Sirtuin6 (SIRT6), a member of the sirtuins protein family, plays multiple complex roles in cancer. Here, we report that elevated SIRT6 expression was correlated with clinicopathological parameters such as T and N classification in non-small cell lung cancer (NSCLC) patient tumors. SIRT6 overexpression in NSCLC cell lines increased extracellular signal-regulated kinase (p-ERK)1/2 phosphorylation, activated matrix metalloproteinase 9 (MMP9) and promoted tumor cell migration and invasion. Upon treatment with a specific mitogen-activated protein kinase (MEK) 1/2 inhibitor, these effects were abolished. Our results demonstrate SIRT6 upregulation in NSCLC for the first time and suggest a functional role for SIRT6 in promoting migration and invasion through ERK1/2/MMP9 signaling. SIRT6 may serve as a potential therapeutic target in NSCLC and its utility as a prognostic indicator warrants further study.
Blood, 111, 1848-1854. Cartron, G., Dacheux, L., Salles, G., Solal-Celigny, P., Bardos, P., Colombat, P. & Watier, H. (2002) GTF2I-RARA is a novel fusion transcript in a t(7;17) variant of acute promyelocytic leukaemia with clinical resistance to retinoic acidAcute promyelocytic leukaemia (APL) is characterized by the PML-RARA fusion gene, arising from t(15;17)(q21;q22) translocation. PML-RARA is a specific molecular marker for APL and an important determinant for the effective induction of differentiation by all-trans retinoic acid (ATRA) (Grignani et al, 1994). We report a novel fusion gene, GTF2I-RARA, in a variant APL with cryptic t(7;17)(q11;q21), which manifested insensitivity to ATRA and conventional chemotherapy. The patient, a previously healthy 35-year-old male, presented with a 3-month history of fatigue and skin ecchymosis for 10 d. Laboratory investigations showed: haemoglobin level, 61 g/l; platelet count, 12 9 10 9 /l; leucocyte count, 53Á7 9 10 9 /l, including 81% abnormal promyelocytes. Coagulopathy was present. A bone marrow (BM) aspirate showed 90% hypergranular promyelocytes with strong myeloperoxidase positivity (Fig 1A, B). The blast cells were positive for CD13, CD33, CD64 and negative for CD34, HLA-DR, CD7, CD14 and CD19 by flow cytometry. Reverse transcription polymerase chain reaction (RT-PCR) analysis of the BM was negative for PML-RARA, ZBTB16-RARA and NPM1-RARA (Table S1). FLT3 internal tandem duplication mutation was not found. Karyotype analysis showed 46,XY,del(7)(q22) [20] ( Fig 1C). Fluorescence in situ hybridization (FISH) confirmed the deletion of 7q (Fig 1D) and detected split RARA signals without PML involvement (Fig 1E). One split RARA signal was located on the truncated long arm of chromosome 7 (Fig 1F). Unfortunately, the patient died of intracranial haemorrhage on day 146 without achieving remission. The combination of APL morphology and immunophenotype suggested the diagnosis of APL. However, the classic PML-RARA fusion transcript and the t(15q+;17pÀ) translocation were absent, indicating this case was atypical. FISH analysis revealed that one split RARA signal was inserted into the disrupted 7q region, documenting the presence of submicroscopic t(7;17)(q?;q21) translocation (Fig 1F).Adopting rapid 5 0 amplification of cDNA ends (5 0 -RACE) and RT-PCR, we identified GTF2I, the general transcription factor IIi, as the novel RARA partner (Fig 2A). GTF2I-RARA results from the fusion between exon 6 of GTF2I and exon 3 of RARA, and is predicted to encode a 599 amino acid protein ( Fig 2B). No alternative splicing variant was found. The reciprocal RARA-GTF2I fusion transcript was not detected (Fig 2C). Mapped at 7q11Á23, GTF2I is ubiquitously expressed and encodes a phosphoprotein with broad roles in transcription and signal transduction involving growth factor signalling, cell cycle regulation, and transforming growth factor, beta 1
CUE domain-containing 2 (CUEDC2) is a multi-functional protein, which regulates cell cycle, growth factor signaling and inflammation. We found that CUEDC2 was low in lung adenocarcinoma cell lines and lung adenocarcinoma tissues at both mRNA and protein levels. Low levels of CUEDC2 were correlated with a shorter survival time in patients with lung adenocarcinoma (p = 0.004). CUEDC2 expression was correlated with tumor T classification (P = 0.001) at clinical stage (P = 0.001) and tumor size (P = 0.033). Multivariate analysis suggested that CUEDC2 expression is an independent prognostic indicator for patients with lung adenocarcinoma. Ectopic expression of CUEDC2 decreased cell proliferation in vitro and inhibited tumor growth in nude mice in vivo. Knockdown of endogenous CUEDC2 by short hairpin RNAs (shRNAs) increased tumor growth. Inhibition of proliferation by CUEDC2 was associated with inactivation of the PI3K/Akt pathway, induction of p21 and down-regulation of cyclin D1. Our results suggest that decreased expression of CUEDC2 contributes to tumor growth in lung adenocarcinoma, leading to a poor clinical outcome.
