Journal

Cancer Biotherapy and Radiopharmaceuticals

Papers (41)

Metformin Affects Paclitaxel Sensitivity of Ovarian Cancer Cells Through Autophagy Mediated by Long Noncoding RNASNHG7/miR-3127-5p Axis

Background : Ovarian cancer is the public health issue worldwide. Paclitaxel is a first-line chemotherapy drug for ovarian cancer, but paclitaxel resistance weakens the therapeutic effect. Metformin (Met) improved the paclitaxel sensitivity in a mouse model of ovarian cancer. However, the mechanism of Met on paclitaxel sensitivity is still unclear in ovarian cancer. Materials and Methods : Cell viability, apoptosis, migration, and invasion were measured by Cell Counting Kit-8 (CCK8), flow cytometry, and transwell assays severally. The expression of long noncoding RNA (lncRNA) small nucleolar RNA host gene 7 (SNHG7) and microRNA-3127-5p (miR-3127-5p) were detected by real-time quantitative polymerase chain reaction. The protein levels of poly (ADP-ribose) polymerase, microtubule-associated protein 1 light chain 3 (LC3)-I, LC3-II, and Beclin 1 were examined by Western blot assay. RNA immunoprecipitation assay detected the relationship between SNHG7 and miR-3127-5p. Then, the binding correlation between SNHG7 and miR-3127-5p was predicted by starBase and verified by the dual-luciferase reporter. The effects of Met and SNHG7 on tumor growth were tested in ovarian cancer mice model. Results : Met inhibited cell viability, migration, invasion, SNHG7 level, and autophagy and promoted apoptosis in paclitaxel-resistant ovarian cancer cells. Moreover, Met partly reversed SNHG7-mediated paclitaxel sensitivity and autophagy in ovarian cancer cells. SNHG7 directly bound to miR-3127-5p. Met abolished the promoting effect of SNHG7 overexpression on tumor growth and autophagy in vivo . Conclusion : The authors' findings indicated that Met expedited paclitaxel sensitivity by regulating SNHG7/miR-3127-5p-mediated autophagy in ovarian cancer cells.

Impact of Proactive Nursing on Postoperative Ovarian and Immune Function in Patients Undergoing Ultrasound-Guided Radiofrequency Ablation for Uterine Fibroids

Objective: This study analyzed the effectiveness of proactive nursing interventions in patients undergoing ultrasound-guided radiofrequency ablation for uterine fibroids. Materials and Methods: A retrospective analysis included 50 patients who received routine postoperative care from April 2022 to April 2023 as control group (CG) and 54 patients who received proactive nursing from May 2023 to May 2024 as intervention group (IG). Eligible participants were adult women with confirmed uterine fibroids and complete medical records, including preoperative, intraoperative, and postoperative data. Exclusion criteria included individuals with severe comorbidities such as uncontrolled diabetes or hypertension, those who were pregnant or breastfeeding during the study period, and patients with significant gaps in medical records or cognitive impairments that hindered participation in the study. Surgical outcomes, ovarian function markers, immune function markers, oxidative stress indicators, and complications were compared between the two groups. Results: In IG, intraoperative blood loss (15.83 ± 4.35 mL vs. 49.75 ± 7.62 mL), surgical duration (27.64 ± 8.04 min vs. 55.08 ± 6.67 min), hospital stay (3.17 ± 0.65 d vs. 5.48 ± 0.83 d), and time to ambulation (1.43 ± 0.27 d vs. 2.56 ± 0.34 d) were significantly lower versus CG ( p < 0.05, Cohen’s d = 0.72∼0.89). Levels of luteinizing hormone, follicle-stimulating hormone, estradiol, reactive oxygen species, malondialdehyde, and advanced oxidation protein products at 1 d and 30 d postoperatively were significantly lower in IG versus CG ( p < 0.05, Cohen’s d = 0.6∼0.80). CD3 and CD8 levels at 1 d and 30 d postoperatively were significantly lower in IG, whereas CD4 and CD4/CD8 (2.45 ± 0.56 vs. 1.58 ± 0.44) were significantly higher versus CG ( p < 0.05, Cohen’s d = 0.65). The incidence of postoperative complications in IG (14.81%) was significantly inferior to that in CG (22%) ( p < 0.05, Cohen’s d = 0.52∼0.87). Conclusions: Proactive nursing interventions applied in the management of patients after ultrasound-guided radiofrequency ablation for uterine fibroids demonstrate significant clinical advantages. Specifically, they reduce intraoperative bleeding, shorten surgical and hospitalization durations, and potentially benefit ovarian and immune functions of patients.

