ABSTRACT Ovarian cancer, one of the most lethal gynecologic malignancies, exhibits marked tumor heterogeneity. Potassium channel modulatory factor 1 (KCMF1), a RING zinc-finger protein with E3 ubiquitin ligase activity, has been implicated in tumorigenesis. However, the role of KCMF1 in ovarian cancer remains unclear. In this study, we found that KCMF1 was up-regulated in ovarian cancer tissues and that high KCMF1 expression correlated with poor survival of patients. Functional assays revealed that KCMF1 knockdown suppressed cell viability, hampered cell cycle progression, and inhibited proliferation in ovarian cancer cells. Moreover, silencing KCMF1 inhibited epithelial-mesenchymal transition (EMT), migration, and invasion in vitro. In vivo experiments confirmed that KCMF1 knockdown inhibited tumor growth and metastasis in nude mice. Conversely, KCMF1 overexpression had opposite effects in vitro and in vivo. IP-LC/MS and Label-free proteomic analysis identified nucleoredoxin (NXN), a multifunctional redox-active protein, as a potential substrate of KCMF1. Silencing NXN facilitated cell proliferation, migration, and invasion through activating the β-catenin signaling pathway. Mechanistically, we discovered that KCMF1 interacted with NXN and facilitates its degradation through K63-linked ubiquitination, thereby reducing NXN expression. Taken together, our study showed that KCMF1 promotes ovarian cancer progression through NXN, and KCMF1 might be a novel target for ovarian cancer therapy.

ABSTRACT Hypertrophic scars (HS) frequently result from severe burns, surgical procedures and other causes of deep skin damage. The impact of serum/glucocorticoid regulated kinase family member 3 (SGK3) on the formation of HS remains unclear. HS model rats were constructed by the scalding method. In addition, tissue samples from clinical patients were collected to detect the SGK3 levels in normal skin and HS tissues by RT-qPCR and western blotting. Human-derived HS fibroblasts (HSFBs) were isolated and identified using immunofluorescence. Cell Counting Kit-8, 5-Ethynyl-2’-deoxyuridine staining and scratch assays were applied to test the ability of the HSFBs to proliferate and migrate. The influence of an SGK3 inhibitor on wound healing in rats was assessed using hematoxylin and eosin staining, Masson staining, immunofluorescence and immunohistochemistry. In addition, the levels of collagen and the proteins involved in the mitogen-activated protein kinase (MAPK)/extracellular regulated protein kinase (ERK) pathway were measured by western blotting. SGK3 was highly expressed in HS tissues. Knockdown of SGK3 resulted in reduced SGK3 levels in HSFBs. Knockdown of SGK3 reduced the proliferation and migration ability of HSFBs and suppressed cellular fibrosis. Injection with an SGK3 inhibitor reduced the burn scar area, decreased epithelial thickness and inhibited collagen deposition in rats. This inhibitor also resulted in the downregulation of collagen and MAPK/ERK pathway-related proteins. In addition, MAPK/ERK pathway agonists attenuated the effect of SGK3 inhibition, promoting HS formation while inhibiting wound healing in rats; however, MAPK inhibitors had the opposite effect. In conclusion, inhibition of SGK3 reduces the proliferation, migration and fibrosis abilities of HSFBs as well as promotes wound healing and inhibits HS formation in rats by downregulating the MAPK/ERK pathway.

ABSTRACT Myocardial hypoxia-reoxygenation (H/R) injury is a frequently observed pathological event in various cardiovascular conditions. Despite the therapeutic promise of human umbilical cord mesenchymal stem cells (hUC-MSCs) in alleviating myocardial damage, their clinical use faces obstacles such as limited implantation efficiency, poor retention, and reduced post-transplantation viability. Exosomes secreted by hUC-MSCs have emerged as a viable alternative, potentially addressing these challenges. Nonetheless, the underlying mechanisms through which these exosomes confer cardioprotection have yet to be fully elucidated. This study aims to explore the protective effect of hUC-MSCs exosomes on myocardial H/R injury via the aryl hydrocarbon receptor (AHR)/NOD-like receptor family pyrin domain containing 3 (NLRP3) pathway and to assess their impact on immune cell phenotype conversion. hUC-MSCs exosomes significantly upregulated AHR expression, inhibited NLRP3-related inflammatory protein expression, enhanced myocardial cell survival, and reduced apoptosis. The protective effect of hUC-MSCs exosomes was abolished following AHR knockdown. Additionally, exosomes from AHR-overexpressing hUC-MSCs promoted the conversion of macrophages, dendritic cells (DCs), and T cells to an anti-inflammatory phenotype, thereby further enhancing myocardial protection. These findings indicted that exosomes from AHR-overexpressing hUC-MSCs protect myocardium via AHR/NLRP3 signaling, improving immune microenvironment and offering new therapeutic potential.

