Sirtuin 1 (SIRT1) is known to play a role in a variety of tumorigenesis processes by deacetylating histone and non‐histone proteins; however, antitumour effects by suppressing SIRT1 activity in ...non‐small cell lung cancer (NSCLC) remain unclear. This study was designed to scrutinize clinicopathological significance of SIRT1 in NSCLC and investigate effects of metformin on SIRT1 inhibition. This study also evaluated new possibilities of drug combination using a SIRT1 inhibitor, tenovin‐6, in NSCLC cell lines. It was found that SIRT1 was overexpressed in 300 (62%) of 485 formalin‐fixed paraffin‐embedded NSCLC tissues. Its overexpression was significantly associated with reduced overall survival and poor recurrence‐free survival after adjusted for histology and pathologic stage. Thus, suppression of SIRT1 expression may be a reasonable therapeutic strategy for NSCLC. Metformin in combination with tenovin‐6 was found to be more effective in inhibiting cell growth than either agent alone in NSCLC cell lines with different liver kinase B1 (LKB1) status. In addition, metformin and tenovin‐6 synergistically suppressed SIRT1 expression in NSCLC cells regardless of LKB1 status. The marked reduction in SIRT1 expression by combination of metformin and tenovin‐6 increased acetylation of p53 at lysine 382 and enhanced p53 stability in LKB1‐deficient A549 cells. The combination suppressed SIRT1 promoter activity more effectively than either agent alone by up‐regulating hypermethylation in cancer 1 (HIC1) binding at SIRT1 promoter. Also, suppressed SIRT1 expression by the combination synergistically induced caspase‐3‐dependent apoptosis. The study concluded that metformin with tenovin‐6 may enhance antitumour effects through LKB1‐independent SIRT1 down‐regulation in NSCLC cells.
Cancer is a catabolic inflammatory disease that causes patients to often experience weight loss, or even cachexia in severe cases. Undernourishment in patients with cancer impairs the quality of life ...and therapeutic response, further leading to poor prognosis. Active and frequent nutritional screening and assessment using valid tools are important for fast and appropriate nutritional intervention. Additionally, a suitable individualized nutritional intervention strategy should be established based on the nutritional assessment result. In general, nutritional intervention begins with nutritional counseling of patients diagnosed with cancer, and a well-planned nutritional counseling improves the treatment adherence and nutritional status. When planning nutritional supplementation for cancer patients, specific nutrients, including amino acids and fatty acids, should be considered. However, there has been no consistent result showing that any particular nutrient significantly improves the prognosis of cancer patients. Hence, continuous attention from clinical physicians is needed to plan nutritional improvement in patients with cancer.
Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory disorder with an unknown etiology. IBD is composed of two different disease entities: Crohn's disease (CD) and ulcerative colitis ...(UC). IBD has been thought to be idiopathic but has two main attributable causes that include genetic and environmental factors. The gastrointestinal tract in which this disease occurs is central to the immune system, and the innate and the adaptive immune systems are balanced in complex interactions with intestinal microbes under homeostatic conditions. However, in IBD, this homeostasis is disrupted and uncontrolled intestinal inflammation is perpetuated. Recently, the pathogenesis of IBD has become better understood owing to advances in genetic and immunologic technology. Moreover, new therapeutic strategies are now being implemented that accurately target the pathogenesis of IBD. Beyond conventional immunesuppressive therapy, the development of biological agents that target specific disease mechanisms has resulted in more frequent and deeper remission in IBD patients, with mucosal healing as a treatment goal of therapy. Future novel biologics should overcome the limitations of current therapies and ensure that individual patients can be treated with optimal drugs that are safe and precisely target IBD.
TNF receptor-associated factor 6 (TRAF6)-BECN1 signaling axis plays a pivotal role in autophagy induction through ubiquitination of BECN1, thereby inducing lung cancer migration and invasion in ...response to toll-like receptor 4 (TLR4) stimulation. Herein, we provide novel molecular and cellular mechanisms involved in the negative effect of ubiquitin-specific peptidase 15 (USP15) on lung cancer progression. Clinical data of the TCGA and primary non-small cell lung cancer (NSCLC) patients (n = 41) revealed that the expression of USP15 was significantly downregulated in lung cancer patients. Importantly, USP15-knockout (USP15KO) A549 and USP15KO H1299 lung cancer cells generated with CRISPR-Cas9 gene-editing technology showed increases in cancer migration and invasion with enhanced autophagy induction in response to TLR4 stimulation. In addition, biochemical studies revealed that USP15 interacted with BECN1, but not with TRAF6, and induced deubiquitination of BECN1, thereby attenuating autophagy induction. Notably, in primary NSCLC patients (n = 4) with low expression of USP15, 10 genes (CCNE1, MMP9, SFN, UBE2C, CCR2, FAM83A, ETV4, MYO7A, MMP11, and GSDMB) known to promote lung cancer progression were significantly upregulated, whereas 10 tumor suppressor genes (FMO2, ZBTB16, FCN3, TCF21, SFTPA1B, HPGD, SOSTDC1, TMEM100, GDF10, and WIF1) were downregulated, providing clinical relevance of the functional role of USP15 in lung cancer progression. Taken together, our data demonstrate that USP15 can negatively regulate the TRAF6-BECN1 signaling axis for autophagy induction. Thus, USP15 is implicated in lung cancer progression.
