ITGB2 fosters the cancerous characteristics of ovarian cancer cells through its role in mitochondrial glycolysis transformation.

Related studies have shown that ITGB2 mediates mitochondrial glycolytic transformation in cancer-associated fibroblasts and participates in tumor occurrence, metastasis and invasion of cancer cells. Based on these studies, we tried to construct a mitochondrial glycolysis regulatory network and explored its effect on mitochondrial homeostasis and ovarian cancer cells' cancerous characteristics. Our research revealed a distinct increase in the expression of ITGB2 and associated signaling pathway elements (PI3K-AKT-mTOR) in cases of ovarian cancer. ITGB2 might control mTOR expression via the PI3K-AKT pathway, thus promote mitochondrial glycolysis transformation and cell energy supply in ovarian cancer. This pathway could also inhibit mitophagy, maintain mitochondrial stability, and enhance the cancerous characteristics in case of ovarian cancer cells by mediating mitochondrial glycolytic transformation. Thus, we concluded that ITGB2-associated signaling route (PI3K-AKT-mTOR) may contribute to the progression of cancerous traits in ovarian cancer via mediating mitochondrial glycolytic transformation.

LncRNA CACNA1G-AS1 up-regulates FTH1 to inhibit ferroptosis and promote malignant phenotypes in ovarian cancer cells.

Previous study revealed that ferritin heavy chain-1 (FTH1) could regulate ferritinophagy and affect intracellular Fe2+ content in various tumors, while its N6-methyladenosine (m6A) RNA methylation was closely related the prognosis of ovarian cancer patients. However, little is known about the role of FTH1 m6A methylation in ovarian cancer (OC) and its possible action mechanisms. In this study we constructed FTH1 m6A methylation regulatory pathway (LncRNA CACNA1G-AS1/IGF2BP1) according to related bioinformatics analysis and research, through clinical sample detections we found that these pathway regulatory factors were significantly up-regulated in ovarian cancer tissues, and their expression levels were closely related to the malignant phenotype of ovarian cancer. In vitro cell experiments showed that LncRNA CACNA1G-AS1 could up-regulate FTH1 expression through IGF2BP1 axis, thus inhibited ferroptosis by regulating ferritinophagy, and finally promoted proliferation and migration in ovarian cancer cells. Tumor-bearing mice studies showed that the knock-down of LncRNA CACNA1G-AS1 could inhibited the tumorigenesis of ovarian cancer cells in vivo condition. Our results demonstrated that LncRNA CACNA1G-AS1 could promote the malignant phenotypes of ovarian cancer cells through FTH1-IGF2BP1 regulated ferroptosis.

C-MYC Inhibited Ferroptosis and Promoted Immune Evasion in Ovarian Cancer Cells through NCOA4 Mediated Ferritin Autophagy.

OBJECTIVE: We aimed to construct the ferritin autophagy regulatory network and illustrate its mechanism in ferroptosis, TME immunity and malignant phenotypes of ovarian cancer. METHODS: First, we used Western blot assays and immunohistochemistry to detect the pathway expression in ovarian cancer samples (C-MYC, NCOA4). Then, we performed RIP and FISH analysis to verify the targeted binding of these factors after which we constructed ovarian cancer cell models and detected pathway regulator expression (NCOA4). Co-localization and Western blot assays were used to detect ferritin autophagy in different experimental groups. We selected corresponding kits to assess ROS contents in ovarian cancer cells. MMP was measured using flow cytometry and mitochondrial morphology was observed through TEM. Then, we chose Clone, EdU and Transwell to evaluate the proliferation and invasion abilities of ovarian cancer cells. We used Western blot assays to measure the DAMP content in ovarian cancer cell supernatants. Finally, we constructed tumor bearing models to study the effect of the C-MYC pathway on ovarian cancer tumorigenesis and TME immune infiltration in in vivo conditions. RESULTS: Through pathway expression detection, we confirmed that C-MYC was obviously up-regulated and NCOA4 was obviously down-regulated in ovarian cancer samples, while their expression levels were closely related to the malignancy degree of ovarian cancer. RIP, FISH and cell model detection revealed that C-MYC could down-regulate NCOA4 expression through directly targeted binding with its mRNA. Ferritin autophagy and ferroptosis detection showed that C-MYC could inhibit ferroptosis through NCOA4-mediated ferritin autophagy, thus reducing ROS and inhibiting mitophagy in ovarian cancer cells. Cell function tests showed that C-MYC could promote the proliferation and invasion of ovarian cancer cells through the NCOA4 axis. The Western blot assay revealed that C-MYC could reduce HMGB1 release in ovarian cancer cells through the NCOA4 axis. In vivo experiments showed that C-MYC could promote tumorigenesis and immune evasion in ovarian cancer cells through inhibiting HMGB1 release induced by NCOA4-mediated ferroptosis. CONCLUSION: According to these results, we concluded that C-MYC could down-regulate NCOA4 expression through directly targeted binding, thus inhibiting ferroptosis and promoting malignant phenotype/immune evasion in ovarian cancer cells through inhibiting ferritin autophagy.

