Advances in Clinical and Experimental Medicine

Translational molecular research has established a novel clinical approach in endometrial cancer patients

Endometrial cancer (EC) is the most common gynecological tumor in developed countries. Nowadays, molecular biomarkers have become increasingly important in the management of EC patients, helping in early detection, risk stratification, prognosis and response to the treatment, and qualification for novel immunotherapies, especially in EC patients with metastatic disease or recurrence. When EC tumor molecular profiling is combined with the standard histopathological features such as clinical stage, histologic grading and evaluation of lymphovascular space invasion, the final therapeutic outcome may bring benefits in terms of personalized and efficient management.

Preliminary exploration of the potential role of salvianolic acid F in regulating ovarian cancer cell proliferation, migration, invasion, and apoptosis and its association with the EP300/PI3K/AKT pathway

Salvianolic acid F (SAF), an important water-soluble monomeric component, is derived from the herbal medicine Salvia miltiorrhiza (SM) Bunge. Although SAF has been suggested to suppress various cancers, its role in ovarian cancer (OC) and the underlying mechanisms remain largely unclear. This study aimed to investigate the effects of SAF on OC cell growth, invasion, migration, and apoptosis, as well as to elucidate the underlying mechanisms, including those involving the EP300/PI3K/AKT signaling pathway. In vitro cell culture experiments were conducted to assess the effects of SAF on the proliferation, migration, invasion, and apoptosis of OVCAR-3 (Ovarian Cancer Cell Line 3) and SK-OV-3 (Sloan-Kettering Ovarian Cancer 3) cells. Network pharmacology was further employed to explore SAF's impact on OC and to elucidate the potential underlying mechanisms. The EP300-mediated PI3K/AKT signaling pathway was selected for validation to confirm SAF's effects on inducing apoptosis and inhibiting cell proliferation in these OC cell lines. Salvianolic acid F suppressed the growth, invasion and migration of SK-OV-3 and OVCAR-3 cells, and induced apoptosis. A network pharmacology analysis of SAF's effects on OC identified core targets, TP53, EP300, STAT3, MMP9, NFKB1, HIF1A, and PTGS2, through protein-protein interaction (PPI) network analysis using the STRING database. Salvianolic acid F inhibited EP300 expression in SK-OV-3 cells, reduced the p-PI3K/PI3K ratio, and increased both the Bax/Bcl-2 ratio and the cleaved caspase-3/caspase-3 ratio in OVCAR-3 and SK-OV-3 cells. However, the addition of A485, an EP300 inhibitor, did not further enhance the effects of SAF. Salvianolic acid F inhibited OC cell growth, migration and invasion while promoting apoptosis. The EP300/PI3K/AKT pathway is a key mechanism through which SAF regulates OC progression. Additionally, SAF may represent a promising candidate drug for treating OC.

Preoperative hemoglobin A1c as a predictor of lymph node metastasis in diabetic women with endometrial cancer

