7469-23,817]; P < 0.05). Additionally, black and 'other' patients were more likely to be transferred (Black 23% versus 'Other' 28% versus White 12% versus Asian 14%; P < 0.05). None of the patients born at CSV centers transferred. CONCLUSIONS: Most Houston-born patients deliver at high-resource centers; however, Black and 'other' patients are less likely to deliver at CSV centers and more likely to require transfer during the critical neonatal period. This suggests a vulnerable population which may benefit from targeted intervention to improve prenatal care and delivery planning.

Target Identification and Mechanistic Characterization of Indole Terpenoid Mimics: Proper Spindle Microtubule Assembly Is Essential for Cdh1-Mediated Proteolysis of CENP-A.

Centromere protein A (CENP-A), a histone H3 variant specific to centromeres, is crucial for kinetochore positioning and chromosome segregation. However, its regulatory mechanism in human cells remains incompletely understood. A structure-activity relationship (SAR) study of the cell-cycle-arresting indole terpenoid mimic JP18 leads to the discovery of two more potent analogs, (+)-6-Br-JP18 and (+)-6-Cl-JP18. Tubulin is identified as a potential cellular target of these halogenated analogs by using the drug affinity responsive target stability (DARTS) based method. X-ray crystallography analysis reveals that both molecules bind to the colchicine-binding site of ß-tubulin. Treatment of human cells with microtubule-targeting agents (MTAs), including these two compounds, results in CENP-A accumulation by destabilizing Cdh1, a co-activator of the anaphase-promoting complex/cyclosome (APC/C) E3 ubiquitin ligase. This study establishes a link between microtubule dynamics and CENP-A accumulation using small-molecule tools and highlights the role of Cdh1 in CENP-A proteolysis.

Detection of CDH1 gene promoter hypermethylation in gastric cancer and chronic gastritis.

Aim: The current study aimed to assess the frequency of CDH1 promoter gene hypermethylation in gastric cancer and chronic gastritis and its correlation with clinicopathological aspects. Methods: Methylation-specific PCR was used to detect CDH1 promoter gene hypermethylation in 53 chronic gastritis patients and 40 gastric cancer patients along with normal adjacent tissues. Results: The chronic gastritis group comprised 29 males and 24 females with a mean age of 51.8 ± 12.96 years, and 49.1 % of them were positive for H. pylori infection. The frequency of CDH1 hypermethylation in gastritis lesions was 18.8 %. CDH1 hypermethylation showed a significant correlation with H. pylori infection (p = 0.039), but no significant association was observed with other clinical features. The gastric cancer group consisted of individuals with a mean age of 65.4 ± 10.6, among them, 77.5 % were male and 22.5 % were female, 62.5 % had PT3 tumors, 40 % had PN1 lymph node involvement, and the majority (47.5 %) of samples were obtained from body segment. CDH1 hypermethylation was significantly associated with depth of invasion (p = 0.017) and nodal invasion (p = 0.041) in this group. In both groups, normal adjacent specimens lacked CDH1 hypermethylation, and there was no statistically significant correlation between CDH1 hypermethylation and age at which the tumor was diagnosed, gender, activity level, or tumor location. Conclusion: This study demonstrates that E-cadherin methylation is associated with some characteristics of chronic gastritis and gastric cancer. These findings support previous research indicating that CDH1 hypermethylation may play a significant role in the development of gastric cancer.

Right-Sided Ectopic Intrathoracic Kidney Associated With Symptomatic Bochdalek Hernia in an Adult Indian Female: Case Report and Review of Literature.

