Cancer stem cells (CSCs) are commonly associated with cancer recurrence and metastasis that occurs in up to 30-55% of non-small-cell lung carcinoma (NSCLC) patients. Herein, we showed that serine-arginine protein kinase 1 (SRPK1) was highly expressed at both the mRNA and the protein levels in human NCSLC. SRPK1 was associated with the clinical features of human NSCLC, including clinical stage (p < 0.001) and T (p = 0.001), N (p = 0.007), and M (p = 0.001) classifications. Ectopic overexpression of SRPK1 promoted the acquisition of a stem cell-like phenotype in human NSCLC cell lines cultured in vitro. Overexpression of SRPK1 increased sphere formation and the proportion of side-population cells that exclude Hoechst dye. Conversely, SRPK1 silencing reduced the number of spheres and the proportion of side-population cells. Mouse studies indicated that SRPK1 promoted NSCLC cell line tumour growth and SRPK1 overexpression reduced the number of tumour cells required to initiate tumourigenesis in vivo. Mechanistically, gene set enrichment analysis showed that Wnt/β-catenin signalling correlated with SRPK1 mRNA levels and this signalling pathway was hyperactivated by ectopic SRPK1 expression in NSCLC cell lines. Immunofluorescence demonstrated that SRPK1 enhanced β-catenin accumulation in the nuclei of NSCLC cell lines, and inhibition of β-catenin signalling abrogated the SRPK1-induced stem cell-like phenotype. Together, our findings suggest that SRPK1 promotes a stem cell-like phenotype in NSCLC via Wnt/β-catenin signalling. Moreover, SRPK1 may represent a novel target for human NSCLC diagnosis and therapy. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Background: Tudor-SN has been observed in lipid droplets, but its role in lipid homeostasis remains unclear. Results: Tudor-SN and PPAR␥ are both regulated by C/EBP␤ during adipogenesis and significantly influence the regulation of PPAR␥ target genes. Conclusion: Tudor-SN functions as a co-activator of PPAR␥ in adipogenesis. Significance: The study has elucidated a new functional mechanism for the regulation of adipogenesis.

Herein, Tudor-SN was identified as a DNA damage response (DDR)-related protein that plays important roles in the early stage of DDR. X-ray or laser irradiation could evoke the accumulation of Tudor-SN to DNA damage sites in a poly(ADP-ribosyl)ation-dependent manner via interaction with PARP-1. Additionally, we illustrated that the SN domain of Tudor-SN mediated the association of these two proteins. The accumulated Tudor-SN further recruited SMARCA5 (ATP-dependent chromatin remodeller) and GCN5 (histone acetyltransferase) to DNA damage sites, resulting in chromatin relaxation, and consequently activating the ATM kinase and downstream DNA repair signalling pathways to promote cell survival. Consistently, the loss-of-function of Tudor-SN attenuated the enrichment of SMARCA5, GCN5 and acetylation of histone H3 (acH3) at DNA break sites and abolished chromatin relaxation; as a result, the cells exhibited DNA repair and cell survival deficiency. As Tudor-SN protein is highly expressed in different tumours, it is likely to be involved in the radioresistance of cancer treatment.

Our study aspires to understand the impact of miR-27b on myocardial fibrosis as well as its functional mechanism. 12 days post the ligation of coronary artery in rats, the expression of miR-27b in the peri-infarction region was elevated. Treating cultivated rat neonatal cardiac fibroblasts (CFs) with angiotensin II (AngII) also enhanced the miR-27b expression. Forced expression of miR-27b promoted the proliferation and collagen production in rat neonatal CFs, as revealed by cell counting, MTT assay, and quantitative reverse transcriptionpolymerase chain reaction. FBW7 was found to be the miR-27b's target since the overexpression of miR-27b reduced the transcriptional level of FBW7. The enhanced expression of FBW7 protein abrogated the effects of miR-27b in cultured CFs, while the siRNA silence of FBW7 promoted the pro-fibrosis activity of AngII. As to the mechanism, we found that the expression of FBW7 led to the degradation of Snail, which is an important regulator of cardiac epithelial-mesenchymal transitions. Importantly, inhibition of miR-27b abrogated the coronary artery ligation (CAL) induced cardiac fibrosis in vivo, suggesting that it might be a potential target for the treatment of fibrosis associated cardiac diseases.