Exosomes Derived by SIRT1-Overexpressing Bone Marrow Mesenchymal Stem Cells Improve Pubococcygeus Muscle Injury in Rats.

BACKGROUND AND OBJECTIVES: To evaluate the effect of exosomes (Exos) derived from silent mating type information regulation 2 homolog 1 (SIRT1)-overexpressing human bone marrow mesenchymal stem cells (BMSCs) on the recovery of pubococcygeus muscle Injury. METHODS AND RESULTS: Exos isolated from SIRT1-overexpressing BMSCs (SIRT1/exos) were injected into a vaginal dilation-induced rat model of Stress urinary incontinence (SUI). The efficacy of Exos treatment on SUI was evaluated by determining the values of urodynamic parameters. The proliferation and differentiation of satellite cells (SCs) were examined by CCK-8 assay, Western blotting, and immunofluorescence staining. The mRNA and protein expression of molecules related to SC differentiation were detected by RT-qPCR and Western blotting, respectively. Treatment with SIRT1/exos significantly improved the values of abdominal leak point pressure (ALPP), maximum bladder volume (MBV), and estimated marginal mean in rats of SUI. Exposure of SIRT1/exos enhanced the proliferation, differentiation, and activation of SCs. Moreover, SIRT1/exos exhibited their positive effect on BMSCs by activating the ERK signaling. CONCLUSIONS: Our findings demonstrated that SIRT1/exos meliorated pubococcygeus muscle injury in rats by promoting ERK pathway, which may provide a novel cell-free therapeutic strategy for SUI.

Upregulation of heme oxygenase-1 protected against brain damage induced by transient cerebral ischemia-reperfusion injury in rats.

The aim of the present study was to identify the effect of heme oxygenase (HO)-1 gene on cerebral ischemia-reperfusion injury. Sprague-Dawley rats were divided randomly into four groups: Sham group, vehicle group, empty adenovirus vector (Ad) group and recombinant HO-1 adenovirus (Ad-HO-1) transfection group. Rats in the vehicle, Ad and Ad-HO-1 groups were respectively injected with saline, Ad or Ad-HO-1 for 3 days prior to cerebral ischemia-reperfusion injury. Subsequently, the middle cerebral artery occlusion method was used to establish the model of cerebral ischemia-reperfusion injury. Following the assessment of neurological function, rats were sacrificed, and the infarction volume and apoptotic index in rat brains were measured. Furthermore, the protein expression levels of HO-1 in brain tissues were detected using western blot analysis. Results indicated that the neurological score of the Ad-HO-1 group was significantly increased compared with the Ad or vehicle groups, respectively (P<0.001). The volume of cerebral infarction and the index score of neuronal apoptosis in the vehicle and Ad groups was significantly increased compared with the Ad-HO-1 group (P<0.01). The death of neuronal cells following cerebral ischemia-reperfusion injury reduced remarkably induced by over-expression of HO-1. These findings suggest a neuroprotective role of HO-1 against brain injury induced by transient cerebral ischemia-reperfusion injury.