Bochdalek hernia is an inherited posterior lateral defect in the diaphragm that allows the abdominal organs to herniate into the thoracic cavity. In addition to being the most prevalent variety of congenital diaphragmatic hernia (CDH), it is also the type that is observed on the left hemithorax the majority of the time. Ectopic kidney is an uncommon condition, and the occurrence of ectopic intrathoracic kidney is even more uncommon, accounting for only a few of all the cases of renal ectopias. The occurrence of intrathoracic kidney associated with Bochdalek hernia is infrequent among adult individuals and is typically an incidental finding. A 52-year-old obese female patient presented to the pulmonology outpatient unit and reported experiencing the symptoms of coughing, wheezing, and difficulty in breathing since three years. A chest radiograph revealed an elevated dome of the diaphragm on the right side. A computed tomography (CT) of the chest revealed a defect in the posterior aspect of the right hemi-diaphragm with herniation of the right kidney and retroperitoneal fat into the right hemi-thorax. CT urography showed normal size and enhancement of the intrathoracic kidney with prompt excretion of contrast into the pelvicalyceal system. With regard to the small size of the hernia and considering the absence of complications on CT urography, a conservative treatment was proposed to the patient. The patient was followed up every year. There was no occurrence of renal complications during the follow-up period. When evaluating patients with 'elevated hemi-diaphragm' or thoracic 'mass', it is essential to check for the presence of intrathoracic kidney to avoid undesirable surgical procedures and image-guided biopsies.

Left atrial strain in neonates with congenital diaphragmatic hernia and length of stay in pediatric intensive care unit.

Introduction: The role of cardiac left ventricle (LV) dysfunction in children with congenital diaphragmatic hernia (CDH) has gained increasing attention. The hernia allows abdominal mass to enter thorax and subsequently both dislocating and compressing the heart. The pressure on vessels and myocardium alters blood flow and may interfere with normal development of the LV. A dysfunctional LV is concerning and impacts the complex pathophysiology of CDH. Hence, assessing both the systolic and diastolic LV function in the newborn with CDH is important, and it may add value for medical treatment and prognostic factors as length of stay (LOS) in pediatric intensive care unit (PICU). LV strain is considered an early marker of systolic dysfunction used in the pediatric population. Left atrial (LA) strain is an echocardiographic marker of LV diastolic dysfunction used in the adult population. When filling pressure of the LV increases, the strain of the atrial wall is decreased. We hypothesized that reduced LA strain and LV strain are correlated with the LOS in the PICU of newborns with CDH. Methods: This retrospective observational cohort study included data of 55 children born with CDH between 2018 and 2020 and treated at Karolinska University Hospital, Sweden. Overall, 46 parents provided consent. Echocardiograms were performed in 35 children <72 h after birth. The LA reservoir strain (LASr), LV global longitudinal strain, LV dimensions, and direction of blood flow through the patent foramen ovale (PFO) were retrospectively assessed using the echocardiograms. Results: Children with LASr <33% (n = 27) had longer stays in the PICU than children with LA strain ≥33% (n = 8) (mean: 20.8 vs. 8.6 days; p < 0.002). The LASr was correlated with the LOS in the PICU (correlation coefficient: -0.378; p = 0.025). The LV dimension was correlated with the LOS (correlation coefficient: -0.546; p = 0.01). However, LV strain was not correlated to LOS. Conclusion: Newborns with CDH and a lower LASr (<33%) had longer stays in the PICU than children with LASr ≥33%. LASr is a feasible echocardiographic marker of diastolic LV dysfunction in newborns with CDH and may indicate the severity of the condition.

Droplet digital PCR analysis of CDH13 methylation status in Slovak women with invasive ductal breast cancer.

Identifying novel epigenetic biomarkers is a promising way to improve the clinical management of patients with breast cancer. Our study aimed to determine the methylation pattern of 25 tumor suppressor genes (TSG) and select the best methylation biomarker associated with clinicopathological features in the cohort of Slovak patients diagnosed with invasive ductal carcinoma (IDC). Overall, 166 formalin-fixed, paraffin-embedded (FFPE) tissues obtained from patients with IDC were included in the study. The methylation status of the promoter regions of 25 TSG was analyzed using semiquantitative methylation-specific MLPA (MS-MLPA). We identified CDH13 as the most frequently methylated gene in our cohort of patients. Further analysis by ddPCR confirmed an increased level of methylation in the promoter region of CDH13. A significant difference in CDH13 methylation levels was observed between IDC molecular subtypes LUM A versus HER2 (P = 0.0116) and HER2 versus TNBC (P = 0.0234). In addition, significantly higher methylation was detected in HER2+ versus HER2- tumors (P = 0.0004) and PR- versus PR+ tumors (P = 0.0421). Our results provide evidence that alteration in CDH13 methylation is associated with clinicopathological features in the cohort of Slovak patients with IDC. In addition, using ddPCR as a methylation-sensitive method represents a promising approach characterized by higher precision and technical simplicity to measure the methylation of target CpGs in CDH13 compared to other conventional methods such as MS-MLPA.

