M2 macrophage-derived exosomal circTMCO3 acts through miR-515-5p and ITGA8 to enhance malignancy in ovarian cancer.

Tumor-associated macrophages of the M2 phenotype promote cancer initiation and progression. Importantly, M2 macrophage-derived exosomes play key roles in the malignancy of cancer cells. Here, we report that circTMCO3 is upregulated in ovarian cancer patients, and its high expression indicates poor survival. M2-derived exosomes promote proliferation, migration, and invasion in ovarian cancer, but these effects are abolished by knockdown of circTMCO3. Furthermore, circTMCO3 functions as a competing endogenous RNA for miR-515-5p to reduce its abundance, thus upregulating ITGA8 in ovarian cancer. miR-515-5p inhibits ovarian cancer malignancy via directly downregulating ITGA8. The decreased oncogenic activity of circTMCO3-silencing exosomes is reversed by miR-515-5p knockdown or ITGA8 overexpression. Exosomal circTMCO3 promotes ovarian cancer progression in nude mice. Thus, M2 macrophage-derived exosomes promote malignancy by delivering circTMCO3 and targeting the miR-515-5p/ITGA8 axis in ovarian cancer. Our findings not only provide mechanistic insights into ovarian cancer progression, but also suggest potential therapeutic targets.

ESM1 enhances fatty acid synthesis and vascular mimicry in ovarian cancer by utilizing the PKM2-dependent warburg effect within the hypoxic tumor microenvironment.

BACKGROUND: The hypoxic tumor microenvironment is a key factor that promotes metabolic reprogramming and vascular mimicry (VM) in ovarian cancer (OC) patients. ESM1, a secreted protein, plays an important role in promoting proliferation and angiogenesis in OC. However, the role of ESM1 in metabolic reprogramming and VM in the hypoxic microenvironment in OC patients has not been determined. METHODS: Liquid chromatography coupled with tandem MS was used to analyze CAOV3 and OV90 cells. Interactions between ESM1, PKM2, UBA2, and SUMO1 were detected by GST pull-down, Co-IP, and molecular docking. The effects of the ESM1-PKM2 axis on cell glucose metabolism were analyzed based on an ECAR experiment. The biological effects of the signaling axis on OC cells were detected by tubule formation, transwell assay, RT‒PCR, Western blot, immunofluorescence, and in vivo xenograft tumor experiments. RESULTS: Our findings demonstrated that hypoxia induces the upregulation of ESM1 expression through the transcription of HIF-1α. ESM1 serves as a crucial mediator of the interaction between PKM2 and UBA2, facilitating the SUMOylation of PKM2 and the subsequent formation of PKM2 dimers. This process promotes the Warburg effect and facilitates the nuclear translocation of PKM2, ultimately leading to the phosphorylation of STAT3. These molecular events contribute to the promotion of ovarian cancer glycolysis and vasculogenic mimicry. Furthermore, our study revealed that Shikonin effectively inhibits the molecular interaction between ESM1 and PKM2, consequently preventing the formation of PKM2 dimers and thereby inhibiting ovarian cancer glycolysis, fatty acid synthesis and vasculogenic mimicry. CONCLUSION: Our findings demonstrated that hypoxia increases ESM1 expression through the transcriptional regulation of HIF-1α to induce dimerization via PKM2 SUMOylation, which promotes the OC Warburg effect and VM.

ANGPTL4 accelerates ovarian serous cystadenocarcinoma carcinogenesis and angiogenesis in the tumor microenvironment by activating the JAK2/STAT3 pathway and interacting with ESM1.

BACKGROUND: Ovarian cancer (OC) is a malignant neoplasm that displays increased vascularization. Angiopoietin-like 4 (ANGPTL4) is a secreted glycoprotein that functions as a regulator of cell metabolism and angiogenesis and plays a critical role in tumorigenesis. However, the precise role of ANGPTL4 in the OC microenvironment, particularly its involvement in angiogenesis, has not been fully elucidated. METHODS: The expression of ANGPTL4 was confirmed by bioinformatics and IHC in OC. The potential molecular mechanism of ANGPTL4 was measured by RNA-sequence. We used a series of molecular biological experiments to measure the ANGPTL4-JAK2-STAT3 and ANGPTL4-ESM1 axis in OC progression, including MTT, EdU, wound healing, transwell, xenograft model, oil red O staining, chick chorioallantoic membrane assay and zebrafish model. Moreover, the molecular mechanisms were confirmed by Western blot, Co-IP and molecular docking. RESULTS: Our study demonstrates a significant upregulation of ANGPTL4 in OC specimens and its strong association with unfavorable prognosis. RNA-seq analysis affirms that ANGPTL4 facilitates OC development by driving JAK2-STAT3 signaling pathway activation. The interaction between ANGPTL4 and ESM1 promotes ANGPTL4 binding to lipoprotein lipase (LPL), thereby resulting in reprogrammed lipid metabolism and the promotion of OC cell proliferation, migration, and invasion. In the OC microenvironment, ESM1 may interfere with the binding of ANGPTL4 to integrin and vascular-endothelial cadherin (VE-Cad), which leads to stabilization of vascular integrity and ultimately promotes angiogenesis. CONCLUSION: Our findings underscore that ANGPTL4 promotes OC development via JAK signaling and induces angiogenesis in the tumor microenvironment through its interaction with ESM1.

