bims-meluca 2018-07-29 papers

Exp Cell Res. 2018 Jul 18. pii: S0014-4827(18)30519-6. [Epub ahead of print]

Fucosyltransferase 2 induced epithelial-mesenchymal transition via TGF-β/Smad signaling pathway in lung adenocarcinaoma.

Deng G, Chen L, Zhang Y, Fan S, Li W, Lu J, Chen X.

Fucosyltransferase 2 (FUT2), the enzyme catalyzing α-1,2-fucosylation in mammals, has been implicated in cancer. The up-regulation of FUT2 has been observed in lung adenocarcinoma (LUAD), and FUT2 can enhance the cell migration and invasion of LUAD cell lines. However, the underlying mechanism of FUT2 in LUAD remains largely unknown. Abundant studies have revealed that epithelial-mesenchymal transition (EMT) played a pivotal role during lung cancer metastasis and progression. In the present study, we showed that knocking down FUT2 in LUAD cell lines increased the expression of E-cadherin and reduced the expression of Vimentin, N-cadherin, TβRII, p-Smad2, p-Smad3 and Snail, which were the makers of EMT. Meanwhile, the expression of E-cadherin was decreased, and the expression of Vimentin was increased by restoring the expression of FUT2 in RNA interference FUT2 (RNAi-FUT2) cells, suggesting that FUT2 enhanced the EMT process in LUAD. Additionally, silencing FUT2 expression can up-regulate E-cadherin and down-regulate Vimentin, significantly attenuated EMT in vivo. Treated with the SIS3, a new-type inhibitor of p-Smad3 of TGF-β signaling, the expression of E-cadherin, Vimentin and Snail were not affected by RNAi-FUT2 cells, indicating that the effect of FUT2 on EMT depended on TGF-β/Smad signaling. Overall, the current results indicated that FUT2 might promote LUAD metastasis through the EMT initiated by TGF-β/Smad signaling. Therefore, FUT2 might be a prognostic factor and therapeutic target for LUAD.

Keywords: EMT; Fucosyltransferase 2; Lung adenocarcinaoma; TGF-β signaling pathway

DOI: https://doi.org/10.1016/j.yexcr.2018.07.026

Life Sci. 2018 Jul 18. pii: S0024-3205(18)30412-0. [Epub ahead of print]

Resveratrol sensitizes lung cancer cell to TRAIL by p53 independent and suppression of Akt/NF-κB signaling.

Rasheduzzaman M, Jeong JK, Park SY.

AIMS: TRAIL is a promising anticancer agent that has the potential to sensitize a wide variety of cancer or transformed cells by inducing apoptosis. However, resistance to TRAIL is a growing concern. Current manuscript aimed to employing combination treatment to investigate resveratrol induced TRAIL sensitization in NSCLC.METHOD: A549 and HCC-15 cells were used in experimental design. Cell viability was determined by morphological image, crystal violet staining and MTT assay. Apoptosis was evaluated by LDH assay, Annexin V and DAPI staining. Autophagy and apoptosis indicator protein were examined by western blotting. TEM and puncta assay were carried out to evaluate the autophagy. MTP and ROS activity were evaluated by JC-1 and H2DCFDA staining.
FINDINGS: Resveratrol is a polyphenolic compound capable of activation of tumor suppressor p53 and its pro-apoptotic modulator PUMA. Herein, we showed the p53-independent apoptosis by decrease the expression of phosphorylated Akt-mediated suppression of NF-κB that is also substantiated with the downregulation of anti-apoptotic factors Bcl-2 and Bcl-xl in NSCLC, resulting in an attenuation of TRAIL resistance in combined treatment. Furthermore, apoptosis was induced in TRAIL-resistant lung cancer cells with a co-treatment of resveratrol and TRAIL assessed by the loss of MMP, ROS generations which resulting the translocation of cytochrome c from the mitochondria into the cytosol due to mitochondrial dysfunction. Moreover, autophagy flux was not affected by resveratrol-induced TRAIL-mediated apoptosis in NSCLC.
SIGNIFICANCE: Overall, targeting the NF-κB (p65) pathway via resveratrol attenuates TRAIL resistance and induces TRAIL-mediated apoptosis which could be the effective TRAIL-based cancer therapy regimen.

Keywords: Akt/NF-κB; Apoptosis; Cytochrome c; Lung cancer cells; Resveratrol; TRAIL

DOI: https://doi.org/10.1016/j.lfs.2018.07.035

Colloids Surf B Biointerfaces. 2018 Jun 18. pii: S0927-7765(18)30389-8. [Epub ahead of print]171 197-204

Three-dimensional alginate hydrogels for radiobiological and metabolic studies of cancer cells.

Read GH, Miura N, Carter JL, Kines KT, Yamamoto K, Devasahayam N, Cheng JY, Camphausen KA, Krishna MC, Kesarwala AH.