CDH1 methylation analysis in invasive lobular breast carcinomas with and without gene mutation.

The proposed role of CDH1 (E-cadherin gene) methylation as a mechanism of gene inactivation in invasive lobular carcinoma (ILC) remains inconclusive. For many years, CDH1 promoter hypermethylation has been regarded as a mechanism for gene inactivation in ILC. However, this assumption has primarily relied on non-quantitative assays, which have reported CDH1 methylation frequencies ranging from 26 to 93% at CpG sites within the island region. Few studies employing quantitative methods and covering CpG island shores, regions of relatively low CpG density situated proximal to conventional promoter CpGs, have been conducted, revealing lower percentages of methylation ranging from 0 to 51%. Therefore, using the quantitative pyrosequencing method, we examined CDH1 methylation in the island region and shores in E-cadherin deficient ILC cases (15 with CDH1 mutation and 22 non-mutated), 19 cases of invasive breast carcinomas non-special type (IBC-NSTs), and five cases of usual ductal hyperplasia (UDH). Our analysis revealed CDH1 methylation frequencies ranging from 3 to 64%, with no significant increase in methylation levels in any group of ILCs (median = 12%) compared to IBC-NST (median = 15%). In addition, considering the poorly studied association between the number of tumor-infiltrating lymphocytes (TILs) and CDH1 methylation in breast cancer, we undertook a thorough analysis within our dataset. Our findings revealed a positive correlation between CDH1 methylation and the presence of TILs (r = 0.5; p-value < 0.05), shedding light on an aspect of breast cancer biology warranting further investigation. These findings challenge CDH1 methylation as a CDH1 inactivation mechanism in ILC and highlight TILs as a potential confounding factor in gene methylation.

Management advances for congenital diaphragmatic hernia: integrating prenatal and postnatal perspectives.

In congenital diaphragmatic hernia (CDH), abdominal organs are displaced into the chest, compress the lungs, and cause mediastinal shift. This contributes to development of pulmonary hypoplasia and hypertension, which is the primary determinant of morbidity and mortality for affected newborns. The severity is determined using prenatal imaging as early as the first trimester and is related to the laterality of the defect, extent of lung compression, and degree of liver herniation. Comprehensive evaluation of fetal CDH includes imaging-based severity assessment, severity assessment, and evaluation for structural or genetic abnormalities to differentiate isolated from complex cases. Prenatal management involves multispecialty counseling, consideration for fetal therapy with fetoscopic endoluminal tracheal occlusion (FETO) for severe cases, monitoring and intervention for associated polyhydramnios or signs of preterm labor if indicated, administration of antenatal corticosteroids in the appropriate setting, and planned delivery to optimize the fetal condition at birth. Integrated programs that provide a smooth transition from prenatal to postnatal care produce better outcomes. Neonatal care involves gentle ventilation to avoid hyperinflation and must account for transitional physiology to avoid exacerbating cardiac dysfunction and decompensation. Infants who have undergone and responded to FETO have greater pulmonary capacity than expected, but cardiac dysfunction seems unaffected. In about 25-30% of CDH neonates extracorporeal life support is utilized, and this provides a survival benefit for patients with the highest predicted mortality, including those who underwent FETO. Surgical repair after initial medical management for the first 24-48 hours of life is preferred since later repair is associated with delayed oral feeding, increased need for tube feeds, and increased post-repair ventilation requirement and supplemental oxygen at discharge. With overall survival rates >70%, contemporary care involves management of chronic morbidities in the context of a multidisciplinary clinic setting.

The Role of T-Cadherin (CDH13) in Treatment Options with Garcinol in Melanoma.

