PLEK2 promotes cancer stemness and tumorigenesis of head and neck squamous cell carcinoma via the c-Myc-mediated positive feedback loop  

作　　者：Xinyuan Zhao Dalong Shu Wenjuan Sun Shanshan Si Wei Ran Bing Guo Li Cui 

机构地区：[1]Department of Endodontics,Stomatological Hospital,Southern Medical University,Guangzhou,Guangdong 510280,P.R.China [2]Department of Oral and Maxillofacial Surgery,The First Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 510080,P.R.China [3]Department of Stomatology,The Third Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 510630,P.R.China [4]Department of Oral Emergency,Stomatological Hospital,Southern Medical University,Guangzhou,Guangdong 510280,P.R.China [5]Department of Dentistry,The First Affiliated Hospital,Sun Yat-sen University,Guangzhou,Guangdong 510080,P.R.China [6]Department of Oral and Maxillofacial Surgery,Stomatological Hospital,Southern Medical University,Guangzhou,Guangdong 510280,P.R.China [7]Division of Oral Biology and Medicine,School of Dentistry,University of California,Los Angeles,Los Angeles,California 90095,United States

出　　处：《Cancer Communications》2022年第10期987-1007,共21页癌症通讯（英文）

基　　金：National Natural Science Foundation of China,Grant/Award Number:81901006;Guangdong Basic and Applied Basic Research Foundation,Grant/Award Number:2020A1515110051;Scientific Research Talent Cultivation Project of Stomatological Hospital,Southern Medical University,Grant/Award Number:RC202005;Science Research Cultivation Program of Stomatological Hospital,Southern Medical University,Grant/Award Number:PY2020002。

摘　　要：Background:Head and neck squamous cell carcinoma(HNSCC)is one of the most frequent malignancies worldwide and is characterized by unfavorable prognosis,high lymph node metastasis and early recurrence.However,the molecular events regulating HNSCC tumorigenesis remain poorly understood.Therefore,uncovering the underlying mechanisms is urgently needed to identify novel and promising therapeutic targets for HNSCC.In this study,we aimed to explore the role of pleckstrin-2(PLEK2)in regulating HNSCC tumorigenesis.Methods:The expression pattern of PLEK2 and its clinical significance in HNSCC were determined by analyzing publicly assessable datasets and our own independent HNSCC cohort.In vitro and in vivo experiments,including cell proliferation,colony formation,Matrigel invasion,tumor sphere formation,ALDEFLUOR,Western blotting assays and xenograft mouse models,were used to investigate the role of PLEK2 in regulating the malignant behaviors of HNSCC cells.The underlying molecular mechanisms for the tumor-promoting role of PLEK2 were elucidated using co-immunoprecipitation,cycloheximide chase analysis,ubiquitination assays,chromatin immunoprecipitation-quantitative polymerase chain reaction,luciferase reporter assays and rescue experiments.Results:The expression levels of PLEK2 mRNA and protein were significantly increased in HNSCC tissues,and PLEK2 overexpression was strongly associated with poor overall survival and therapeutic resistance.Additionally,PLEK2 was important for maintaining the proliferation,invasion,epithelial-mesenchymal transition,cancer stemness and tumorigenesis of HNSCC cells and could alter the cellular metabolism of the cancer cells.Mechanistically,PLEK2 interacted with c-Myc and reduced the association of F-box and WD repeat domain containing 7(FBXW7)with c-Myc,thereby avoiding ubiquitination and subsequent proteasome-mediated degradation of c-Myc.Moreover,the c-Myc signaling activated by PLEK2 was important for sustaining the aggressive malignant phenotypes and tumorigenesis of HNSCC cells.c-Myc

关 键 词：C-MYC cancer stemness FBXW7 HNSCC PLEK2 positive feedback loop tumorigenesis ubiquitination-mediated degradation 

分 类 号：R739.91[医药卫生—肿瘤]