Glycated hemoglobin A1c (HbA1c) is a well-established marker for glycemic control; recent studies suggest its potential role in cancer prognosis. Understanding the relationship between preoperative HbA1c levels and lymph node metastasis (LNM) in diabetic women with endometrial cancer (EC) can enhance prognostic assessments and treatment strategies. This study aimed to evaluate the predictive value of preoperative HbA1c levels for LNM in diabetic women with EC. A retrospective analysis was conducted on 233 diabetic women who underwent surgery for endometrioid-type EC at a tertiary referral hospital between 2010 and 2021. Data collected included demographic information, fasting plasma glucose, HbA1c levels, ultrasound findings, and tumor characteristics. Receiver operating characteristic (ROC) analysis was used to assess the predictive power of HbA1c levels for LNM. Univariate and multivariate regression analyses were performed to identify independent risk factors for LNM. The mean preoperative HbA1c level was 7.03 ±1.37%. A cutoff HbA1c level ≥7.26% demonstrated a sensitivity of 73.7%, a specificity of 72.3% and an area under the curve (AUC) of 0.781 for predicting LNM (p < 0.001). Significant correlations were found between HbA1c levels and endometrial thickness (r = 0.231, p < 0.001), primary tumor diameter (PTD) (r = 0.173, p = 0.008) and duration of diabetes (r = 0.203, p = 0.002). Multivariate analysis identified HbA1c level (odds ratio (OR) = 2.621, 95% confidence interval (95% CI): 1.722-3.987, p < 0.001), lymphovascular space involvement (LVSI) (OR = 19.193, 95% CI: 5.805-63.458, p < 0.001), body mass index (BMI) (OR = 1.095, 95% CI: 1.010-1.188, p = 0.029), and duration of diabetes (OR = 1.019, 95% CI: 1.001-1.301, p = 0.039) as independent risk factors for LNM. Preoperative HbA1c levels serve as a significant predictor for LNM in diabetic women with EC. A cutoff HbA1c level ≥7.26% indicates higher risk of LNM. These findings underscore the importance of glycemic control in reducing cancer progression risks and improving the prognosis of diabetic patients with EC. Integrating HbA1c monitoring into preoperative assessments can help tailor personalized treatment strategies for better outcomes.

Chromosomal and gene mapping of uterine fibroids: A systematic review

Genetic mutations and their phenotypic manifestation have been recognized as critical factors in tumorigenesis. However, the relationship between these mutations and the pathogenesis of uterine leiomyomas (UL) remains inadequately characterized. There is compelling evidence to suggest a genetic underpinning in UL development, alongside influences from epigenetics, environmental stimuli, growth hormones, and growth factors. A plethora of studies have tried to elucidate the genetic and epigenetic etiologies associated with UL, but the definitive implications of these findings remain unclear. An extensive systematic review was conducted to investigate the genetic etiologies of UL. This systematic review aimed to consolidate current knowledge on genetic and epigenetic causes of UL, offering a comprehensive perspective on the evidence and its relevance in other solid tumors. A secondary focus was to identify the most significant genetic association with the genesis of UL. A total of 60 articles were identified, and 10 chromosomes and 51 genes were found to be implicated in the development of UL. The main trend in fibroid research focuses on genetic abnormalities and aberrations as the etiology of UL development. It has been estimated that 40% of UL can be associated with chromosome-specific aberrations. Chromosomal gain, loss, rearrangement, single nucleotide polymorphism (SNP), and translocation are the most common aberrations associated with UL development. The most recurrent ones include chromosome X and 7q deletions, and rearrangements of 12q15, 6p21 and 10q22. MED12 has been identified as a gene of particular importance in the development of UL.

Evaluation of the association between angiotensin converting enzyme insertion/deletion polymorphism and the risk of endometrial cancer in and characteristics of Polish women

Endometrial cancer is the most common malignant neoplasm of the female reproductive organs. A dysfunctional endometrial renin-angiotensin system (RAS) might contribute to the growth and spread of endometrial cancer. The RAS-related gene polymorphisms, including the polymorphism of insertion/deletion (I/D) in the angiotensin-converting enzyme (ACE) gene, influence RAS activity. In the present study, we examined the association between the I/D polymorphism of the ACE gene and endometrial cancer risk in Polish women. Genotype analysis of the ACE I/D polymorphism was carried out using polymerase chain reaction (PCR) on 142 endometrial cancer type 1 patients and 68 cancer-free subjects. The results of the analyses were correlated with clinical data. The frequency of DD, DI and II ACE genotypes did not vary significantly between the experimental group and the control group (40 (28%), 61 (43%) and 41 (29%) vs 18 (26%), 31 (46%), and 19 (28%), respectively; p = 0.935). In addition, the incidence of the DD, DI and II polymorphisms in the ACE gene did not vary significantly between the experimental subgroups when stratified by cancer grade - G1, G2 and G3 endometrioid carcinoma - and the control group. Furthermore, the ACE polymorphism was not significantly associated with hypertension, diabetes or lymph node metastasis. The ACE I/D gene polymorphism was not associated with endometrial cancer risk or the clinicopathological features in Polish women.

