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Aging is marked by a decline in tissue integrity, particularly in skin and muscle, driven by oxidative stress and extracellular matrix (ECM) degradation. Superoxide dismutase 1 (SOD1) deficiency exacerbates these processes, accelerating atrophy. Matrix metalloproteinase‐2 (MMP‐2), a key enzyme in ECM breakdown, targets collagen type XVII (COLXVII), which is critical for tissue structure and stability. In this study, we investigated the role of MMP‐2 in SOD1‐deficient models and assessed the therapeutic potential of its inhibition. To assess the impact of MMP inhibition on wound healing and skin atrophy, we applied batimastat, a broad‐spectrum MMP inhibitor, to Sod1‐deficient mice. While batimastat inhibits multiple MMPs, including MMP‐2, MMP‐9, and MMP‐14, its application allows us to evaluate the general role of MMP activity in SOD1‐related ECM degradation and repair processes. Using Sod1/Mmp2 double‐knockout mice and the MMP inhibitor batimastat, we observed that MMP‐2 deletion restored skin thickness, increased COLXVII expression, and improved wound healing. Batimastat application yielded similar benefits, reversing skin atrophy and enhancing repair. In muscle tissue, MMP‐2 inhibition restored muscle mass and function, with parallel improvements in SOD1 mutant Caenorhabditis elegans. Preservation of COLXVII emerged as a critical mechanism, significantly mitigating SOD1‐related tissue degeneration. These findings highlight MMP‐2's pivotal role in senescence‐associated tissue atrophy and underscore the therapeutic potential of targeting the SOD1‒MMP‐2‒COLXVII axis to combat age‐related tissue degeneration. Our work identifies a novel role for MMP‐2 in driving senescence‐associated skin and muscle degeneration through ECM degradation. We demonstrate that inhibiting MMP‐2 activity restores tissue integrity by preserving COLXVII, revealing a new therapeutic pathway for combating oxidative stress‐induced tissue aging. Using both mammalian and nematode models, we provide robust evidence that targeting the SOD1‒MMP‐2‒COLXVII axis can reverse aging‐related structural and functional declines, offering translational potential for clinical intervention in age‐related disorders.

Vasculogenic mimicry (VM)‐positive melanomas are usually associated with poor prognosis. Rictor, the key component of the rapamycin‐insensitive complex of mTOR (mTORC2), is up‐regulated in several cancers, especially in melanomas with poor prognosis. The aim of this study was to investigate the role of Rictor in the regulation of VM and the mechanism underlying this possible regulation. VM channels were found in 35 of 81 tested melanoma samples and high Rictor expression correlated with VM structures. Moreover, Kaplan–Meier survival curves indicated that VM structures and high Rictor expression correlated with shorter survival in patients with melanoma. In vitro, Rictor knockdown by short hairpin RNA (shRNA) significantly inhibited the ability of A375 and MUM‐2B melanoma cells to form VM structures, as evidenced by most tubes remaining open. Cell cycle analysis revealed that Rictor knockdown blocked cell growth and resulted in the accumulation of cells in G2/M phase, and cell migration and invasion were greatly affected after Rictor down‐regulation. Western blotting assays indicated that down‐regulating Rictor significantly inhibited the phosphorylation of AKT at Ser473 and Thr308, which subsequently inhibited the expression and activity of downstream MMP‐2/9, as confirmed by real‐time PCR and gelatin Zymography. MK‐2206, a small‐molecule inhibitor of AKT, similarly inhibited the activity of AKT and secretion of MMP‐2/9, further supporting that Rictor down‐regulation inhibits the phosphorylation of AKT and activity of downstream MMP‐2/9 to affect VM formation. In conclusion, Rictor plays an important role in melanoma VM via the Rictor—AKT—MMP‐2/9 signalling pathway.