Clinical Dose Preparation of [ 177 Lu]Lu-DOTA-Pertuzumab Using Medium Specific Activity [ 177 Lu]LuCl 3 for Radioimmunotherapy of Breast and Epithelial Ovarian Cancers, with HER2 Receptor Overexpression

Background: The overexpression of human epidermal growth factor receptor 2 (HER2) is commonly associated with metastatic breast cancer and epithelial ovarian cancer. The U.S. Food and Drug Administration (FDA) has approved Trastuzumab as an anti-HER2 agent for the metastatic breast and epithelial ovarian cancer. However, Trastuzumab has severe limitations in the treatment of metastatic breast cancer associated with ligand-dependent dimerization of HER2 receptor at the extracellular domain-II (ECD-II) region. The therapeutic approach in combination of pertuzumab and trastuzumab is found to be effective in preventing HER2 dimerization at the ECD-II region. The radioimmunotherapeutic approach, utilizing both these anti-HER2 agents (trastuzumab/pertuzumab), radiolabeled with [ 177 Lu]Lu 3+ , has proved to be clinically efficacious with promising potential. Toward this, the formulation for clinical doses of [ 177 Lu]Lu-DOTA-pertuzumab has been optimized using medium specific activity (0.81 GBq/μg) [ 177 Lu]LuCl 3 . Materials and Methods: Preconcentrated pertuzumab was conjugated with p -NCS-benzyl-DOTA. Purified DOTA-benzyl-pertuzumab conjugate was radiolabeled with carrier-added [ 177 Lu]LuCl 3 . Quality control parameters were evaluated for the [ 177 Lu]Lu-DOTA-pertuzumab. In vivo biodistribution was carried out at different time points postadministration. Specific cell binding, immunoreactivity, and internalization were investigated by using SKOV3 and SKBR3 cells. Results: In this study, the authors reported a consistent and reproducible protocol for clinical dose formulations of [ 177 Lu]Lu-DOTA-pertuzumab, with a radiochemical yield of 86.67% ± 1.03% and radiochemical purity (RCP) of 99.36% ± 0.36% ( n  = 10). Preclinical cell binding studies of [ 177 Lu]Lu-DOTA-pertuzumab revealed specific binding with SKOV3 and SKBR3 cells up to 24.4% ± 1.4% and 23.2% ± 0.8%, respectively. The uptakes in SKOV3- and SKBR3-xenografted tumor in severe combined immunodeficiency mice were observed to be 25.9% ± 0.8% and 25.2% ± 1.2% ID/g at 48 and 120 h postinjection, respectively. Conclusions: A protocol was optimized for the preparation of ready-to-use clinical dose of [ 177 Lu]Lu-DOTA-pertuzumab, in hospital radiopharmacy settings. The retention of RCP of the radiopharmaceutical, on storage in saline and serum, at −20°C, up to 120 h postradiolabeling, confirmed its in vitro stability.

miR-141-5p Affects the Cell Proliferation and Apoptosis by Targeting BTG1 in Cervical Cancer