Abbreviations SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 TLR toll-like receptor NSCLC non-small cell lung cancer ACE2 angiotensin-converting enzyme 2 TMPRSS2 transmembrane protease ...serine subtype 2 GSEA gene set enrichment analysis Pam3CSK4 tripalmitoyl-S-glycero-Cys-(Lys) 4 FSL-1 fibroblast stimulating lipopeptide 1 NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells IKK inhibitor of nuclear factor-κB kinase ERK extracellular signal-regulated kinase CRISPR-Cas9 clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9 Dear editor, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to severe outcomes in patients with cancer 1. Abbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TLR, toll-like receptor; NSCLC, non-small cell lung cancer; ∆Mag; magnitude difference; ACE2, angiotensin-converting enzyme 2; TMPRSS2, transmembrane protease serine subtype 2; LTTs, lung tumor tissues; mLNTs, matched lung normal tissues; GSEA, gene set enrichment analysis; IL-1R, interleukin-1 receptor; TNF, tumor necrosis factor; Pam3CSK4, tripalmitoyl-S-glycero-Cys-(Lys) 4; FSL-1, fibroblast stimulating lipopeptide 1; TLR2-KO, TLR2-knockout; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; ELISA, enzyme-linked immunosorbent assay; IKK, inhibitor of nuclear factor-κB kinase; ERK, extracellular signal-regulated kinase; CRISPR-Cas9, clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9; IL-6, interleukin 6. SARS-CoV-2 virus can infect human cells and induce inflammatory cytokines and chemokines, including IL-6, IL-1β, TNF-α, C-X-C motif chemokine ligand 1 (CXCL1), CXCL2, and C-C motif chemokine ligand 2 (CCL2), via TLR2-dependent activation of the NF-κB pathway 3–6. ...we further assessed whether expression levels of ACE2, TMPRSS2, TLR1, TLR2, and TLR6 were associated with gene sets related to inflammatory cytokines and chemokines. Upon treatment with the SARS-CoV-2 S protein, Pam3CSK4 (an agonist of TLR1/2), or FSL-1 (an agonist of TLR2/6), migration and invasion abilities of A549 and H1299 lung cancer cells were significantly enhanced compared to those upon treatment with vehicle control (Figure 1G-H, Supplementary Figure S6). ...colony-forming and cell proliferation assay revealed significant increases in response to the SARS-CoV-2 S protein, Pam3CSK4, or FSL-1 (Supplementary Figure S7).
In recent years, methylammonium lead halide (MAPbX3, where X = Cl, Br, and I) perovskites have attracted tremendous interest caused by their outstanding photovoltaic performance. Mixed halides have ...been frequently used as the active layer of solar cells, as a result of their superior physical properties as compared to those of traditionally used pure iodide. Herein, we report a remarkable finding of reversible halide-exchange reactions of MAPbX3, which facilitates the synthesis of a series of mixed halide perovskites. We synthesized MAPbBr3 plate-type nanocrystals (NCs) as a starting material by a novel solution reaction using octylamine as the capping ligand. The synthesis of MAPbBr3–x Cl x and MAPbBr3–x I x NCs was achieved by the halide exchange reaction of MAPbBr3 with MACl and MAI, respectively, in an isopropyl alcohol solution, demonstrating full-range band gap tuning over a wide range (1.6–3 eV). Moreover, photodetectors were fabricated using these composition-tuned NCs; a strong correlation was observed between the photocurrent and photoluminescence decay time. Among the two mixed halide perovskite series, those with I-rich composition (x = 2), where a sole tetragonal phase exists without the incorporation of a cubic phase, exhibited the highest photoconversion efficiency. To understand the composition-dependent photoconversion efficiency, first-principles density-functional theory calculations were carried out, which predicted many plausible configurations for cubic and tetragonal phase mixed halides.
To understand the molecular mechanisms involved in regulation of DNA methyltransferases (DNMTs) by metformin in non-small cell lung cancer (NSCLC) cells.
Expression levels of DNMTs in response to ...metformin were analyzed in NSCLC cells. MicroRNAs regulating expression of DNMTs at the post-transcriptional level were searched using miRNA-target databases (miRDB and miRTarBase), TCGA RNASeqV2 lung cancer data, and miRNA-seq.