Human pharyngeal squamous cell carcinoma (HPSCC) is the most common malignancy in the head and neck region, characterized by high mortality and a propensity for metastasis. Fucoxanthin, a carotenoid isolated from brown algae, exhibits pharmacological properties associated with the suppression of tumor proliferation and metastasis. Nevertheless, its potential to inhibit HPSCC proliferation and metastasis has not been fully elucidated. This study represents the first exploration of the inhibitory effects of fucoxanthin on two human pharyngeal squamous carcinoma cell lines (FaDu and Detroit 562), as well as the mechanisms underlying those effects. The results showed dose-dependent decreases in the proliferation, migration, and invasion of HPSCC cells after fucoxanthin treatment. Further studies indicated that fucoxanthin caused a significant reduction in the expression levels of proteins in the phosphoinositide 3−kinase (PI3K)/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, as well as the downstream proteins matrix metalloproteinase (MMP)−2 and MMP−9. Specific activators of PI3K/AKT reversed the effects of fucoxanthin on these proteins, as well as on cell proliferation and metastasis, in FaDu and Detroit 562 cells. Molecular docking assays confirmed that fucoxanthin strongly interacted with PI3K, AKT, mTOR, MMP−2, and MMP−9. Overall, fucoxanthin, a functional food component, is a potential therapeutic agent for HPSCC.

In order to solve the problems of receptor promiscuity and poor blood‐brain barrier (BBB) penetration in the treatment of glioblastomas (GBM), a novel dual‐functional nanocomplex drug delivery system is developed based on the strategy of peptide‐drug conjugates. In this study, SynB3‐PVGLIG‐PTX is designed and screened out by matrix metalloproteinase‐2 (MMP‐2), to which it exhibits the best affinity. The MMP‐2‐sensitive peptide (PVGLIG) and a cell‐penetration peptide (SynB3) are combined to form a dual‐functional peptide. Moreover, as a drug‐peptide nanocomplex, SynB3‐PVGLIG‐PTX exhibited a high potential to form an aggregation with good solubility that can release paclitaxel (PTX) through the cleavage of MMP‐2. From a functional perspective, it is found that SynB3‐PVGLIG‐PTX can specifically inhibit the proliferation, migration, and invasion of GBM cells in vitro in the presence of MMP‐2, in contrast to that observed in MMP‐2 siRNA transfected cells. Further investigation in vivo shows that SynB3‐PVGLIG‐PTX easily enters the brain of U87MG xenograft nude mice and can generate a better suppressive effect on GBM through a controlled release of PTX from SynB3‐PVGLIG‐PTX compared with PTX and temozolomide. Thus, it is proposed that SynB3‐PVGLIG‐PTX can be used as a novel drug‐loading delivery system to treat GBM due to its specificity and BBB permeability. SynB3‐PVGLIG‐PTX exhibits a strong affinity with MMP‐2, and it can enhance water solubility by agglomerating to form a special structure with a positive charge; a controlled release of PTX from SynB3‐PVGLIG‐PTX occurs upon cleavage of MMP‐2, implying that SynB3‐PVGLIG‐PTX has a specific cytotoxicity in GBM cells; SynB3‐PVGLIG‐PTX can effectively inhibit GBM in vitro and in vivo.

Among matrix metalloproteinases (MMPs), MMP-9/2 are key enzymes involved in the proteolysis of extracellular matrices in the inflammatory process and in cancer. Since MMP-9/2 expression levels, activity, and secretion is up-regulated during inflammation in response to pro-inflammatory cytokines, such as interleukin-6 (IL-6), many efforts have been devoted to identifying factors that could inhibit the IL-6-induced MMP-9/2 expression. Up to now, several reports indicated that polyphenols from fruits and vegetables are among the major components of health promotion for their antioxidant properties and also for their anti-inflammatory and anti-cancer agents. Among plant derived polyphenols, lemon (Citrus limon) peel extract (LPE) shows anti-cancer properties in various cancer types. In our previous work, we demonstrated that LPE can reduce IL-6-induced migration/invasiveness and MMP-9/2 up-regulation in some gastric cancer cell lines. This study aims to exploit the anti-cancer properties of LPE using an in vitro system model of inflammation, consisting of IL-6-exposed human primary colon cancer cells. We first analyzed the effect of LPE on IL-6-induced cell migration and invasiveness by wound healing and Boyden chamber assay, respectively. The MMP-2 mRNA expression levels and gelatinolytic activity in the cell culture media were determined by q-PCR analysis and gelatin zymography, respectively, and finally, the effects of LPE on IL-6-induced JAK2/STAT3 signaling pathways have been investigated by Western blotting analysis. Our results show that LPE is able to inhibit the IL-6-dependent cell migration and invasiveness associated with the up-regulation of MMP-2 expression levels and that these effects are correlated to the STAT3 phosphorylation in human primary T88 and T93 colon cancer cells.