Background: MicroRNAs have been discovered to have the possibility to play a significant role in cancer development. While miR-141-5p has been found upregulated in various cancers, its functions in cervical cancer have rarely been reported. Methods: The expression level of miR-141-5p was assessed in cervical cancer tissues and cell lines by RT-qPCR. The function of miR-141-5p in C33A and HeLa cells was detected by CCK-8, and colony formation, wound-healing, transwell chamber, and flow cytometry assays. Dual luciferase reporter was carried out to identify the interaction between miR-141-5p and BTG antiproliferation factor 1 ( BTG1 ). Results: miR-141-5p was upregulated in cervical cancer and was negatively associated with the prognosis of patients with cervical cancer. Functional analyses demonstrated that silenced miR-141-5p expression inhibited the cell proliferation, migration, and invasion, and alleviated apoptosis of C33A and HeLa cells. In addition, miR-141-5p suppresses the activity of BTG1–3′-UTR. Rescue assays demonstrated that the cervical cancer progression is suppressed by miR-141-5p inhibitor and retrieved by sh-BTG1. Conclusions: The authors' findings reveal that miR-141-5p exerts its role through targeting BTG1 in cervical cancer progression, indicating that miR-141-5p may represent a promising target for the treatment of cervical cancer patients. The Clinical Trial Registration number: (2019-KY013).

SND1 Promotes Radioresistance in Cervical Cancer Cells by Targeting the DNA Damage Response

Background: Radiotherapy is one of the most effective therapeutic strategies for cervical cancer patients, although radioresistance-mediated residual and recurrent tumors are the main cause of treatment failure. However, the mechanism of tumor radioresistance is still elusive. DNA damage response pathways are key determinants of radioresistance. The purpose of this study was to investigate the role and mechanism of SND1 in radioresistance of cervical cancer. Methods: A stable HeLa cell line with SND1 knockout (HeLa-KO) was generated through a modified CRISPR/Cas9 double-nicking gene editing system. The stable CaSki cell lines with SND1 knockdown (CaSki-Ctrl, CaSki-SND1-sh-1, CaSki-SND1-sh-2) were constructed through lentivirus transfection with the pSil-SND1-sh-1 and pSil-SND1-sh-2 plasmids. Results: It was observed that SND1 deficiency significantly increased the radiosensitivity of cervical cancer cells. It was also found that silencing SND1 promotes radiation-induced apoptosis. Significantly, the cells with a loss of SND1 function exhibited inefficient ataxia telangiectasia mutated pathway activation, subsequently impairing DNA repair and G2/M checkpoint arrest. In addition, threonine 103 is an important phosphorylation site of SND1 under DNA damaging stress. Conclusion: Collectively, the results of this study reveal a potent radiosensitizing effect of silencing SND1 or T103 mutation on cervical cancer cells, providing novel insights into potential therapeutic strategies for cervical cancer treatment.

Feasibility of One-Day PET/CT Scanning Protocol with 68 Ga-DOTA-FAPI-04 and 18 F-FDG for the Detection of Ovarian Cancer Recurrence and Metastasis

Objective: The objective of this study was to investigate the feasibility of 1-d 68 Ga-DOTA-FAPI-04 and 18 F-FDG (2-deoxy-2[ 18 F]fluoro- d -glucose) positron emission tomography/computed tomography (PET/CT) for detecting ovarian cancer recurrence and metastasis. Materials and Methods: Fifty-two patients who underwent 18 F-FDG and 68 Ga-DOTA-FAPI-04 PET/CT were divided into 1- and 2-d groups. Image acquisition, injection time, and total waiting time were compared. For the 68 Ga-DOTA-FAPI-04 PET/CT scans, low-dose CT scans and low injection dosages were employed, and total radiation dose was assessed for both protocols. The comparative analysis included assessment of patient-based detection rates and lesion-based diagnostic efficacy. Results: The total waiting time was significantly shorter in the 1-d group than in the 2-d group ( p  = 0.000). The radiation doses stemming from internal radiation and external radiation between the groups showed no differences ( p  = 0.151 vs. 0.716). In the patient-based analysis, the detection rates for local recurrence, peritoneal, lymph node, and other metastases were not significantly different in both protocols ( p ∈ [0.351, 1.000]). For the lesion-based analysis, no differences were noted in terms of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy ( p ∈ [0.371, 1.000]). Conclusions: The 1-d PET/CT protocol reduced waiting time and exhibited equivalent detectability compared with the 2-d protocol, suggesting its clinical value.