Metformin dose-dependently downregulated expression of DNMT1 and DNMT3a at the post-transcriptional level and expression of DNMT3b at the transcriptional level in A549 lung cancer cells. Activity of DNMTs was reduced by about 2.6-fold in A549 cells treated with 10 mM metformin for 72 h. miR-148/-152 family members (miR-148a, miR-148b, and miR-152) targeting the 3'UTR of DNMTs were associated with post-transcriptional regulation of DNMTs by metformin. Metformin upregulated expression of miR-148a, miR-148b, and miR-152 in A549 and H1650 cells. Transfection with an miR-148b plasmid or a mimic suppressed expression of DNMT1 and DNMT3b in A549 cells. Transfection with the miR-148a mimic in A549 and H1650 cells decreased the luciferase activity of DNMT1 3'UTR. A combination of metformin and cisplatin synergistically increased expression levels of miR-148/-152 family members but decreased expression of DNMTs in A549 cells. Low expression of miR-148b was associated with poor overall survival (HR = 2.56, 95% CI 1.09-6.47; P = 0.04) but not with recurrence-free survival.
The present study suggests that metformin inhibits expression of DNMTs by upregulating miR-148/-152 family members in NSCLC cells.
The genetic landscape of medullary thyroid cancer (MTC) is not yet fully understood, although some oncogenic mutations have been identified. To explore genetic profiles of MTCs, formalin-fixed, ...paraffin-embedded tumor tissues from MTC patients were assayed on the Ion AmpliSeq Cancer Panel v2. Eighty-four sporadic MTC samples and 36 paired normal thyroid tissues were successfully sequenced. We discovered 101 hotspot mutations in 18 genes in the 84 MTC tissue samples. The most common mutation was in the ret proto-oncogene, which occurred in 47 cases followed by mutations in genes encoding Harvey rat sarcoma viral oncogene homolog (N = 14), serine/threonine kinase 11 (N = 11), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (N = 6), mutL homolog 1 (N = 4), Kiesten rat sarcoma viral oncogene homolog (N = 3) and MET proto-oncogene (N = 3). We also evaluated anaplastic lymphoma kinase (ALK) rearrangement by immunohistochemistry and break-apart fluorescence in situ hybridization (FISH). Two of 98 screened cases were positive for ALK FISH. To identify the genomic breakpoint and 5' fusion partner of ALK, customized targeted cancer panel sequencing was performed using DNA from tumor samples of the two patients. Glutamine:fructose-6-phosphate transaminase 1 (GFPT1)-ALK and echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions were identified. Additional PCR analysis, followed by Sanger sequencing, confirmed the GFPT1-ALK fusion, indicating that the fusion is a result of intra-chromosomal translocation or deletion. Notably, a metastatic MTC case harboring the EML4-ALK fusion showed a dramatic response to an ALK inhibitor, crizotinib. In conclusion, we found several genetic mutations in MTC and are the first to identify ALK fusions in MTC. Our results suggest that the EML4-ALK fusion in MTC may be a potential driver mutation and a valid target of ALK inhibitors. Furthermore, the GFPT1-ALK fusion may be a potential candidate for molecular target therapy.
Silicon (Si) application has been known to enhance the tolerance of plants against abiotic stresses. However, the protective mechanism of Si under heavy metals contamination is poorly understood. The ...aim of this study was to assess the role of Si in counteracting toxicity due to cadmium (Cd) and copper (Cu) in rice plants (Oryza sativa).
Si significantly improved the growth and biomass of rice plants and reduced the toxic effects of Cd/Cu after different stress periods. Si treatment ameliorated root function and structure compared with non-treated rice plants, which suffered severe root damage. In the presence of Si, the Cd/Cu concentration was significantly lower in rice plants, and there was also a reduction in lipid peroxidation and fatty acid desaturation in plant tissues. The reduced uptake of metals in the roots modulated the signaling of phytohormones involved in responses to stress and host defense, such as abscisic acid, jasmonic acid, and salicylic acid. Furthermore, the low concentration of metals significantly down regulated the mRNA expression of enzymes encoding heavy metal transporters (OsHMA2 and OsHMA3) in Si-metal-treated rice plants. Genes responsible for Si transport (OsLSi1 and OsLSi2), showed a significant up-regulation of mRNA expression with Si treatment in rice plants.
The present study supports the active role of Si in the regulation of stresses from heavy metal exposure through changes in root morphology.
The first step in treating lung cancer is to establish the stage of the disease, which in turn determines the treatment options and prognosis of the patient. Many factors are involved in lung cancer ...staging, but all involve anatomical information. However, new approaches, mainly those based on the molecular biology of cancer, have recently changed the paradigm for lung cancer treatment and have not yet been incorporated into staging. In a group of patients of the same stage who receive the same treatment, some may experience unexpected recurrence or metastasis, largely because current staging methods do not reflect the findings of molecular biological studies. In this review, we provide a brief summary of the latest research on lung cancer staging and the molecular events associated with carcinogenesis. We hope that this paper will serve as a bridge between clinicians and basic researchers and aid in our understanding of lung cancer.
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