Oleuropein (OP), the predominant natural constituent of leaves of the olive tree, exerts anti-inflammatory and antioxidant effects. The purpose of this study was to assess the protective effects of OP under the conditions of paraquat (PQ)-induced oxidative stress in vitro, using the human hepatocarcinoma cell line, HepG2. Cell viability and death were determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 4′,6-diamidino-2-phenylindole-propidium iodide staining, respectively. Superoxide anion and lipid peroxidation levels were evaluated using nitroblue tetrazolium and thiobarbituric acid-reactive substances assays, respectively. Apoptosis was assessed by measuring poly(ADP-ribose) polymerase (PARP) and caspase-3 (Casp-3) cleavage via immunoblotting and immunofluorescence analyses. PQ induced a decrease in cellular viability by promoting necrosis through a mechanism involving superoxide generation and nuclear translocation of cleaved Casp-3. Co-treatment with OP afforded significant protection against the suppressive effects of PQ, as evident from increased cell viability, reduction of Casp-3 immunofluorescence, and normalization of β-tubulin expression levels. Unexpectedly, these OP-mediated protective effects were associated with increased superoxide and malondialdehyde generation and PARP cleavage. OP protects HepG2 cells against PQ-induced necrosis by suppressing Casp-3 cleavage while concomitantly acting as a pro-oxidant agent. This paradoxical mechanism of action of OP requires further investigation.

Chronic inflammation is an important factor in the development of cancer. Macrophages found in tumors, known as tumor associated macrophages (TAMs), are key players in this process, promoting tumor growth through humoral and cellular mechanisms. 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), an arachidonic acid metabolite, has been described to possess a potent chemoattractant activity for human white blood cells (WBCs). The biological actions of 5-oxo-ETE are mediated through the GPCR 5-oxo-6E,8Z,11Z,14Z-eicosatetraenoic acid receptor (OXER1). In addition, we have previously reported OXER1 as one of the membrane androgen receptors with testosterone antagonizing 5-oxo-ETE’s actions. OXER1 is highly expressed in inflammatory cells and many normal and cancer tissues and cells, including prostate and breast cancer, promoting cancer cell survival. In the present study we investigate the expression and role of OXER1 in WBCs, THP-1 monocytes, and THP-1 derived macrophages, as well as its possible role in the interaction between macrophages and cancer cells (DU-145 and T47D). We report that OXER1 is differentially expressed between WBCs and macrophages and that receptor expression is modified by LPS treatment. Our results show that testosterone and 5-oxo-ETE can act in an antagonistic way affecting Ca²⁺ movements, migration, and cytokines’ expression in immune-related cells, in a differentiation-dependent manner. Finally, we report that 5-oxo-ETE, through OXER1, can attract macrophages to the tumor site while tumor cells’ OXER1 activation in DU-145 prostate and T47D breast cancer cells, by macrophages, induces actin cytoskeletal changes and increases their migration.

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The extracellular matrix (ECM) is a key determinant of melanoma progression, regulating tumor cell behavior through biochemical and biomechanical cues. MicroRNAs (miRNAs) have emerged as critical post-transcriptional regulators of gene expression and are increasingly recognized as important modulators of ECM remodeling in cancer. This review summarizes current evidence on miRNA-mediated regulation of ECM components and ECM-associated pathways in melanoma (matrix-miRNAs). We examine studies reporting miRNAs that directly target structural ECM molecules such as collagens, laminins, fibronectin, hyaluronan-related enzymes, and proteoglycans, as well as miRNAs that indirectly regulate ECM dynamics through modulation of matrix metalloproteinases, signaling pathways, and transcription factors. The collected evidence indicates that miRNAs form complex regulatory networks that influence tumor proliferation, invasion, metastasis, angiogenesis, immune evasion, and therapy resistance by reshaping the tumor microenvironment. Tumor-suppressive miRNAs generally inhibit ECM remodeling and metastatic behavior, whereas oncogenic miRNAs promote matrix degradation and a pro-invasive microenvironment. Importantly, many miRNAs exert pleiotropic effects by targeting multiple components of interconnected signaling pathways, resulting in context-dependent outcomes during melanoma progression. Overall, miRNA-dependent regulation of the ECM represents a crucial layer of control in melanoma biology. Understanding these regulatory circuits may provide novel opportunities for biomarker development and therapeutic intervention targeting both tumor cells and their surrounding microenvironment.