Cervical cancer is the fourth most common malignant tumor in women worldwide. The persistent infection of high-risk Human Papillomavirus (hrHPV) is considered to be the primary cause of this disease. As an innate immune receptor, the nucleotide-binding oligomerization domain protein-1 (NOD1) recognizes the pathogen-associated molecular pattern (PAMP), subsequently initiating immune responses. NOD1 is also involved in the apoptotic signaling pathway and mutates in many cancer cells. In the study, we revealed that NOD1 expression decreased during the progression of cervical intraepithelial neoplasia to cervical cancer and that HPV16 E6/E7 oncoproteins induced down-regulation of NOD1. Moreover, the activation of NOD1 promoted the apoptosis of HPV16-positive cervical cancer cells. The data indicated that the dysregulation of NOD1-mediated inflammation and apoptosis may contribute to cervical intraepithelial neoplasia progression and cervical cancer.
Tumor endothelial marker 8 (TEM8) was recently suggested as a putative anti-tumor target in several types of human cancer based on its selective overexpression in tumor versus normal endothelial cells. The objective of this study was to detect the potential functions of TEM8 in osteosarcoma. Overall, TEM8 was mainly located in cytoplasm and was up-regulated in osteosarcoma compared to benign bone lesions and adjacent non tumor tissue (ANT). High TEM8 expression group had a significant lower overall survival rate than that in the low TEM8 expression group. TEM8 knock-down by siRNA or shRNA results in significant reduction of osteosarcoma cell growth and proliferation both in vitro and in vivo. Ablation of TEM8 led to increasing of p21 and p27 and suppression of cyclin D1 mediated by Erk1/2 activity. These findings suggest that down-regulation of TEM8 play an important role in the inhibition of tumorigenesis and development of osteosarcoma.
The genus Colocasiomyia de Meijere (Diptera, Drosophilidae) is known to include 30 described and nearly 60 undescribed species classified into six species groups. Among these, the C. gigantea group of seven known species (two Southeast Asian and five Chinese) proved to be peculiar for its specificity on monsteroid (subfamily Monsteroideae, family Araceae) host plants. In this paper, two new species, C. todai Jiao & Gao, sp. nov. and C. liae Jiao & Gao, sp. nov., are described as members of the C. gigantea group with specimens collected from inflorescences of the monsteroid host species Rhaphidophora peepla (Roxb.) Schott and R. crassicaulis Engl. & Krause, respectively, in Yunnan, China. The two new species are delimitated, in comparison with all known species, based on not only morphological but also DNA barcode (partial sequence of the mitochondrial COI, i.e., cytochrome c oxydase subunit I, gene) data. A revised key to all the nine species of the C. gigantea species group is provided.
Soluble semaphorin 4D (SEMA4D) is a 120 kDa transmembrane protein, which belongs to the semaphorin family of axon guidance molecules that act primarily axonal repellents. SEMA4D elicits its migration-promoting and immunomodulatory effects through activation of PLXNB1 and CD72, respectively. In this study, SEMA4D combined with heparin were adsorbed onto cationic surfaces. The biocompatibility evaluation results indicated that the SEMA4D-heparin-modified surfaces displayed less platelet adhesion and activation, prolonged activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT) and reduced fibrinogen gamma chain (FGG) exposure and fibrinogen adhesion. Additionally, endothelial cells (ECs) showed improved adhesion density and proliferation activity on the SEMA4D-heparin-modified surfaces. Chemotactic and haptotaxis assays indicated a highly guided migration for ECs on the modified surfaces. The immunological tests revealed that the SEMA4D-heparin complexes had a positive immunomodulatory effect on macrophages and promoted macrophages polarization into M2 phenotypes. Overall, the results suggested that the SEMA4D-heparin complexes can be a potential therapeutic agent to promote tissue healing and accelerate in situ endothelialization with minimal side effects and positive immunomodulatory effect.
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