No abstract

A non-immunogenic tumor microenvironment (TME) is a significant barrier to immune checkpoint blockade (ICB) response. The impact of Polybromo-1 (PBRM1) on TME and response to ICB in renal cell carcinoma (RCC) remains to be resolved. Here we show that PBRM1/Pbrm1 deficiency reduces the binding of brahma-related gene 1 (BRG1) to the IFNγ receptor 2 (Ifngr2) promoter, decreasing STAT1 phosphorylation and the subsequent expression of IFNγ target genes. An analysis of 3 independent patient cohorts and of murine pre-clinical models reveals that PBRM1 loss is associated with a less immunogenic TME and upregulated angiogenesis. Pbrm1 deficient Renca subcutaneous tumors in mice are more resistance to ICB, and a retrospective analysis of the IMmotion150 RCC study also suggests that PBRM1 mutation reduces benefit from ICB. Our study sheds light on the influence of PBRM1 mutations on IFNγ-STAT1 signaling and TME, and can inform additional preclinical and clinical studies in RCC.

A full-thickness burn wound model was used to evaluate the effects of a topically applied gel-based nitric oxide donor on wound healing in rats. The histological study demonstrated that the nitric oxide (NO) application significantly promoted re-epithelization that resulted in a fast recovery of burn wound. The histological sections further revealed that inflammatory cell infiltration in the NO-treated group was significantly increased in comparison to the control group. The enhanced accumulation of inflammatory cells resulted in a higher expression of myeloperoxidase (MPO) that was detected with imunoblotting. An immunohistochemistry study with CD31, a specific marker for endothelial cells, indicated that NO treatment markedly stimulated angiogenesis. Evaluation of collagen synthesis by immunohistochemistry with procollagen antibody demonstrated a significantly increased collagen synthesis in NO-treated wound bed. We concluded that NO treatment promoted re-epithelialization and wound closure by means of enhanced inflammatory cell infiltration, and that it promoted angiogenesis and facilitated collagen synthesis in the wound bed.

• B-cell lymphomas with surface nucleolin-Fas complexes are resistant to Fas-mediated apoptosis through decreased ligand binding.• Expression of nucleolin protects mice from a lethal agonistic Fas challenge, whereas a non-Fas binding nucleolin mutant does not.Resistance to Fas-mediated apoptosis is associated with poor cancer outcomes and chemoresistance. To elucidate potential mechanisms of defective Fas signaling, we screened primary lymphoma cell extracts for Fas-associated proteins that would have the potential to regulate Fas signaling. An activation-resistant Fas complex selectively included nucleolin. We confirmed the presence of nucleolin-Fas complexes in B-cell lymphoma cells and primary tissues, and the absence of such complexes in B-lymphocytes from healthy donors. RNA-binding domain 4 and the glycine/arginine-rich domain of nucleolin were essential for its association with IntroductionSurvival of individuals with non-Hodgkin's lymphoma (NHL) has improved with recent advancements in chemotherapy regimens, which now include targeted therapies. Despite these advancements, NHL demonstrates frequent relapses and a high mortality rate (30%). 1The principal source of NHL relapse is the survival and expansion of cells resistant to chemotherapy. Stimulation of Fas, a member of the tumor necrosis factor superfamily of apoptosis receptors, by Fas ligand (FasL)-bearing cells or from within damaged cells is an important mechanism of cell elimination, particularly in the lymphoid system. 2,3 Genetic models featuring Fas-disabling mutations develop autoreactive lymphocytes, arising from ineffective negative selection that results in autoimmune disorders and lymphoma. 4,5 Moreover, cells lacking Fas or Fas-defective cells are resistant to customary doses of chemotherapy and radiation. [6][7][8][9] Further investigations determined that Fas is a key component of responses to radiation and chemotherapy regimens, 6 as several forms of chemotherapy, including genotoxic chemotherapy, induce higher expression levels of Fas and/or FasL in order to effectively eliminate tumor cells. 10,11 However, Fas-resistant NHL cells often express normal levels of wild-type Fas and FasL while remaining resistant to Fas activation. The lack of correlation between Fas levels and sensitivity to Fasmediated apoptosis in lymphoid cancer cells indicates additional modulation of the apoptosis pathway. Investigations into the defects of Fas-mediated apoptosis have shown multiple layers of control over Fas signaling. The signaling is initiated by binding of trimeric FasL complexes to a Fas receptor, which recruits the adaptor molecule FADD and subsequently procaspase-8 through the homologous death domain and death effector domain, respectively, to form the death-inducing signaling complex. 3,12 Formation of this complex promotes cleavage and activation of the initiator caspase-8, resulting in activation of an intricate caspase cascade and cell death.13,14 Each of these signaling stages is subjected to different inhibitory mechanisms aimed at pr...

Gastric cancer is the fourth most common malignancy in the world. Although microRNA-200 (miR-200) family members are thought to play roles in tumorigenesis, their functions in carcinogenesis are tumor specific, and the underlying mechanism of action still remains elusive. Few studies to date have addressed the dysregulation and function of miR-200 family members in gastric cancer progression. Here, we report that the miR-200 family members, miR-200c and miR-141, were significantly downregulated in gastric cancer specimens and gastric cancer cell lines. Importantly, on clinical samples, the expression of miR-200c and miR-141 was inversely correlated with TNM stage, tumor invasion depth (T), tumor embolus and disease-free survival. Wound-healing assay results showed that co-transfected miR-200c/141 could inhibit the migration and invasion capability of the gastric cell line SGC-7901. We also found that miR-200c and miR-141 directly targeted zinc finger E-box-binding homeobox 1/2 (ZEB1/2) and upregulated E-cadherin expression. In specimens from gastric cancer patients, reduced expression of miR-200c/141 was associated with increased expression of ZEB1 and/or ZEB2. In addition, the downregulation of miR-200c and miR-141 was found to be due to a highly methylated CpG island located upstream of their genomic sequence and/or upregulated TGF-β signaling. Treatment with the chemotherapeutic agent decitabine, a known DNA methyltransferase inhibitor, increased miR-200c/141 expression and ameliorated decreased expression of miR-200c/141 induced by TGF-β in SGC-7901 cells. Our study revealed that miR-200c/141 was downregulated by CpG island methylation and TGF-β signaling, which decreased ZEB1/2 expression and increased E-cadherin expression to inhibit migration and invasion of gastric cancer cells and provides powerful evidence for the application of decitabine in gastric cancer treatment.