Participation of Long Noncoding RNA FOXP4-AS1 in the Development and Progression of Endometrioid Carcinoma with Epigenetically Silencing DUSP5

Background: Long noncoding RNAs (lncRNAs), as emerging regulators of a wide variety of biological processes via diverse mechanisms, have been demonstrated to be of increasing importance in biology. Genome-wide association studies of tumor samples have identified several lncRNAs as either oncogenes or tumor suppressors in various types of cancers. In recent years, the importance of lncRNAs, especially in endometrioid cancer (EEC), has become increasingly well understood. The lncRNA Forkhead box P4 antisense RNA 1 (FOXP4-AS1) has been reported to fulfill roles in several types of cancers; however, the main biological function and associated underlying molecular mechanism of FOXP4-AS1 in EEC have yet to be fully elucidated. The present study therefore aimed to investigate how RNA FOXP4-AS1 may participate in the development and progression of endometrioid carcinoma tissues. Materials and Methods: In the present study, the expression level of FOXP4-AS1 was investigated in endometrioid carcinoma tissues and matching nearby normal endometrial tissues collected from patients receiving surgery at the hospital. A series of molecular biological assays were performed to investigate the effect of FOXP4-AS1 on cell proliferation, cell migration, and cell invasion. Results: An increased concentration of FOXP4-AS1 was identified in endometrioid carcinoma samples and cell lines compared with the corresponding controls, and this lncRNA was found to be positively correlated with advanced FIGO stages in patients with endometrial cancer. Furthermore, knocking down endogenous FOXP4-AS1 led to a significant reduction in the colony formation number and a significant inhibition of cell proliferation, cell migration, and cell invasion in endometrioid carcinoma cells. Moreover, dual-specificity phosphatase 5 (DUSP5), which is lowly expressed in endometrioid carcinoma tissues cells and negatively modulated by FOXP4-AS1, was identified as the downstream target molecule of FOXP4-AS1. Subsequently, the mechanistic experiments confirmed that, through binding to enhancer of zeste homolog 2 (EZH2; one of the catalytic subunits of polycomb repressive complex 2 [PRC2]), FOXP4-AS1 could epigenetically suppress the expression of DUSP5. Finally, the oncogenic function of the FOXP4-AS1/EZH2/DUSP5 axis in endometrioid carcinoma was confirmed via rescue assays. Conclusions: The findings of the present study have highlighted how FOXP4-AS1 fulfills an oncogenic role in endometrioid carcinoma, and targeting FOXP4-AS1 and its pathway may provide new biomarkers for patients with endometrioid carcinoma.

Nomogram for Predicting Survival in Locally Advanced Cervical Cancer with Concurrent Chemoradiotherapy plus or Not Adjuvant Chemotherapy: A Retrospective Analysis Based on 2018 FIGO Staging