Molecular features as promising biomarkers in ovarian cancer

Ovarian cancer (OC) is a global challenge for modern medicine, ranking 7th for incidence and the 8th most common cause of mortality from cancers in women. Ovarian cancer has a poor prognosis, characterized by high morbidity and mortality, with detection occurring more frequently in advanced stages. Further issues lie within the heterogeneous nature of this pathology, as well as in its ability to develop multidrug resistance. Therefore, there is a burgeoning need to introduce effective screening for the general population, especially in high-risk groups such as individuals with a family history of cancer. Achieving this would be greatly assisted by identifying new biomarkers in order to, in turn, develop targeted therapies for patients. Advances in molecular biology techniques that enable cancer genetic characterization offer hope for personalized medicine. This article reviews the current findings on the biology of OC at the molecular level. Such knowledge may prove to be crucial and constitute a starting point for the development of new options for the early detection, prevention and treatment of OC.

miR-214-5p increases the radiosensitivity of cervical cancer by targeting ROCK1 expression

The tolerance of cervical cancer to radiotherapy is a major factor affecting treatment outcomes. The miR-214-5p is involved in the regulation of biological processes such as tumor proliferation and metastasis. The aim of the study was to explore the role of miR-214-5p and Rho-associated coiled-coil containing protein kinase 1 (ROCK1) in cervical cancer and their response to radiotherapy in cervical cancer patients. Fifty-three cervical cancer tissue samples were collected to analyze the level of miR-214-5p in patients with different responses to radiotherapy. Cervical cancer cell lines with radiation resistance were selected to explore the role of miR-214-5p in radiosensitivity. The wound healing, transwell migration, clone formation assay, and in vivo analysis were utilized to evaluate the effect of miR-214-5p on the radiation sensitivity of cervical cancer cells. Patients with poor radiotherapy responses demonstrated low levels of miR-214-5p. The upregulation of miR-214-5p decreased migration and invasion ability of radiotherapy-resistant cells. The bioinformatic analysis showed that ROCK1 is a candidate target gene of miR-214-5p, and this was confirmed with dual luciferase reporter assay showing that miR-214-5p directly interacts with the 3'untranslated region (3'UTR) of ROCK1. Decreased ROCK1 improved the radiosensitivity of cervical cancer in vitro and in vivo, and the overexpression of ROCK1 decreased the radiosensitivity effect of miR-214-5p in cervical cancer cells. The miR-214-5p can regulate the radiation sensitivity of cervical cancer cells by targeting the mRNA of ROCK1 and regulating its expression.

The RANKL/RANK system in female reproductive organ tumors: A preclinical and clinical overview

The receptor activator of nuclear factor-κB (RANK) and its ligand RANKL are members of the tumor necrosis factor (TNF) super-family of cytokines with a role in progestogen-associated malignancies in breast. Basic and clinical data support the participation of the cytokine pathway in metastatic disease and as poor prognosis markers. The value of RANK/RANKL as prognostic indicators in endometrial and ovarian tumors, as well as the data suggesting a potential role of RANK/RANKL in hormone dependent tumorigenesis in the endometrium, have been described. The D-CARE study could not confirm benefit in the modulation of RANKL in breast cancer.

