Cancer Letters 483 (2020) 75–86 Contents lists available at Science Direct

 Cancer Letters 483 (2020) 75–86 Contents lists available at ScienceDirect Cancer Letters journal homepage: www.elsevier.com/locate/canlet MICAL2 is a novel nucleocytoplasmic shuttling protein promoting cancer T invasion and growth of lung adenocarcinoma a a a a a a a WolongZhou ,YuanqiLiu ,YangGao ,YuandaCheng ,RuiminChang ,XizheLi ,YanwuZhou , b c a,d,∗∗ a,d,e,∗ Shaoqiang Wang , Lubiao Liang , Chaojun Duan , Chunfang Zhang a Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, PR China b Department of Thoracic Surgery, Affiliated Hospital of Jining Medical College, Jining Medical College, Jining, 272000, PR China c Department of Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi Medical University, Zunyi, 563000, PR China d National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, PR China e Hunan Engineering Research Center for Pulmonary Nodules Precise Diagnosis and Treatment, Xiangya Hospital, Central South University, Changsha, 410008, PR China ARTICLE INFO ABSTRACT Keywords: MICAL2isatumor-promotingfactorinvolvedincellmigration,invasion,deformation Acarbose,andproliferationnotyet MICAL-2 fully explored in lung adenocarcinoma (LUAD). This study demonstrated that MICAL2 was overexpressed and Nucleoplasm shuttling protein cytoplasm-enrichedinLUADtissues.Moreover,highcytoplasmicMICAL2and/ortotalMICAL2expressionlevels EMT were positively correlated with lymphatic metastasis and shorter overall survival in LUAD patients. MICAL2 MYH9 promoted LUAD cell proliferation, migration, invasion, and epithelial to mesenchymal transition—all of which LUAD involved the AKT and myosin-9 pathways. 

Furthermore, MICAL2 was identified as a nucleoplasm shuttling –ΔC protein dependent on myosin-9 and its C-terminal fragment. MICAL2 —enriched in the nucleus—had less impact on tumor malignancy in LUAD in vitro and in vivo. Tumor promotion by MICAL2 was reduced by nuclear-exportinhibitor,myosin-9inhibitor,orsi-myosin-9—allofwhicheffectivelyinhibitedMICAL2\'snuclear export. Finally, the expression and subcellular location as well as clinical significance of MICAL2 and myosin-9 were analyzed across TCGA data and LUAD tissue arrays. Our data revealed that MICAL2 overexpression and nuclear export were associated with cancer progression; inhibiting its expression and/or nuclear export may provide a new target for LUAD therapy Dorsomorphin (Compound C). 1. Introduction remodeling, autop###http://www.glpbio.com/simage/GA11233-L-NAME-hydrochloride-1.png####hagy and phagocytosis, cell division, cell movement, cellproliferation,axonguidance,andangiogenesis[5–10].MICAL2isa Lungcanceristhemostfrequentlydiagnosedcancerandtheleading special member of the MICALs family—the activation of which is not causeofdeathfromcancerworldwide,accountingfornearly13%ofall inhibited by self-inhibitory activity [11]— that hasbeen identifiedas a cancer diagnoses and approximately 19% of total cancer deaths [1] Benazepril. tumorpromoterinseveralcancersincludingprostate[12],gastric[13], Lung adenocarcinoma (LUAD) accounts for approximately 40% of lung breast [14], and colorectal [15]. 

MICAL2 directly binds to and dis- cancers. Although surgery and chemotherapy offer remarkable ther- assembles F-actin [9], regulates SRF signaling [16], stabilizes EGFR apeuticeffectsinearlystageLUAD,latestageandmetastaticLUADsare protein [14], mediates P53 ubiquitin [15], and promotes EMT through challenging based on their unresectable properties and drug-resistant various pathways [9,17,18]. Although it is reportedly enriched in the tendencies. Advances in research offer insight into the molecular and nucleiofHEK293T,COS7,andHeLacells[16]andincolorectalcancers cell-biological changes involved in metastasis [2]; the investigation of [15], the subcellular localization of MICAL2 is not fully defined. Other such factors is essential for developing new therapies as well as pro- articles report cytoplasmic enrichment in HeLa [19], neoplastic viding potential novel biomarkers for LUAD [3]. emboli [18], and activated endothelial cells of blood vessels [20]. The family of molecules interacting with CasL Certain studies also showed MICAL2 diffusely located in both the nu- (MICAL)—characterized by the N-terminal flavoprotein mono-oxyge- cleus and the cytoplasm [14,18]. However, the expression pattern and nase (MO) domain [4]—is involved in vesicle trafficking, cytoskeleton role of MICAL2 in LUAD have not been thoroughly explored. ∗ Corresponding author. Department ofThoracic Surgery, Xiangya Hospital, Central South University No.87, Xiangya Road, Changsha, Hunan, 410008, PR China. ∗∗ Corresponding author. Department of Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, PR China. E-mail addresses: duancjxy@126.com (C. Duan), zcf6169@outlook.com (C. Zhang). https://doi.org/10.1016/j.canlet.2020.04.019 Received 13 November 2019; Received in revised form 2 April 2020; Accepted 22 April 2020 0304-3835/ © 2020 Elsevier B.V. All rights reserved.

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