Background: The comprehensive treatment mode of combining concurrent chemoradiotherapy (CCRT) with adjuvant chemotherapy (AC) is a commonly used mainstream model in the clinical practice of locally advanced cervical cancer (LACC). However, the necessity for AC after CCRT lacks sufficient evidence-based medical support. This study constructs a predictive model for the survival time dependence of CCRT ± AC for LACC based on the 2018 International Federation of Gynecology and Obstetrics (FIGO) staging with internal validation, the prognosis was assessed with intensity-modulated radiotherapy (IMRT) and concurrent cisplatin, and provides guidance for future stratified treatment. Materials and Methods: The retrospective analysis included 482 patients with LACC who CCRT from January 2016 to January 2023. Patients who used the 2009 FIGO staging were all standardized for the 2018 FIGO staging. The 482 patients with LACC were divided into a training set ( n = 290) and a validation set ( n = 192) at a ratio of 6:4. COX multivariate regression model and LASSO regression were used to screen for independent prognostic factors affecting progression-free survival (PFS) and overall survival (OS), and a nomogram clinical prediction model was constructed based on these factors. Evaluate the effectiveness of the model through the receiver operating characteristic curve, calibration curve, decision curve, risk heat map, and survival curves for risk stratification. Results: The PFS and OS independent prognostic risk factors affecting the 2018 FIGO staging of LACC during CCRT were validated to be similar to the 2009 FIGO staging prediction model reported in previous literature. In the training cohort, area under the curve (AUC) values at 1, 3, and 5 years were 0.941, 0.882, and 0.885 for PFS, and 0.946, 0.946, and 0.969 for OS, respectively. When applied to a test cohort, the model also showed accurate prediction result (AUC at 1, 3, and 5 years were 0.869, 0.891, and 0.899 for PFS, and 0.891, 0.941 and 0.878 for OS, respectively). Subgroup analysis suggests that patients with LACC, adenocarcinoma, stage IVA, pelvic lymph node metastasis, pretreatment hemoglobin ≤100 g/l and residual tumor diameter >2 cm, who received CCRT in the 2018 FIGO stage, may benefit more from adjuvant chemtherapy. Conclusions: Based on the 2018 FIGO staging, a nomogram prediction model for PFS and OS in patients with LACC undergoing CCRT was developed. The model, established by combining weighted clinical and pathological factors, can provide more personalized treatment predictions in clinical practice. For patients with high-risk factors such as residual tumor diameter > 2 cm after CCRT for LACC, AC may bring benefits.

Chelation-Tamoxifen Conjugates for Imaging of Estrogen Receptors

Background: The differential diagnosis of estrogen receptor-positive (ER+) pathway-activated systems by using a labeled antiestrogen helps to select the patients for optimal response to endocrine therapy and to discontinue the treatment when resistance occurs. The authors' purpose was to synthesize chelator-tamoxifen conjugates for imaging ER (+) diseases. Materials and Methods: A hydroxypropyl linker was incorporated between either cyclam or cyclam diacetic acid and tamoxifen analog to produce SC-05-L-1 (Z-1-(1,4,8,11-tetraazacyclotetradecan-1-yl)-3-((5-(4-(2-(diethylamino)ethoxy)phenyl)-4,5-diphenylpent-4-en-1-yl)oxy)propan-2-ol) and SC-05-N-1 (Z-2,2′-(4-(3-((5-(4-(2-(diethylamino)ethoxy)phenyl)-4,5-diphenylpent-4-en-1-yl)oxy)-2-hydroxy-propyl)-1,4,8,11-tetraazacyclotetradecane-1,8-diyl)diacetic acid), respectively. In vitro cell uptake and cell/media ratios of 99m Tc-SC-05-L-1 and 99m Tc- SC-05-N-1 in ER (+) ovarian cancer cells (TOV-112D and OVCAR3) were performed. To ascertain the specificity of cell uptake, the cell uptake was blocked with estrone. In vivo 99m Tc-SC-05-L-1 or 99m Tc-SC-05-N-1 single-photon emission computed tomography/computed tomography was conducted in tumor-bearing rodents and compared to 18 F-fluoro-2-deoxy- d -glucose ( 18 F-FDG) positron emission tomography/magnetic resonance imaging (a reference technology). Results: The radiochemical purities of 99m Tc-SC-05-L-1 and 99m Tc-SC-05-N-1 were greater than 99% ( n  = 10). 99m Tc-SC-05-L-1 had higher cell/media ratios than 99m Tc-SC-05-N-1 in OVCAR-3 ER (+) cells. The cell uptake of 99m Tc-SC-05-L-1 was blocked 80% by estrone indicating an ER-mediated process occurred. 99m Tc-SC-05-N-1 was further selected for in vivo imaging studies due to higher maximum tolerated dose and superior water solubility than 99m Tc-SC-05-L-1. 99m Tc-SC-05-N-1 showed higher tumor uptake and tumor/muscle count density ratios than 18 F-FDG in tumor-bearing rodents. Conclusion: 99m Tc-SC-05-N-1 showed better differential diagnosis of ovarian tumors than 18 F-FDG, indicating great promising in chelator-tamoxifen conjugate for ER pathway-directed systems imaging.

Publisher

SAGE Publications

ISSN

1084-9785