Lung cancer is the most common cause of cancer-related deaths. Tobacco smoke exposure is the strongest aetiological factor associated with lung cancer. In this study, using serial analysis of gene expression (SAGE), we comprehensively examined the effect of active smoking by comparing the transcriptomes of clinical specimens obtained from current, former and never smokers, and identified genes showing both reversible and irreversible expression changes upon smoking cessation. Twenty-four SAGE profiles of the bronchial epithelium of eight current, twelve former and four never smokers were generated and analyzed. In total, 3,111,471 SAGE tags representing over 110 thousand potentially unique transcripts were generated, comprising the largest human SAGE study to date. We identified 1,733 constitutively expressed genes in current, former and never smoker transcriptomes. We have also identified both reversible and irreversible gene expression changes upon cessation of smoking; reversible changes were frequently associated with either xenobiotic metabolism, nucleotide metabolism or mucus secretion. Increased expression of TFF3, CABYR, and ENTPD8 were found to be reversible upon smoking cessation. Expression of GSK3B, which regulates COX2 expression, was irreversibly decreased. MUC5AC expression was only partially reversed. Validation of select genes was performed using quantitative RT-PCR on a secondary cohort of nine current smokers, seven former smokers and six never smokers. Expression levels of some of the genes related to tobacco smoking return to levels similar to never smokers upon cessation of smoking, while expression of others appears to be permanently altered despite prolonged smoking cessation. These irreversible changes may account for the persistent lung cancer risk despite smoking cessation.

/pdf/effect-of-active-smoking-on-the-human-bronchial-epithelium-13nktpm674.pdf

Effect of active smoking on the human bronchial epithelium transcriptome.

The constitutively active protein glycogen synthase kinase 3 (GSK3), a serine/threonine kinase, acts paradoxically as a tumor suppressor in some cancers while potentiates growth in others. Deciphering what governs its actions is vital for understanding many pathological conditions, including brain cancer. What are seemingly disparate roles of GSK3 stems from the complex regulation of many cellular functions by GSK3. This review focuses on the regulation of GSK3, its role in survival, apoptosis and DNA damage, and finally its potential therapeutic impact in brain cancer. A thorough understanding of this versatile protein is critical for improving the outcome of various diseases, especially cancer.

/pdf/emerging-roles-of-glycogen-synthase-kinase-3-in-the-ozmyydwfr8.pdf

Emerging roles of glycogen synthase kinase 3 in the treatment of brain tumors.

Tobacco smoke (TS) is the most important single risk factor for bladder cancer. Epithelial-mesenchymal transition (EMT) is a transdifferentiation process, involved in the initiation of TS-related cancer. Cancer stem cells (CSCs) have an essential role in the progression of many tumors including TS-related cancer. However, the molecular mechanisms of TS exposure induced urocystic EMT and acquisition of CSCs properties remains undefined. Wnt/β-catenin pathway is critical for EMT and the maintenance of CSCs. The aim of our present study was to investigate the role of Wnt/β-catenin pathway in chronic TS exposure induced urocystic EMT, stemness acquisition and the preventive effect of curcumin. Long time TS exposure induced EMT changes and the levels of CSCs' markers were significant upregulated. Furthermore, we demonstrated that Wnt/β-catenin pathway modulated TS-triggered EMT and stemness, as evidenced by the findings that TS elevated Wnt/β-catenin activation, and that TS-mediated EMT and stemness were attenuated by Wnt/β-catenin inhibition. Treatment of curcumin reversed TS-elicited activation of Wnt/β-catenin, EMT and CSCs properties. Collectively, these data indicated the regulatory role of Wnt/β-catenin in TS-triggered urocystic EMT, acquisition of CSCs properties and the chemopreventive effect of curcumin.

/pdf/curcumin-reversed-chronic-tobacco-smoke-exposure-induced-2h2xn40qht.pdf

Curcumin reversed chronic tobacco smoke exposure induced urocystic EMT and acquisition of cancer stem cells properties via Wnt/β-catenin.

Problem

To determine the role of inactivated GSK3β with respect to Wnt/β-catenin pathway activation in HPV-16/18-associated cervical cancer.



Method of study

The expression of active (pGSK3β-Try216), inactive (pGSK3β-Ser9), and c-Myc as well as HPV-16/18 infection was analyzed in cervical intra-epithelial neoplasia (CIN), squamous cell carcinoma (SCCs) and normal by immunohistochemistry and multiplex PCR. The proteins level was also compared with β-catenin and APC expression.



Results

The dramatic decrease of pGSK3β-Try216 expression but ectopic overexpression of pGSK3β-Ser9 and c-Myc was observed both in CIN and SCCs samples compared to normal tissues. 57/67 CIN and 132/153 SCCs showed HPV-16 infection, while 3/67 CIN and 4/153 SCCs were harbored with HPV-18 infection. Both the proteins were significantly upregulated in HPV-16 infected cases (P = 0.0001; P = 0.001) and also positively correlated with nuclear β-catenin (P = 0.0001; P = 0.0001).