An artificial receptor for proMMP‐9 was created by fusing tissue inhibitor of MMP‐1 (TIMP‐1) with type II transmembrane mosaic serine protease (MSP‐T1). Expression of MSP‐T1 in 293T cells induced binding of proMMP‐9, which was processed by MMP‐2 activated by membrane type 1 MMP (MT1‐MMP). HT1080 cells transfected with the MSP‐T1 gene produced activated MMP‐9 in collagen gel, and addition of proMMP‐2 to the culture augmented it, which resulted in intensive collagen digestion. These cells metastasized into chick embryonic liver more than control cells. Treatment of HT1080 cells with concanavalin A in the presence of exogenous proMMP‐2 induced activation of not only proMMP‐2 but also proMMP‐9. Knockdown of MT1‐MMP or TIMP‐2 expression with siRNA suppressed activation of both proMMP‐2 and proMMP‐9. Transfection of TIMP‐1 siRNA suppressed cell binding and activation of proMMP‐9, but not proMMP‐2 activation. Knockdown of a disintegrin and metalloproteinase 10 (ADAM10) expression reduced cell binding and processing of proMMP‐9. These results suggest that proMMP‐9, which binds to a receptor complex containing TIMP‐1 and ADAM10, is activated by the MT1‐MMP/MMP‐2 axis, and MMP‐9 thus activated stimulates cellular proteolysis and metastasis. ProMMP‐9 which binds to a receptor complex containing TIMP‐1 and ADAM10 is activated by MT1‐MMP/MMP‐2 axis. MMP‐9 thus activated stimulates cellular proteolysis and metastasis.

ABSTRACT This study aimed to elucidate the roles of junctional adhesion molecule 2 (JAM‐2), collagen I and matrix metalloproteinase 2 (MMP‐2) in the pathogenesis of pelvic organ prolapse (POP) and explore their potential as diagnostic markers. We examined 82 POP patients and 64 controls using enzyme‐linked immunosorbent assay (ELISA) and quantitative Polymerase Chain Reaction (qPCR) to analyse protein and gene expression levels of JAM‐2, Collagen I and MMP‐2. Receiver operating characteristic (ROC) analysis evaluated their diagnostic efficacy, with correlation analyses linking molecular markers to POP severity based on POP‐Q grades. Our study found no significant differences in age, BMI and vaginal parity between POP patients and controls. Molecular analyses revealed significant alterations in the expression levels of JAM‐2, Collagen I and MMP‐2 in POP patients. Specifically, there was a marked decrease in JAM‐2 and collagen I levels, accompanied by an increase in MMP‐2 expression, indicating a disruption in the balance between tissue synthesis and degradation. ROC analysis demonstrated the significant discriminative power of these markers, with substantial area under the curve (AUC) values for diagnosing POP. Correlation analysis further showed a significant association between the expression of JAM‐2, Collagen I and MMP‐2 and the clinical severity of POP, as indicated by POP‐Q grades. Our findings revealed the significant changes in the expression of JAM‐2, Collagen I and MMP‐2 that may contribute to the POP pathogenesis. The diagnostic potential of these markers was substantiated, suggesting their utility in developing noninvasive diagnostic tools for POP.

