title: Positive Feedback Loops Between NrCAM and Major Signaling Pathways Contribute to Thyroid Tumorigenesis.
abstract: Although neuronal cell adhesion molecule (NrCAM) has been reported to be overexpressed in papillary thyroid cancer (PTCs), its role in this disease remains largely unclear.
  
  
  
  The aim of this study was to explore the biological functions of NrCAM and its potential as a diagnostic marker and therapeutic target in thyroid cancer.
  
  
  
  Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to evaluate messenger RNA expression of investigated genes. The functions of knockdown and ectopic expression of NrCAM in thyroid cancer cells were determine by a series of in vitro and in vivo experiments.
  
  
  
  We found that NrCAM was highly expressed in PTCs and demonstrated that NrCAM might be a potential marker for preoperative diagnosis of PTC. Moreover, NrCAM depletion dramatically inhibited thyroid cancer cell growth, invasiveness and tumorigenic potential in nude mice. On the other hand, ectopic expression of NrCAM significantly enhanced its tumor-promoting effects. Mechanically, NrCAM exerted its oncogenic function by activating MAPK/Erk and PI3K/Akt pathways via its ectodomain shedding and binding to EGFR and α4β1 integrins. In turn, these 2 pathways were also responsible for NrCAM overexpression through GSK3β/β-catenin signaling axis in thyroid cancer cells. Similar results were also found in transgenic mice with thyroid-specific knock-in of oncogenic BrafV600E (TPO-Cre/LSL-BrafV600E).
  
  
  
  Our data first reveal positive feedback loops between NrCAM and major signaling pathways contributing to thyroid tumorigenesis by modulating tumor microenvironment, and suggest that NrCAM may represent a potential diagnostic marker and therapeutic target for thyroid cancer.
authors.affiliation: Department of Endocrinology.|Department of Endocrinology, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang 471009, People's Republic of China.
authors.forename: Yanfang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology.
authors.forename: Fang
authors.initials: F
authors.lastname: Sui
authors.affiliation: Department of Endocrinology.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Endocrinology.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Ren
authors.affiliation: Department of Endocrinology and Metabolism, The First Affiliated Hospital of China Medical University, Shenyang 110001, People's Republic of China; and.
authors.forename: Haixia
authors.initials: H
authors.lastname: Guan
authors.affiliation: Department of Endocrinology.
authors.forename: Qi
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Department of Endocrinology.
authors.forename: Jing
authors.initials: J
authors.lastname: Shi
authors.affiliation: Center for Translational Medicine, and.
authors.forename: Meiju
authors.initials: M
authors.lastname: Ji
authors.affiliation: Department of Endocrinology.|Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
authors.forename: Bingyin
authors.initials: B
authors.lastname: Shi
authors.affiliation: Philips Institute for Oral Health Research, Virginia Commonwealth University, Richmond, Virginia 23298.
authors.forename: Yue
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Endocrinology.|Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, People's Republic of China.
authors.forename: Peng
authors.initials: P
authors.lastname: Hou
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D063646:Carcinogenesis / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism*; D002291:Carcinoma, Papillary; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D015815:Cell Adhesion Molecules; C491152:NRCAM protein, human; D012333:RNA, Messenger; D019869:Phosphatidylinositol 3-Kinases; C512478:EGFR protein, human; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt