Metabolic-associated fatty liver disease (MAFLD) is a spectrum of clinical manifestations ranging from benign steatosis to cirrhosis. A key event in the pathophysiology of MAFLD is the development of nonalcoholic steatohepatitis (NASH), which can potentially lead to fibrosis and hepatocellular carcinoma, but the triggers of MAFLD-associated inflammation are not well understood. We have observed that lipid accumulation in hepatocytes induces expression of ligands specific to the activating immune receptor NKG2D. Tissue-resident innate-like T cells, most notably γδ T cells, are activated through NKG2D and secrete IL-17A. IL-17A licenses hepatocytes to produce chemokines that recruit proinflammatory cells into the liver, which causes NASH and fibrosis. NKG2D-deficient mice did not develop fibrosis in dietary models of NASH and had a decreased incidence of hepatic tumors. The frequency of IL-17A ⁺ γδ T cells in the blood of patients with MAFLD correlated directly with liver pathology. Our findings identify a key molecular mechanism through which stressed hepatocytes trigger inflammation in the context of MAFLD.

The aim of this study was to analyze the association between vascular endothelial growth factor (VEGF) expression on tumor cells and other clinicopathologic parameters in breast cancer that could give additional information on its prognostic significance. Immunohistochemical analysis of expression of VEGF, estrogen (ER) and progesterone receptor (PR), HER-2/neu, and Ki67 was performed in 233 breast cancers. VEGF expression estimated semiquantitatively was correlated with all the above-mentioned parameters as well as with clinicopathologic characteristics of breast cancer such as menopausal status of patients, tumor size, histologic and nuclear grade, vascular invasion, and lymph node status. Most of the tumor cells and some stromal components expressed VEGF. A higher percentage of VEGF-positive tumor cells was present in premenopausal patients and in ER-negative tumors. In postmenopausal patients tumors with a higher expression of VEGF were associated not only with ER-negative but also with HER-2/neu-positive tumor cells. These ER-negative tumors were characterized by a higher proliferative activity. Angiogenic switch as well as proliferative activity of breast cancer cells probably are unfavorably dependent on estrogen activity. This negative correlation between VEGF expression and ER status may not only shed more light on tumor biology but may also have future therapeutic implications.

The aim of this study was to evaluate the expression of matrix metalloproteinase 2 (MMP-2) and matrix metalloproteinase 9 (MMP-9) in prostate cancer in the main tumor mass and tumor cells at the positive margin as well as the influence of these biomarkers on the biochemical recurrence of the disease in prostatectomy patients. Tissue microarrays of 120 archival prostate carcinoma samples were immunohistochemically evaluated for MMP-2 and MMP-9 expression and compared with clinicopathological parameters. Tumors with positive surgical margins showed significantly higher overall expression of MMP-9 versus tumors with negative resection marginsP=0.0121. MMP-9 expression was significantly elevated in tumors from patients who had biochemical recurrenceP=0.0207. In the group of patients with negative margins, MMP-9 expression above the cut-off value was significantly associated with recurrenceP=0.0065. Multivariate analysis indicated that MMP-9 is a good predictor of biochemical recurrence (odds ratio = 10.29;P=0.0052). Expression of MMP-2 in tumor cells was significantly higher at the positive margins than in the main tumor massP=0.0301. The present results highlight the potential value of MMP-2 and MMP-9 expression for predicting the behavior of prostate tumors after prostatectomy with both positive and negative surgical margins.

BRAFV600E mutations are found in approximately 10% of colorectal cancer patients and are associated with worse prognosis and poor outcomes with systemic therapies. The aim of this study was to identify novel druggable features of BRAFV600E-mutated colon cancer (CC) cells associated with the response and resistance to BRAFV600E inhibitor vemurafenib. Towards this aim, we carried out global proteomic profiling of BRAFV600E mutant vs. KRAS mutant/BRAF wild-type and double wild-type KRAS/BRAF CC cells followed by bioinformatics analyses. Validation of selected proteomic features was performed by immunohistochemistry and in silico using the TCGA database. We reveal an increased abundance and activity of nucleophosmin (NPM1) in BRAFV600E-mutated CC in vitro, in silico and in tumor tissues from colon adenocarcinoma patients and demonstrate the roles of NPM1 and its interaction partner c-Myc in conveying the resistance to vemurafenib. Pharmacological inhibition of NPM1 effectively restored the sensitivity of vemurafenib-resistant BRAF-mutated CC cells by down-regulating c-Myc expression and activity and consequently suppressing its transcriptional targets RanBP1 and phosphoserine phosphatase that regulate centrosome duplication and serine biosynthesis, respectively. Altogether, findings from this study suggest that the NPM1/c-Myc axis could represent a promising therapeutic target to thwart resistance to vemurafenib in BRAF-mutated CC.