No abstract

| INTRODUC TI ONOesophageal cancer is one of the most leading cause of mortality cancer worldwide, and oesophageal squamous cell carcinoma (ESCC) is the main type for oesophageal cancer arising from oesophageal epithelial cells. 1,2 The recent epidemiology showed that oesophageal cancer is one of the five most common cancers in China, especially in middle area of China, and attributed for about 1 396 000 people mortalities. 3 Despite the multiple efforts made in recent years, treatments for oesophageal cancer are still not satisfied and chemotherapy resistance has becoming a new challenge for its treatment.Therefore, it is important to reveal the mechanism of ESCC and improve the therapeutic effect of ESCC.Epidermal growth factor receptor (EGFR), a transmembrane tyrosine kinase, plays critical role in several solid cancers and its chemotherapy resistance regulation. 4 It is reported that about 40%-70% of patients with ESCC have presented with high levels of EGFR expression 5,6 and inhibiting the activity of EGFR might be promising to improve the outcome of patients with ESCC. Gefitinib is a wellknown orally active, reversible and selective EGFR inhibitor applied for ESCC treatment in clinic. 7,8 However, the resistance of gefitinib has become a new challenge for ESCC treatment with unclear mechanism. 9Long non-coding RNAs (lncRNAs) is a class of transcripts without coding capacity at a length of >200 nt and has reported to play critical roles in the pathogenesis and drug resistance of ESCC. 10,11 AbstractThis study aimed to explore the underlying mechanism of linc01014 in oesophagus cancer gefitinib resistance. Gefitinib-resistant oesophagus squamous cell carcinoma (ESCC gefitinibR) cell lines were constructed by using different gefitinib treatment in FLO-1, KYAE-1, TE-8 and TE-5 cell lines and confirmed by MTS50 and proliferation assays. Expression of linc01014 was overexpressed/silenced in FLO-1 cells followed by gefitinib treatment, and then, the apoptosis-associated markers Bax and Bcl-2, and PI3KCA in PI3K signalling pathway were determined using Western blotting. MST50 and morphology analyses showed that ESCC gefitinibR cell lines presented obvious gefitinib resistance than their parental ESCC cell lines. ESCC gefitinibR cell lines showed significantly higher proliferation abilities than their parental ESCC cell lines after treating with gefitinib. Overexpression of linc01014 significantly inhibited the apoptosis of FLO-1 cells induced by gefitinib and silencing linc01014 obviously promoted the apoptosis of FLO-1 cells induced by gefitinib. Silencing linc01014 could significantly increase the gefitinib chemotherapy sensitivity of oesophagus cancer via PI3K-AKT-mTOR signalling pathway.

IL-4 activates STAT6 and causes the subsequent up-regulation of Ig heavy chain germline Ige via chromatin remodeling involved in B lymphocytes development. STAT6 acts as a molecular switch to regulate the higher-order chromatin remodeling via dynamically orchestrating co-activators (CBP/Tudor-SN) and co-repressors (HDAC1/PSF). Here, we demonstrated that STAT6/Tudor-SN/PSF form a complex, balancing the acetylation and deacetylation states to co-regulate IL-4/STAT6 gene transcription. In addition, we confirmed that IL-4 treatment increased the HATs activity in Ramos cells. As "active" markers, the expression of H3K9ac and H3K27ac increased after treatment with IL-4. However, transcriptional repressors such as H3K9me3 and H3K27me3 decreased in response to IL-4 stimulation. Moreover, IL-4 treatment enhanced H3 acetylation at the Ige promoter regions. Our results revealed that the Ige gene transcription is regulated by histone modifications in the IL-4/STAT6 pathway. The study will provide novel insights into the pathogenesis of allergic diseases.

Scutellaria baicalensis Georgi has been widely used in China for treatment of various diseases. This study investigated the effect of Scutellaria baicalensis Georgi extracts (SBE) against Coxsackievirus B3 (CVB3)-induced myocarditis in vitro and in vivo. In vitro, Hela cells and primary myocardial cells were infected with CVB3 and treated with SBE (50-800 µg/ml) and ribavirin (200 µM) for 48 h and then determined by CCK8 assay. Real-time PCR and western blotting assays were performed. In vivo, a myocarditis model was induced in male BALB/c mice by injecting CVB3 suspension intraperitoneally for three times, followed by treatment with SBE (400 and 200 mg/kg) and ribavirin (100 mg/kg) for 28 days. SBE ameliorated the cytotoxicity of CVB3 in Hela cells, especially at 400 µg/ml (39.93% vs 65.67%, p < 0.05) without influencing cell growth and also significantly reduced CVB3 replication in primary myocardial cells. The levels of AKT, ERK, and p38 were increased after CVB3 infection. SBE could downregulate the expressions of AKT and p38. In vivo, the mortality rate from CVB3 reached to 66.67%, while 10.00% and 23.33% of this came after 400 and 200 mg/kg SBE treatment, respectively (p < 0.05). The CVB3 replication was obviously reduced after SBE administration from day 5. Similarly, the levels of AKT, ERK, and p38 mRNAs and proteins were increased, and SBE suppressed the expression of AKT and p38. Our study indicates that SBE is a promising potent antiviral agent against CVB3-induced myocarditis by inhibition of virus replication via depressing AKT and p38 expressions.