Conclusion

The process of generation of HPV-16-associated cervical tumorigenesis is synergized with GSK3β inactivation and overactivation of Wnt/β-catenin pathway.

Clinical significance of inactivated glycogen synthase kinase 3β in HPV-associated cervical cancer: Relationship with Wnt/β-catenin pathway activation.

// Dexin Yu 1, * , Hao Geng 1, * , Zhiqi Liu 1, * , Li Zhao 1 , Zhaofeng Liang 2 , Zhiqiang Zhang 1 , Dongdong Xie 1 , Yi Wang 1 , Tao Zhang 1 , Jie Min 1 , Caiyun Zhong 3 1 Department of Urology, The Second Affiliated Hospital of Anhui Medical University, Hefei 230032, China 2 Department of Preventive Medicine and Public Health Laboratory Sciences, School of Medicine, Jiangsu University, Jiangsu 212013, China 3 Department of Toxicology and Nutritional Science, School of Public Health, Nanjing Medical University, Nanjing 210029, China * These authors have contributed equally to this work Correspondence to: Dexin Yu, email: ay2fy_uro@126.com Caiyun Zhong, email: cyzhong@njmu.edu.cn Keywords: bladder cancer, cigarette smoke, epithelial mesenchymal transition, MAPK pathways Received: October 09, 2016      Accepted: December 06, 2016      Published: January 02, 2017 ABSTRACT Cigarette smoke has been shown to be a major risk factor for bladder cancer. Epithelial-mesenchymal transition (EMT) is a crucial process in cancer development. The role of MAPK pathways in regulating cigarette smoke-triggered urocystic EMT remains to be elucidated. Human normal urothelial cells and BALB/c mice were used as in vitro and in vivo cigarette smoke exposure models. Exposure of human normal urothelial cells to cigarette smoke induced morphological change, enhanced migratory and invasive capacities, reduced epithelial marker expression and increased mesenchymal marker expression, along with the activation of MAPK pathways. Moreover, we revealed that ERK1/2 and p38 inhibitors, but rather JNK inhibitor, effectively attenuated cigarette smoke-induced urocystic EMT. Importantly, the regulatory function of ERK1/2 and p38 pathways in cigarette smoke-triggered urocystic EMT was further confirmed in mice exposed to CS for 12 weeks. These findings could provide new insight into the molecular mechanisms of cigarette smoke-associated bladder cancer development as well as its potential intervention.

/pdf/cigarette-smoke-induced-urocystic-epithelial-mesenchymal-dklpf085th.pdf

Cigarette smoke induced urocystic epithelial mesenchymal transition via MAPK pathways

Role of glycogen synthase kinase 3 in squamous differentiation induced by cigarette smoke in porcine tracheobronchial epithelial cells.

To investigate if glycogen synthase kinase 3 (GSK3) is involved in squamous differentiation of airway (tracheobronchial) epithelial cells, primary pig airway epithelial cells were treated with lithium chloride, a highly selective inhibitor of GSK3. Change in morphology of cells was monitored under microscopy, and expression of beta-catenin, phosphorylated GSK3 and involucrin, a squamous differentiation marker, were dectected by Western blotting, while expression of mRNA of another squamous differentiation marker, small proline-rich protein, was detected by RT-PCR. Further, luciferase reporter assay was used to assess the activation of beta-catenin/Tcf signaling. The results demonstrated that lithium was able to induce a squamous morphology of the cells, and to enhance the expression of involucrin and small proline-rich protein mRNA. Moreover, lithium increased inhibitory phosphorylation of GSK3, augmented nuclear translocation of beta-catenin in a dose- and time-dependent manner. Activation of beta-catenin/Tcf signaling was observed after the elevation of squamous differentiation markers. Taken together, these data suggest that GSK3 is possibly involved in squamous differentiation of pig airway epithelial cells.

Role of glycogen synthase kinase 3 in squamous differentiation of pig airway epithelial cells: A primary study.

For a preliminary study of the role of β-catenin/Tcf signaling in squamous differentiation of airway (tracheobronchial) epithelial cells, a stable mutant of β-catenin was transfected into primarily cultured porcine airway epithelial cells. Western blotting revealed that exogenous protein was observed in large quantity in cytoplasm and nucleus. When co-transfected with Tcf luciferase reporter plasmids, β-catenin mutant increased the reporter’s transcriptional activities. However, mRNA expression of a squamous differentiation marker, small proline-rich protein (SPRP), was not elevated, as shown by reverse transcription-polymerase chain reaction. These findings suggest that β-catenin/Tcf signaling may not be directly involved in the squamous differentiation of porcine airway epithelial cells.

β-catenin/Tcf signaling in squamous differentiation of porcine airway epithelial cells

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Role of glycogen synthase kinase 3 in squamous differentiation induced by cigarette smoke in porcine tracheobronchial epithelial cells.

Role of glycogen synthase kinase 3 in squamous differentiation of pig airway epithelial cells: A primary study.

β-catenin/Tcf signaling in squamous differentiation of porcine airway epithelial cells