Tasquinimod enhances the sensitivity of ovarian cancer cells to cisplatin by regulating the Nur77-Bcl-2 apoptotic pathway

Resistance to cisplatin (DDP) in ovarian cancer therapy has been a major clinical barrier. Drug-resistant cancers have been shown to downregulate the proapoptotic protein B-cell lymphoma-2 (Bcl-2) to inhibit apoptosis. Therefore, we explored whether tasquinimod could modulate resistance to DDP through apoptotic pathways. We aimed to explore the relationship between tasquinimod, Nur77-Bcl-2 apoptosis pathway and sensitivity of the ovarian carcinoma cell line SKOV3 and the DDP-resistant strain SKOV3/DDP cells to DDP. First, SKOV3 and SKOV3/DDP cells were treated with 2 μg/mL DDP or 40 μM tasquinimod. Western blot and quantitative real-time polymerase chain reaction (qPCR) were then used to analyze the expression of histone deacetylase 4 (HDAC4), Nur77, Bcl-2 (BH3 domain-specific), and caspase-3. Flow cytometry, scratch-wound assay and immunofluorescence were used to detect apoptosis, migration rate, and related expression of Nur77 and Bcl-2 (BH3 domain-specific). Subsequently, 5×107 SKOV3 or SKOV3/DDP cells cultured with 2 μg/mL DDP were injected into 4-week-old female BALB/c nude mice. Then, the mice were administered 4 mg/kg DDP and 50 mg/kg tasquinimod every 3 days. Finally, the changes in tumor diameter and weight were measured. After treatment of SKOV3 and SKOV3/DDP cells with tasquinimod, cell migration and HDAC4 expression levels were significantly reduced, while Nur77 expression was increased. Tasquinimod treatment enhanced the expression of Nur77 and caspase-3, and cells transfected with si-Nur77 showed the opposite result. Transfection of si-Nur77 reduced the expression of caspase-3 and Nur77 in the SKOV3/DDP cells that were treated with both DDP and tasquinimod. After injection of SKOV3/DDP cells into the mice, the tumor diameter, mass and in vivo HDAC4 level were significantly decreased by tasquinimod. Meanwhile, the levels of Nur77 and Bcl-2 (BH3 domain-specific) were increased. Tasquinimod upregulated the Nur77/Bcl-2 pathway to induce apoptosis in SKOV3/DDP cells and enhanced the anti-tumor effect of DDP in SKOV3/DDP xenografts. Therefore, tasquinimod can be expected to find clinical applications in enhancing DDP resistance.

Transferrin receptor modulated by microRNA-497-5p suppresses cervical cancer cell malignant phenotypes

Cervical cancer is prevalent throughout the world, and microRNA-497-5p (miR-497-5p) plays an important role in its development. However, the specific mechanism by which miR-497-5p targets the transferrin receptor (TFRC) during cervical cancer development has not been clarified. The aim of the study was to unravel TFRC expression and its role in cervical cancer cells, as well as the impact of the miR-497-5p/TFRC axis on cervical cancer cells. The target mRNA was determined through differential analysis, followed by the evaluation of its impact on survival and clinical staging. Then, quantitative real-time polymerase chain reaction (qPCR) was conducted to analyze the TFRC mRNA level in cervical cancer cells and normal cervical epithelial cells. Western blot (WB) was utilized to examine the expression levels of TFRC, cleaved caspase-3, cleaved caspase-9, and epithelial-mesenchymal transition (EMT)-related proteins. The miRNAs upstream of the target mRNA were predicted, and Pearson correlation analysis was performed, followed by the validation through the dual-luciferase reporter assay. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and colony formation assays were performed to analyze cancer cell viability, followed by a transwell assay aimed at measuring cell migratory and invasive abilities. Finally, flow cytometry was conducted to examine cell apoptosis and cell cycle. The transferrin receptor was significantly increased in cervical cancer cells and positively associated with clinical T and N stages. Silencing TFRC could constrain cell proliferative, migratory and invasive abilities, arrest the cell cycle and facilitate cell apoptosis in cervical cancer cells. The bioinformatics analysis showed a significantly negative correlation between miR-497-5p and TFRC in cervical cancer. Moreover, upregulated miR-497-5p hampered cervical cancer progression and decreased TFRC expression. The overexpression of TFRC reversed the suppressive impact of miR-497-5p overexpression on cervical cancer progression. The modulatory role of the miR-497-5p/TFRC axis was confirmed in cervical cancer cells. This axis may present a new avenue for the diagnosis of cervical cancer and provide a novel target for cervical cancer treatment.