Targeted therapies with chemotherapeutic agents and immunotherapy with checkpoint inhibitors are among the systemic therapies recommended in the guidelines for clinicians to treat melanoma. Although there have been constant improvements in the treatment of melanoma, resistance to the established therapies continues to occur. Therefore, the purpose of this study was to explore the function of garcinol with regards to specific cancer properties such as proliferation and apoptosis. Garcinol, a natural compound isolated from the plant also known as mangosteen (Garcinia mangostana), is a newly discovered option for cancer treatment. Numerous pharmaceutical substances are derived from plants. For example, the derivates of camptothecin, extracted from the bark of the Chinese tree of happiness (Camptotheca acuminate), or paclitaxel, extracted from the bark of the Western yew tree (Taxus brevifolia), are used as anti-cancer drugs. Here, we show that garcinol reduced proliferation and induced apoptosis in melanoma cell lines. In addition, we found that those cells that are positive for the expression of the cell-cell adhesion molecule T-cadherin (CDH13) respond more sensitively to treatment with garcinol. After knock-down experiments with an siRNA pool against T-cadherin, the sensitivity to garcinol decreased and proliferation and anti-apoptotic behavior of the cells was restored. We conclude that patients who are T-cadherin-positive could especially benefit from a therapy with garcinol.

Gastrointestinal Cancer Precursor Conditions and Their Detection.

Gastrointestinal cancers are a leading cause of cancer morbidity and mortality. Many gastrointestinal cancers develop from cancer precursor lesions, which are commonly found in individuals with hereditary cancer syndromes. Hereditary cancer syndromes have advanced our understanding of cancer development and progression and have facilitated the evaluation of cancer prevention and interception efforts. Common gastrointestinal hereditary cancer syndromes, including their organ-specific cancer risk and surveillance recommendations, are reviewed in this article. The management of common gastroesophageal, pancreatic, and colonic precursor lesions is also discussed, regardless of their genetic background. Further research is needed to advance chemoprevention and immunoprevention strategies.

E-cadherin expression and gene expression profiles in corticotroph pituitary neuroendocrine tumor subtypes.

Corticotroph adenomas/pituitary neuroendocrine tumors (PitNETs) are associated with significant morbidity and mortality. Predictors of tumor behavior have not shown high prognostic accuracy. For somatotroph adenomas/PitNETs, E-cadherin expression correlates strongly with prognosis. E-cadherin expression has not been investigated in other PitNETs. A retrospective chart review of adults with corticotroph adenomas/PitNETs was conducted to assess correlation between E-cadherin expression and tumor characteristics. In addition, gene expression microarray was performed in subset of tumors (n = 16). Seventy-seven patients were identified; 71% were female, with median age of cohort 45.2 years. Seventy-five percent had macroadenomas, of which 22% were hormonally active. Ninety-five percent of microadenomas were hormonally active. Adrenocorticotropic hormone granulation pattern by IHC identified 63% as densely granulated (DG) and 34% as sparsely granulated (SG). All microadenomas were DG (p < .001); 50% of macroadenomas were DG associated with increased tumor invasion compared to SG. E-cadherin IHC was positive in 80%, diminished in 17%, and absent in 20% and did not correlate with corticotroph PitNETs subtype, size, or prognosis. In contrast to the distinct transcriptomes of corticotroph PitNETs and normal pituitaries, a comparison of clinically active and silent corticotroph PitNETs demonstrated similar molecular signatures indicating their common origin, but with unique differences related to their secretory status.

Analysis of CDO1, PITX2, and CDH13 Gene Methylation in Early Endometrial Cancer for Prediction of Medical Treatment Outcomes.