The purpose of this study is to demonstrate calcium alginate hydrogels as a system for in vitro radiobiological and metabolic studies of cancer cells. Previous studies have established calcium alginate as a versatile three-dimensional (3D) culturing system capable of generating areas of oxygen heterogeneity and modeling metabolic changes in vitro. Here, through dosimetry, clonogenic and viability assays, and pimonidazole staining, we demonstrate that alginate can model radiobiological responses that monolayer cultures do not simulate. Notably, alginate hydrogels with radii greater than 500 μm demonstrate hypoxic cores, while smaller hydrogels do not. The size of this hypoxic region correlates with hydrogel size and improved cell survival following radiation therapy. Hydrogels can also be utilized in hyperpolarized magnetic resonance spectroscopy and extracellular flux analysis. Alginate therefore offers a reproducible, consistent, and low-cost means for 3D culture of cancer cells for radiobiological studies that simulates important in vivo parameters such as regional hypoxia and enables long-term culturing and in vitro metabolic studies.

Keywords: 3D culture; Alginate; Cancer cell metabolism; Hypoxia; Radiation therapy

DOI: https://doi.org/10.1016/j.colsurfb.2018.06.018

Cancer Lett. 2018 Jul 18. pii: S0304-3835(18)30478-6. [Epub ahead of print]

Genome-wide identification of transcription factors that are critical to non-small cell lung cancer.

Zhang DL, Qu LW, Ma L, Zhou YC, Wang GZ, Zhao XC, Zhang C, Zhang YF, Wang M, Zhang MY, Yu H, Sun BB, Gao SH, Cheng X, Guo MZ, Huang YC, Zhou GB.

To systematically unveil transcription factors (TFs) that are critical to lung carcinogenesis, here we conducted a genome-wide lethality screening in non-small cell lung cancer (NSCLC) cells and reported that among the 1530 TFs tested, 21 genes were required for NSCLC cell proliferation and were negatively or positively associated with overall survival (OS) of patients with NSCLC. These included 11 potential tumor suppressing genes (AFF3, AhR, AR, CBFA2T3, CHD4, KANK2, NR3C2, PTEN, PRDM16, RB1, and STK11) and 10 potential oncogenic TFs (BARX1, DLX6, ELF3, EN1, ETV1, FOXE1, HOXB7, IRX4, IRX5, and SALL1). The expression levels of IRX5 were positively associated with OS of smoker and inversely associated with OS of non-smoker patients with lung adenocarcinoma. We showed that tobacco carcinogen benzo(a)pyrene (BaP) induced upregulation of IRX5 in lung epithelial cells, and Cyclin D1 was a downstream target of IRX5. Furthermore, silencing of IRX5 by lentivirus mediated transfection of short hairpin RNA significantly inhibited tumor growth in nude mice. These results indicate that tobacco smoke can modulate TFs to facilitate lung carcinogenesis, and inhibition of IRX5 may have therapeutic potentials in NSCLCs.

Keywords: IRX5; RNAi Screen; cyclin D1; lung cancer; tobacco smoke

DOI: https://doi.org/10.1016/j.canlet.2018.07.020

Lipids Health Dis. 2018 Jul 21. 17(1): 166

Plasma apolipoprotein E level is associated with the risk of endobronchial biopsy-induced bleeding in patients with lung cancer.

Wang S, Ye Q, Lu X.

BACKGROUND: Factors affecting the risk of bleeding by bronchoscopic biopsy in patients with lung cancer remain unclear. The levels of plasma apolipoprotein E (ApoE) that may be associated with endobronchial biopsy (EBB)-induced bleeding have never been examined.METHODS: This was a retrospective study using data collected from 615 consecutive patients who had undergone EBB and been diagnosed with primary lung cancer from January 2014 through February 2018. Patients were either classified as the bleeding group (n = 214) or the non-bleeding group (n = 391) based on the bronchoscopy report. Multiple regression analysis was done to estimate the independent relationship between ApoE levels and EBB-induced bleeding, with an adjustment for potential confounders.
RESULTS: The mean plasma ApoE concentration was higher in the non-bleeding group compared to that in the bleeding group (P < 0.05). However, a non-linear relationship with threshold effects was observed between plasma ApoE levels and EBB-induced bleeding in a piecewise linear regression analysis. The risk of EBB-induced bleeding decreased with ApoE concentrations from 3.5 mg/dL up to 5.9 mg/dL (adjusted odds ratio, 0.64; 95% confidence interval, 0.43-0.94); however, the incidence of EBB-induced bleeding increased with ApoE levels above the turning point (ApoE = 5.9 mg/dL).
CONCLUSIONS: There was a non-linear association between plasma ApoE levels and the risk of EBB-induced bleeding. Higher plasma ApoE concentrations (> 5.9 mg/dL) are the independent risk factor for hemorrhage during EBB in patients with lung cancer.

Keywords: Apolipoprotein E; Bleeding; Endobronchial biopsy; Lung cancer

DOI: https://doi.org/10.1186/s12944-018-0821-6