NF-κB signaling plays a critical role in tumor growth and treatment resistance in GBM as in many other cancers. However, the molecular mechanisms underlying high, constitutive NF-κB activity in GBM remains to be elucidated. Here, we screened a panel of tripartite motif (TRIM) family proteins and identified TRIM22 as a potential activator of NF-κB using an NF-κB driven luciferase reporter construct in GBM cell lines. Knockout of TRIM22 using Cas9-sgRNAs led to reduced GBM cell proliferation, while TRIM22 overexpression enhanced proliferation of cell populations, in vitro and in an orthotopic xenograft model. However, two TRIM22 mutants, one with a critical RING-finger domain deletion and the other with amino acid changes at two active sites of RING E3 ligase (C15/18A), were both unable to promote GBM cell proliferation over controls, thus implicating E3 ligase activity in the growth-promoting properties of TRIM22. Co-immunoprecipitations demonstrated that TRIM22 bound a negative regulator of NF-κB, NF-κB inhibitor alpha (IκBα), and accelerated its degradation by inducing K48-linked ubiquitination. TRIM22 also formed a complex with the NF-κB upstream regulator IKKγ and promoted K63linked ubiquitination, which led to the phosphorylation of both IKKα/β and IκBα. Expression of a non-phosphorylation mutant, srIκBα, inhibited the growth-promoting properties of TRIM22 in GBM cell lines. Finally, TRIM22 was increased in a cohort of primary GBM samples on a tissue microarray, and high expression of TRIM22 correlated with other clinical parameters associated with progressive gliomas, such as wild-type IDH1 status. In summary, our study revealed that TRIM22 activated NF-κB signaling through posttranslational modification of two critical regulators of NF-κB signaling in GBM cells.

BackgroundHiatus hernia (HH) contributes to the pathophysiology of gastroesophageal reflux disease (GERD). Mesh-augmentation of surgical repair might be associated with a reduced risk of recurrence and GERD. However, recurrence rates, mesh-associated complications and quality of life (QOL) after mesh versus suture repair are debated. The aim of this meta-analysis was to determine HH recurrence following mesh-augmentation versus suture repair. Secondary aims were to compare complications, mortality, QOL and GERD symptoms following different repair techniques.MethodsA systematic literature search of the PubMed, Medline, Embase, Cochrane Library, and Springer database was performed to identify relevant studies comparing mesh-augmentation versus suture repair of the esophageal hiatus. Data pertinent to the benefit versus risk outcomes for these techniques were extracted and compared by meta-analysis. The odd ratio (OR) and mean differences (MD) with 95% confidence intervals were calculated.ResultsEleven studies (4 randomized, 9 non-randomized) comparing mesh (n = 719) versus suture (n = 755) repair were identified. Mesh-augmentation was associated with a reduced overall recurrence rate compared to suture repair [2.6 vs. 9.4%, OR 0.23 (95% CI 0.14–0.39), P < 0.00001]. There was no significant difference in the incidence of complications (P = 0.400) between groups. Improvement in QOL measured by SF-36 was greater following biological mesh-augmentation compared to suture repair (MD = 13.68, 95% CI 2.51–24.85, P = 0.020), as well as GERD-HRQL. No differences were seen for the GIQLI scores with permanent mesh (P = 0.530). Dysphagia improvements were better following suture repair (MD = 1.47, 95% CI 0.20–2.74, P = 0.020).ConclusionsMesh repair of HH conferred some advantages and disadvantages at short-term follow-up. Compared to a suture repair alone, mesh-augmentation might be associated with less short-term recurrences, and biological mesh was associated with improved short-term QOL. However, these advantages were offset by more dysphagia. Long-term outcomes are still needed to determine the place of mesh repair of HH.

Although some effective therapies have been available for cancer, it still poses a great threat to human health and life due to its drug resistance and low response in patients. Here, we develop a ferroptosis-based therapy by combining iron nanoparticles and cancer-specific gene interference. The expression of two iron metabolic genes (FPN and LCN2) was selectively knocked down in cancer cells by Cas13a or microRNA controlled by a NF-κB-specific promoter. Cells were simultaneously treated by iron nanoparticles. As a result, a significant ferroptosis was induced in a wide variety of cancer cells. However, the same treatment had little effect on normal cells. By transferring genes with adeno-associated virus and iron nanoparticles, the significant tumor growth inhibition and durable cure were obtained in mice with the therapy. In this work, we thus show a cancer therapy based on gene interference-enhanced ferroptosis.

ADP-ribosylation is a unique posttranslational modification catalyzed by poly(ADP-ribose) polymerases (PARPs) using NAD+ as ADP-ribose donor. PARPs play an indispensable role in DNA damage repair and small molecule PARP inhibitors have emerged as potent anticancer drugs. However, to date, PARP inhibitor treatment has been restricted to patients with BRCA1/2 mutation-associated breast and ovarian cancer. One of the major challenges to extend the therapeutic potential of PARP inhibitors to other cancer types is the absence of predictive biomarkers. Here, we show that ovarian cancer cells with higher level of NADP+, an NAD+ derivative, are more sensitive to PARP inhibitors. We demonstrate that NADP+ acts as a negative regulator and suppresses ADP-ribosylation both in vitro and in vivo. NADP+ impairs ADP-ribosylation-dependent DNA damage repair and sensitizes tumor cell to chemically synthesized PARP inhibitors. Taken together, our study identifies NADP+ as an endogenous PARP inhibitor that may have implications in cancer treatment.

In the past decades, carotid angioplasty and stenting (CAS) has been developed into a credible option for the patients with carotid stenosis. However, restenosis remains a severe and unsolved issue after CAS treatment. Restenosis is characterized by neointimal hyperplasia, which is partially caused by vascular smooth muscle cells (VSMC) proliferation. However, the molecular mechanism involved in the restenosis is still unclear. In this study, we demonstrated a functional crosstalk between two TGF-β superfamily signaling pathway members, Smad3 and BMPR2, in VSMC proliferation. Smad3 plays an important role in the TGF-β/Smad3 signaling pathway, and is significantly up-regulated in the carotid artery with restenosis to promote VSMC proliferation. In contrast, BMP receptor II (BMPR2), an inhibitor of VSMC proliferation is down-regulated in carotid restenosis. We further found that BMPR2 down-regulation is mediated by miR-17~92 cluster, which is transcriptionally regulated by Smad3. Thus, Smad3 up-regulation and Smad3/miR-17~92 cluster -dependent BMPR2 down-regulation are likely to promote VSMC proliferation and restenosis. Taken together, our results may provide novel clues for early diagnosis of carotid restenosis and developing new therapeutic strategy.