The effect of cuproptosis-relevant genes on the immune infiltration and metabolism of gynecological oncology by multiply analysis and experiments validation.

Gynecological cancers are a leading cause of mortality for women, including ovarian cancer (OC), cervical squamous cell carcinoma (CESC), and uterine corpus endometrial carcinoma (UCEC). Nevertheless, these gynecological cancer types have not elucidated the role of cuproptosis and the correlated tumor microenvironment (TME) infiltration features. CRGs had important potential molecular functions and prognostic significance in gynecological cancers, especially in UCEC. Hub CRG, FDX1, was correlated with the CD8+ T cell immune infiltration in UCEC and CESC. FDX1 OE could significantly repress the proliferation ability in UCEC cells by MTT, EdU, and clone formation. High levels of FDX1 could repress ATP and lactic acid but enhance ROS and glucose levels by metabolism assay. The xenograft tumor model indicated that FDX1 OE significantly inhibited the growth of UCEC and attenuated the PCNA, HK2, PKM2, and Ki-67 expression. These CRGs are significant roles that could be potential markers and treatment targets to optimize the TME immune cell infiltration features for gynecological cancer types. FDX1 is a hub CRGs in UCEC to promote immune infiltration and attenuate proliferation and metabolism.

Efficacy and safety of PD-1 inhibitor combined with concurrent chemoradiotherapy in locally advanced cervical cancer with pelvic and/or para-aortic lymph node metastases: a retrospective cohort study.

BACKGROUND: The prognosis remains poor after standard chemoradiotherapy in locally advanced cervical cancer patients with pelvic and/or para-aortic lymph node metastases. Programmed cell death receptor-1 (PD-1) inhibitors have been recommended as the first-line treatment for recurrent cervical cancer. The efficacy of PD-1 inhibitor combined with concurrent chemoradiotherapy in locally advanced cervical cancer was still uncertain. This study aimed to explore the efficacy and safety of PD-1 inhibitors combined with concurrent chemoradiotherapy in locally advanced cervical cancer patients with pelvic and/or para-aortic lymph node metastases. METHODS: This retrospective study included patients with pelvic and/or para-aortic lymph node positive diseases [International Federation of Gynecology and Obstetrics (FIGO) stage IIB-IVA] who had received PD-1 inhibitors plus chemoradiotherapy/radiotherapy between April 1, 2020, and March 31, 2022 at the Hunan Cancer Hospital. The baseline clinicopathological characteristics, treatment, and clinical outcomes were collected. The major clinical outcomes were objective response rate (ORR), progression-free survival (PFS), and treatment-related adverse events (TRAEs). RESULTS: A total of 29 patients were included. The mean age was 55.8 [standard deviation (SD): 8.8] years. Most patients had stage IIIA-IIIB disease (72.4%) and squamous cell carcinoma (93.1%). All patients had lymph node metastases, including 24 (82.8%) with multiple metastases and 11 (37.9%) with para-aortic lymph node metastases. Among the 29 patients, 18 received sintilimab and 11 received camrelizumab concurrently with chemoradiotherapy or radiotherapy. The ORR was 96.6% [95% confidence interval (CI): 0.828, 0.993] at 3 months after radiotherapy (including 15 complete responses and 13 partial responses). At the data cutoff (August 31, 2022), the median follow-up was 14 (range, 5-30) months. The median PFS was not mature. The estimated 1- and 2-year PFS rates were 85.3% (95% CI: 60.1%, 95.2%) and 76.8% (95% CI: 47.0%, 91.2%), respectively. TRAEs of any grade occurred in 27 (93.1%) patients, most commonly as a decrease in white blood counts (82.8%), anemia (58.6%), and fatigue (48.3%). TRAEs of grade 3 or greater occurred in eight (27.6%) patients. There were no treatment-related deaths. CONCLUSIONS: PD-1 inhibitor combined with concurrent chemoradiotherapy showed potential benefit in term of tumor response and PFS in locally advanced cervical cancer patients with pelvic and/or para-aortic lymph node metastases.

