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Destrin Contributes to Lung Adenocarcinoma Progression By Published OnlineFirst September 2, 2020; DOI: 10.1158/1541-7786.MCR-20-0187 MOLECULAR CANCER RESEARCH | CANCER GENES AND NETWORKS Destrin Contributes to Lung Adenocarcinoma Progression by Activating Wnt/b-Catenin Signaling Pathway A C Hui-Juan Zhang1, Wen-Jing Chang1, Cai-Yun Jia1, Ling Qiao1, Jing Zhou1, Qing Chen1, Xiao-Wei Zheng1,4, Jian-Hua Zhang4, Hong-Chao Li5, Zheng-Yan Yang1, Zhong-Hua Liu3, Guang-Chao Liu1, Shao-Ping Ji2, and Feng Lu1 ABSTRACT ◥ Lung cancer, especially lung adenocarcinoma, is one of the with the poor prognosis of lung adenocarcinoma patients. Fur- most common neoplasms worldwide. However, the mechanisms thermore, we also found that DSTN promotes cell proliferation, underlying its initiation, development, and metastasis are still invasion, and migration in vitro, and facilitates subcutaneous poorly understood. Destrin (DSTN) is a member of ADF/cofilin tumor formation and lung metastasis via intravenous injection family. Its detailed biological function remains unknown, in vivo. Mechanically, DSTN associates with and facilitates although it is reported that DSTN is involved in cytoskeleton nuclear translocation of b-catenin, which promotes epithelial- remodeling and regulation of actin filament turnover. Recent to-mesenchymal transition (EMT). Taken together, our results evidence has shown that high expression of cofilin-1 is associated indicated that DSTN enhances lung cancer malignancy through with invasion and poor prognosis of several types of human facilitating b-catenin nuclear translocation and inducing EMT. tumors, but the detailed mechanism is still entirely unclear, Combined with multivariate analyses, DSTN might potentially particularly in lung cancer tumorigenesis and malignancy. Here, serve as a therapeutic target and an independent prognostic we report that DSTN was highly expressed in a mouse lung marker of lung adenocarcinoma. cancer model induced by urethane and in clinical lung adeno- carcinoma tissue samples. Its expression level was positively Implications: This finding indicates that DSTN facilitates correlated with cancer development, as well as metastasis to the b-catenin nuclear translocation and promotes malignancy in lung liver and lymph nodes. Consistently, it was directly associated adenocarcinoma. Introduction which results in the loss of opportunity for curative surgical resection and a poor prognosis (3). Lung adenocarcinoma is the most prevalent Lung cancer is the leading cause of cancer-related deaths in China histologic type of lung cancer, which accounts for approximately 40% and worldwide. Despite a great progress in cancer research and of all lung cancers. During the last few years, lung adenocarcinoma has therapeutic strategies over the last decades, the prognosis of lung an increasing frequency, and its prognosis has not been obviously cancer remains poor with a 5-year survival rate of less than 15% (1, 2). improved (4). The prognosis of lung adenocarcinoma is highly asso- Therefore, both understanding the mechanism of cancer development ciated with lymph node and distant metastasis. Therefore, it is of great and progression and early diagnosis are critical to lung cancer treat- interest to identify novel biomarkers that serve for early diagnosis and ment. Unfortunately, because of the lack of early and reliable diag- accurate prognosis prediction, which allow improving the prognosis. nostic biomarkers together with the limited understanding of its Proteomic technologies have been widely used in the global analysis carcinogenic mechanisms, more than 70% of the patients are found for lung cancer biomarker discovery (5). Although many proteomic in advanced stages accompanied by extensive invasion and metastasis, studies on lung adenocarcinoma have been reported (6, 7), to our knowledge, little is known about the changes in protein expressional profiles at the early-stage of human lung adenocarcinoma, neither any 1 Joint National Laboratory for Antibody Drug Engineering, Henan University, clinically established biomarkers available for early detection of lung 2 Kaifeng, P.R. China. Department of Biochemistry and Molecular Biology, adenocarcinoma. Comparative proteomics analysis of successive Medical School, Henan University, Kaifeng, P.R. China. 3Laboratory for NanoMedical Photonics, School of Basic Medical Science, Henan University, stages of human lung adenocarcinoma is the most direct and persua- Kaifeng, P.R. China. 4Department of Clinical Laboratory, Puyang Hospital of sive way to identify biomarkers for early diagnosis of lung adenocar- Traditional Chinese Medicine, Puyang, P.R. China. 