ABSTRACT Growth hormone (GH) is given to GH-deficient but also to non-GH-deprived children to promote growth. Since standard treatment requires tedious daily injections, long-release formulations are sought. However, non-GH-deficient conditions require higher dosing, which could entail cancer risk. To evaluate the hepatic pro-oncogenic potential of continuous GH under non-GH-deprived conditions, mice were implanted with osmotic minipumps for 5 wk during the growth period. GH secretion and hepatic actions are sexually dimorphic, thus both sexes were studied. Body growth was assessed since birth, whereas the impact on liver, a major GH target organ, was evaluated upon treatment ending, at 8 wk of age. Used dose, 6 µg/g BW, effective when given intermittently, failed to promote growth when infused continuously. Hepatocytes presented higher PCNA-stain, indicative of proliferation, in GH-treated males. STAT5 phosphorylation, related to somatic growth and metabolic GH actions, was not affected by continuous GH levels, whereas STAT3, associated with cellular growth and proliferation, was activated in females. In males, continuous GH treatment induced a female-like hepatic expression of IGF1 and cyclin D1, as well as that of MUPs and EGFR, showing that they are regulated by GH but, moreover, by the GH continuous concentration pattern. GHR and SOCS2 mRNA levels were upregulated by continuous GH in both sexes, whereas c-myc and CIS mRNA were mainly induced in female liver. These results indicate that although continuous GH administration in the used dose is not sufficient to promote growth in non-GH-deprived conditions, it may foster hepatic molecular signatures associated with potentially prooncogenic signaling in mice.

ABSTRACT Glioblastoma multiforme (GBM) is the most common form of malignant brain cancer and is generally approached with palliative intent. Preclinical studies suggest that short-term fasting may be an effective tool for enhancing existing cancer therapies by disrupting the glucose-dependent, oncogenic phenotype of many cancers. In this study, we investigated whether a fasting-mimicking environment (FME) enhances the efficacy of an emerging proapoptotic drug, procaspase-activating compound 1 (PAC-1), in 2D and 3D GBM cell models. Ad libitum food consumption (Fed) and FME conditions were simulated in vitro by modifying glucose, ketone and serum concentrations. The FME conditions enhanced PAC-1 in U87-MG, T98G and 9L-GS monolayer experiments by significantly reducing the PAC-1 50% inhibitory concentration (IC50), delaying cell growth and increasing apoptosis. Similarly, in the 3D spheroid models, the minimum concentration of PAC-1 required to reduce U87-MG and 9L-GS spheroid area was lower in the FME conditions than the Fed conditions. Additionally, we discovered that serum restriction was primarily responsible for the FME-induced PAC-1 enhancement. These finding are the first to demonstrate that fasting-mimicking conditions sensitize 2D and 3D glioma cell models to PAC-1, supporting the use of short-term fasting as a low-cost and widely accessible strategy for enhancing cancer therapies.

ABSTRACT Transposable elements (TEs) are mobile DNA sequences capable of self-replication (especially retrotransposons) within the genome, which may lead to various forms of DNA damage. The introduction of this review encompasses the diverse classes and subclasses of TEs, particularly emphasizing the most active TEs present in the human genome. An analysis of the retrotransposition process of TEs is presented, illustrating how this mechanism can result in DNA damage and gene rearrangements. Furthermore, the review meticulously examines the implications of TE insertions on gene expression and genomic organization, which may contribute to the development of various diseases, including cancer. The relationship between TE activation and the aging process is also explored, with an emphasis on that epigenetic modifications associated with aging can lead to the derepression of TEs, thereby promoting genomic instability and inflammation. These factors may play a significant role in the pathogenesis of age-related diseases, such as cancer, cardiovascular disorders, and neurodegenerative conditions. Finally, the review considers potential therapeutic approaches aimed at targeting TE activity to alleviate the impacts of aging and associated diseases.