An observational cohort study of patients diagnosed with endometrial cancer (EC) stage IA G1, or atypical endometrial hyperplasia (AEH), undergoing organ-preserving treatment, was conducted. OBJECTIVE OF THE STUDY: To determine CDO1, PITX2, and CDH13 gene methylation levels in early endometrial cancer and atypical hyperplasia specimens obtained before organ-preserving treatment in the patients with adequate response and with insufficient response to hormonal treatment. MATERIALS AND METHODS: A total of 41 endometrial specimens obtained during diagnostic uterine curettage in women with EC (n = 28) and AEH (n = 13), willing to preserve reproductive function, were studied; 18 specimens of uterine cancer IA stage G1 from peri- and early postmenopausal women (comparison group) were included in the study. The control group included 18 endometrial specimens from healthy women obtained by diagnostic curettage for missed abortion and/or intrauterine adhesions. Methylation levels were analyzed using the modified MS-HRM method. RESULTS: All 13 women with AEH had a complete response (CR) to medical treatment. In the group undergoing organ-preserving treatment for uterine cancer IA stage G1 (n = 28), 14 patients had a complete response (EC CR group) and 14 did not (EC non-CR group). It was found that all groups had statistically significant differences in CDO1 gene methylation levels compared to the control group (p < 0.001) except for the EC CR group (p = 0.21). The p-value for the difference between EC CR and EC non-CR groups was <0.001. The differences in PITX2 gene methylation levels between the control and study groups were also significantly different (p < 0.001), except for the AEH group (p = 0.21). For the difference between EC CR and EC non-CR groups, the p-value was 0.43. For CDH13 gene methylation levels, statistically significant differences were found between the control and EC non-CR groups (p < 0.001), and the control and EC comparison groups (p = 0.005). When comparing the EC CR group with EC non-CR group, the p-value for this gene was <0.001. The simultaneous assessment of CDO1 and CDH13 genes methylation allowed for an accurate distinction between EC CR and EC non-CR groups (AUC = 0.96). CONCLUSION: The assessment of CDO1 and CDH13 gene methylation in endometrial specimens from patients with endometrial cancer (IA stage G1), scheduled for medical treatment, can predict the treatment outcome.

Xanthohumol Promotes Skp2 Ubiquitination Leading to the Inhibition of Glycolysis and Tumorigenesis in Ovarian Cancer.

Ovarian cancer is a common, highly lethal tumor. Herein, we reported that S-phase kinase-associated protein 2 (Skp2) is essential for the growth and aerobic glycolysis of ovarian cancer cells. Skp2 was upregulated in ovarian cancer tissues and associated with poor clinical outcomes. Using a customized natural product library screening, we found that xanthohumol inhibited aerobic glycolysis and cell viability of ovarian cancer cells. Xanthohumol facilitated the interaction between E3 ligase Cdh1 and Skp2 and promoted the Ub-K48-linked polyubiquitination of Skp2 and degradation. Cdh1 depletion reversed xanthohumol-induced Skp2 downregulation, enhancing HK2 expression and glycolysis in ovarian cancer cells. Finally, a xenograft tumor model was employed to examine the antitumor efficacy of xanthohumol in vivo. Collectively, we discovered that xanthohumol promotes the binding between Skp2 and Cdh1 to suppress the Skp2/AKT/HK2 signal pathway and exhibits potential antitumor activity for ovarian cancer cells.

F. Nucleatum enhances oral squamous cell carcinoma proliferation via E-cadherin/ß-Catenin pathway.

BACKGROUND: Fusobacterium nucleatum (F. nucleatum) is a microbial risk factor whose presence increases the risk of oral squamous cell carcinoma (OSCC) progression. However, whether it can promote the proliferation of OSCC cells remains unknown. METHODS: In this study, we investigated F. nucleatum effect on OSCC cell proliferation using in vitro and in vivo experiments. RESULTS: Our results showed that F. nucleatum promoted OSCC cell proliferation, doubling the cell count after 72 h (CCK-8 assay). Cell cycle analysis revealed G2/M phase arrest. F. nucleatum interaction with CDH1 triggered phosphorylation, upregulating downstream protein ß-catenin and activating cyclinD1 and Myc. Notably, F. nucleatum did not affect noncancerous cells, unrelated to CDH1 expression levels in CAL27 cells. Overexpression of phosphorylated CDH1 in 293T cells did not upregulate ß-catenin and cycle-related genes. In vivo BALB/c nude experiments showed increased tumor volume and Ki-67 proliferation index after F. nucleatum intervention. CONCLUSION: Our study suggests that F. nucleatum promotes OSCC cell proliferation through the CDH1/ß-catenin pathway, advancing our understanding of its role in OSCC progression and highlighting its potential as a therapeutic target.