5Department of Pathology, cinoma. However, a major obstacle in the analysis of tissue specimens Puyang Oilfeld General Hospital, Puyang, P.R. China. is tissue heterogeneity, in which different cells are collected. Further- Note: Supplementary data for this article are available at Molecular Cancer more, it is difficult to obtain a large amount of early-stage clinical lung Research Online (http://mcr.aacrjournals.org/). adenocarcinoma tissue. H.-J. Zhang and W. -J. Chang contributed equally to this article. To search for the early biomarkers and explore the underlying mechanisms of initiation and metastasis of lung adenocarcinoma, in Corresponding Authors: Feng Lu, Henan University, Kaifeng 475004, P.R. China. Phone/Fax: 8637-1238-80398; E-mail: [email protected]; and this study, we developed a urethane-induced mouse lung adenocar- Shao-Ping Ji, [email protected] cinoma model, which exhibits similar histologic appearance and molecular changes to human lung adenocarcinoma (8, 9). We used Mol Cancer Res 2020;XX:XX–XX a laser capture microdissection (LCM) approach to purify the target doi: 10.1158/1541-7786.MCR-20-0187 cells from lung tissues of a mouse model with early carcinogenesis Ó2020 American Association for Cancer Research. lesion, then investigated the differential proteins in tumor and control AACRJournals.org | OF1 Downloaded from mcr.aacrjournals.org on September 28, 2021. © 2020 American Association for Cancer Research. Published OnlineFirst September 2, 2020; DOI: 10.1158/1541-7786.MCR-20-0187 Zhang et al. tissue using isobaric tagging for relative and absolute protein quan- lungs were prepared for histologic, iTRAQ, and Western blotting tification (iTRAQ) combined with two-dimensional 2D-LC/MS-MS analyses. Five mice in each group were examined at each time point. approach. Subsequently, we further validated our observations by IHC and Western blot analysis. Among the identified 191 potential pro- Sample preparation and LC-ESI-MS/MS analysis teins, destrin (DSTN) protein expression (Dstn, tr|Q4FK36|) displayed Lung tissue protein sample preparation, iTRAQ labeling, LC- a significant upregulation (3.67-fold to control) in early-stage mouse electrospray (ESI)-MS/MS analysis and protein identification were lung cancer tissues compared with the control group. performed as described previously (18, 19). Additional details are DSTN belongs to the ADF/cofilin family, consisting of DSTN, provided in the Supplementary Data. cofilin-1, and muscle-specificcofilin-2 (10). These proteins are abun- dant and essential in almost all eukaryotic cell types. They involve in Clinical lung adenocarcinoma and adjacent nontumor lung cytoskeleton remodeling and precise regulation of the actin filament tissues turnover and take part in numerous cellular processes such as cell A total of 30 paired samples of lung adenocarcinoma and adjacent cytokinesis, proliferation, and membrane trafficking (11, 12). Recent nontumor lung tissues were obtained from patients who underwent studies showed that actin dynamics and their regulation of target surgery between 2013 and 2015 and preserved in the Department of proteins are not only essential for the healthy development and Pathology, Puyang Oilfield General Hospital (Henan, P.R. China). All function of the cells, but also play a crucial role in human diseases, patients gave written informed consent before sample collection. including cancers. However, most research on ADF/cofilin family None of the lung adenocarcinoma patients received radio- or chemo- proteins in metastatic invasion has focused on cofilin-1 (13, 14). As a therapy before surgery. Lung adenocarcinoma tissue microarray member of the ADF/cofilin protein family, the DSTN with the least (HLugA180Su02) purchased from Shanghai Outdo Biotech Co., Ltd. study, and is only found to regulate the migration and invasion of colon included 86 lung adenocarcinoma patients undergoing surgery cancer through regulating action dynamics (15). Its high expression between 2004 and 2009. This study was approved by the Ethic was the association with growth and perineural invasion of pancreatic Committee of the Medical School, Henan University (Kaifeng, P.R. cancer (16). However, its precise roles in human cancers, particularly China) and all methods in this study were carried out in accordance in lung adenocarcinoma, and its downstream signaling pathway in with the recommended guidelines. these processes, remain largely unclear. Here, we have found that overexpressed DSTN seems to be a Cell culture, expression plasmids, and stable transfection of functional oncogenic molecule at lung adenocarcinoma both shRNA in vitro and in vivo. For the first time, we have demonstrated that The human NSCLC cell lines, A549, HCI-H1299, HCI-H460, HCI- DSTN expression is associated with progression of lung cancer H1373, HCI-H1573, and immortalized lung epithelial cell line BEAS- development and liver metastasis in urethane-induced lung adeno-
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