MCT1 gene silencing enhances the immune effect of dendritic cells on cervical cancer cells

Dendritic cells (DCs) are a key class of immune cells that migrate to the draining lymph nodes and present processed antigenic peptides to lymphocytes after being activated by external stimuli, thereby establishing adaptive immunity. Moreover, DCs play an important role in tumor immunity. The aim of the study was to investigate whether MCT1 gene silencing in DCs affects their ability to mount an immune response against cervical cancer cells. We silenced the expression of MCT1 in DCs from mouse bone marrow (BM) by infection with adenovirus. The surface antigen profile of DCs was analyzed by flow cytometry and cytokine secretion was evaluated using enzyme-linked immunosorbent assay (ELISA) following sodium lactate (sLA) exposure and lipopolysaccharide (LPS) stimulation. Then, various groups of DC-induced cytotoxic T lymphocytes (CTLs) were prepared and their cytotoxicity against U14 was tested. Without sLA exposure, silencing MCT1 did not affect the expression of CD1a, CD80, CD83, CD86, and major histocompatibility complex class II (MHCII) in DCs after LPS challenge. Similar results were found for interleukin (IL)-6, IL-12 p70 and tumor necrosis factor alpha (TNF-α). After sLA exposure, silencing MCT1 significantly decreased the expression of CD1a, CD80, CD83, CD86, and MHCII in DCs after the LPS challenge, as well as the secretion of IL-6, IL-12 p70 and TNF-α. In addition, sLA exposure significantly reduced the toxicity and inhibited the proliferation of DC-induced CTLs compared to U14 cells in vitro and in vivo. However, silencing MCT1 significantly attenuated the changes caused by sLA exposure. At the same time, in the absence of sLA, silencing MCT1 did not affect the toxicity nor inhibit the proliferation of DC-induced CTLs on U14 cells. Lactate exposure reduces the immune effect of DCs on cervical cancer cells, but MCT1 gene silencing attenuates these alterations.

Combination of serum FOXR2 and transvaginal three-dimensional power Doppler ultrasonography in the diagnosis of uterine lesions

Cervical carcinoma and endometrial carcinoma are the most common gynecologic cancers worldwide. Forkhead-box R2 (FOXR2) plays an important role in the progression of various malignant tumors. However, the effects of FOXR2 on the development of uterine lesions remain unclear. This prospective observational study aimed to investigate the diagnostic performance of FOXR2 and transvaginal three-dimensional power Doppler ultrasonography (3D-PDU) for malignant uterine lesions. This study included 404 uterine lesion patients and 200 healthy individuals who visited the hospital for a physical examination from April 2014 to May 2016. All patients received FOXR2 detection and 3D-PDU examination at admission. The demographic data and clinical data, including age, body mass index (BMI), and the International Federation of Gynecology and Obstetrics (FIGO) stage, were collected. All the patients were followed up for 5 years. The overall survival (OS) was analyzed using Kaplan-Meier (K-M) curve analysis. The diagnostic value of FOXR2 and 3D-PDU was evaluated using receiver operating characteristic (ROC) curves. Serum levels of FOXR2 mRNA were upregulated in patients with malignant uterine lesions. Patients with high expression of FOXR2 showed a higher expression of the cancer biomarkers CA125, CA199, CEA, and SCCA. It was also found that FOXR2 expression was associated with the clinical outcomes of patients with malignant uterine lesions. Moreover, higher expression of FOXR2 predicted a poor prognosis. The combined use of FOXR2 and 3D-PDU showed favorable potential for the diagnosis of malignant uterine lesions, especially for cervical carcinoma and endometrial carcinoma. The combination of serum FOXR2 and transvaginal 3D-PDU has a potential in the diagnosis of uterine lesions.