Passive Location Resource Scheduling Based on an Improved Genetic Algorithm.

With the development of science and technology, modern communication scenarios have put forward higher requirements for passive location technology. However, current location systems still use manual scheduling methods and cannot meet the current mission-intensive and widely-distributed scenarios, resulting in inefficient task completion. To address this issue, this paper proposes a method called multi-objective, multi-constraint and improved genetic algorithm-based scheduling (MMIGAS), contributing a centralized combinatorial optimization model with multiple objectives and multiple constraints and conceiving an improved genetic algorithm. First, we establish a basic mathematical framework based on the structure of a passive location system. Furthermore, to balance performance with respect to multiple measures and avoid low efficiency, we propose a multi-objective optimal function including location accuracy, completion rate and resource utilization. Moreover, to enhance its practicability, we formulate multiple constraints for frequency, resource capability and task cooperation. For model solving, we propose an improved genetic algorithm with better convergence speed and global optimization ability, by introducing constraint-proof initialization, a penalty function and a modified genetic operator. Simulations indicate the good astringency, steady time complexity and satisfactory location accuracy of MMIGAS. Moreover, compared with manual scheduling, MMIGAS can improve the efficiency while maintaining high location precision.

DBN Structure Design Algorithm for Different Datasets Based on Information Entropy and Reconstruction Error.

Deep belief networks (DBNs) of deep learning technology have been successfully used in many fields. However, the structure of a DBN is difficult to design for different datasets. Hence, a DBN structure design algorithm based on information entropy and reconstruction error is proposed. Unlike previous algorithms, we innovatively combine network depth and node number and optimizes them simultaneously. First, the mathematical model of the structural design problem is established, and the boundary constraint for node number based on information entropy is derived by introducing the idea of information compression. Moreover, the optimization objective of the network performance based on reconstruction error is proposed by deriving the fact that network energy is proportional to reconstruction error. Finally, the improved simulated annealing (ISA) algorithm is used to adjust the DBN network layers and nodes simultaneously. Experiments were carried out on three public datasets (MNIST, Cifar-10 and Cifar-100). The results show that the proposed algorithm can design its proper structure to different datasets, yielding a trained DBN which has the lowest reconstruction error and prediction error rate. The proposed algorithm is shown to have the best performance compared with other algorithms and can be used to assist the setting of DBN structural parameters for different datasets.

Autophagy plays an important role in stemness mediation and the novel dual function of EIG121 in both autophagy and stemness regulation of endometrial carcinoma JEC cells.

Endometrial cancer (EC) is the third most common gynecologic malignancy in the world, and is considered a chemotherapy poor responding cancer. There are two underlying mechanisms on chemoresistance: the stemness of cancer stem cells (CSCs) and activation of pro-survival autophagy. It was found that autophagy is one of the main factors of cancer stem cell survival, multidrug resistance and maintenance of the homeostasis of cancer stem cells and normal cancer cells. However, the relationship between CSCs and autophagy of EC cells is still unknown. In this study, higher autophagy level was found in endometrial cancer stem cells (ECSCs) and stemness kept in line with autophagy in successive cultured JEC spheres. Autophagy inhibition decreased the properties of CSCs in JEC spheres and enhanced sensitivity of ECSCs to paclitaxel. Besides, it was found that EIG121 exerted dual functions in the regulation of autophagy and stemness not only in normal JEC cells but also JEC obtained CSCs. These findings could be useful for developing targeted therapies for endometrial carcinoma.

MiR-218 inhibits HMGB1-mediated autophagy in endometrial carcinoma cells during chemotherapy.

Endometrial carcinoma is the most common gynecological malignancy among women worldwide. Although treatment for EC has improved with the introduction of Paclitaxel (Tax) chemotherapy, the majority of patients will develop resistance to the treatment, leading to poor prognosis. One of the causes of chemoresistance is the increased ability to undergo autophagy. In this study, we identified that miR-218 was significantly down-regulated in Tax-resistant EC cells compared to the non-drug resistant cell lines, and overexpression of miR-218 sensitized paclitaxel resistant EC cells to paclitaxel. Moreover, we demonstrated that miR-218 directly binds to the 3'-UTR of HMGB1 gene. HMGB1 was upregulated in paclitaxel resistant EC cells, it mediated autophagy and contributed to chemotherapy resistance in endometrial carcinoma in vitro. HMGB1-mediated autophagy could be suppressed by miR-218 overexpression in Tax resistant EC cells. In summary, we determined the targeting role of miR-218 to HMGB1 and the regulation of miR-218 on the HMGB1-mediated cell autophagy during chemotherapy resistance in endometrial carcinoma cells. These results reveal novel potential role of miR-218 against chemotherapy resistance during the treatment of endometrial carcinoma.