Vasculogenic mimicry (VM) constitutes a novel approach for tumour blood supply and contributes to tumour metastasis and poor prognosis in patients with melanoma. Myoferlin (MYOF), a type II membrane protein involved in membrane regeneration and repair, is elevated in several malignant tumours, especially in advanced melanomas. This study aims to investigate the role and mechanism of MYOF in the regulation of VM. VM structures were found in 14 of 52 tested melanoma samples, and high MYOF expression correlated with VM structures. According to Kaplan–Meier survival curves, VM channels and elevated MYOF expression both correlated with poor prognosis in melanoma patients. Down‐regulation of MYOF by siRNA severely impaired the capability of A375 cells to form VM structures in vitro. Further studies demonstrated MYOF knockdown inhibited cell migration and invasion, which is required for VM formation, via decreasing MMP‐2 expression as evidenced by Western blotting, RT‐RCP and ELISA results. SB‐3CT, a specific inhibitor of MMP‐2, showed similar inhibiting effects with siMYOF, further supporting that MYOF down‐regulation inhibits MMP‐2 expression to affect VM formation. Moreover, MYOF knockdown suppress VM formation by A375 cells by inducing mesenchymal‐to‐epithelial transition (MET). After down‐regulating MYOF, focal adhesions were enlarged and A375 cells developed into a clear epithelial morphology. Such cells acquired the expression of E‐cadherin at adherens junctions along with a loss of mesenchymal markers, such as Vimentin and Twist1. In conclusion, MYOF plays an important role in VM and knockdown of MYOF suppresses VM formation via decreasing MMP‐2 and inducing MET in A375 melanoma cells.

Golgi phosphoprotein 73 (GP73) has been regarded as a novel serum biomarker for the diagnosis of hepatocellular carcinoma (HCC) in recent years. It has been reported that the upregulation of GP73 may promote the carcinogenesis and metastasis of HCC; however, the mechanisms remain poorly understood. In this study, GP73 correlates positively with matrix metalloproteinase‐2 (MMP‐2) in HCC‐related cells and tissues. Further studies indicate that the knockdown of GP73 blocks MMP‐2 trafficking and secretion, resulting in cell invasion inhibition. Additionally, the knockdown of GP73 induces the accumulation of intracellular MMP‐2, which inhibits the phosphorylation of Src at Y416 and triggers the inhibition of SAPK/JNK and p53‐p21 signalling pathways through a negative feedback loop. Finally, the transactivation of MMP2 was inhibited by the reduction in E2F1. This study reveals that GP73 plays functional roles in the trafficking and equilibrium of epithelial‐mesenchymal transition (EMT)‐related secretory proteins and that GP73 serves as a new potential target for combating the metastasis of HCC.

In solid tumours, elevated interstitial fluid pressure (osmotic and hydrostatic pressure) is a barrier to drug delivery and correlates with poor prognosis. Glioblastoma (GBM) further experience compressive force when growing within a space limited by the skull. Caveolae are proposed to play mechanosensing roles, and caveola‐forming proteins are overexpressed in GBM. We asked whether caveolae mediate the GBM response to osmotic pressure. We evaluated in vitro the influence of spontaneous or experimental down‐regulation of caveola‐forming proteins (caveolin‐1, CAVIN1) on the proteolytic profile and invasiveness of GBM cells in response to osmotic pressure. In response to osmotic pressure, GBM cell lines expressing caveola‐forming proteins up‐regulated plasminogen activator (uPA) and/or matrix metalloproteinases (MMPs), some EMT markers and increased their in vitro invasion potential. Down‐regulation of caveola‐forming proteins impaired this response and prevented hyperosmolarity‐induced mRNA expression of the water channel aquaporin 1. CRISPR ablation of caveola‐forming proteins further lowered expression of matrix proteases and EMT markers in response to hydrostatic pressure, as a model of mechanical force. GBM respond to pressure by increasing matrix‐degrading enzyme production, mesenchymal phenotype and invasion. Caveola‐forming proteins mediate, at least in part, the pro‐invasive response of GBM to pressure. This may represent a novel target in GBM treatment.