title: Drug-resistant CXCR4-positive cells have the molecular characteristics of EMT in NSCLC.
abstract: High expression of Chemokine receptor 4 (CXCR4) is important in tumor invasion, metastasis, drug-resistance and maintenance of stemness in non-small cell lung cancer (NSCLC). We therefore studied the molecular characteristics of drug-resistant CXCR4-positive cells on epithelial-mesenchymal transition (EMT) for the future identification of the tumor cells with the properties of both EMT and stemness. EMT RT2Profier PCR Array was performed to determine the expression levels of mRNA genes in A549 with TGF-β1 induced EMT (A549/TGF-β1) and gefitinib-resistant CXCR4-positive cells (A549/GR). TCGA database on the cBio Cancer Genomics Portal website and Gene Network Central (GNC) Pro Tutorial were used to analyze their clinical relevance and pathway interactions. CXCR4 was up-regulated both in TGF-β induced EMT cells and in gefitinib-resistant cells. In 84 mRNA genes related to EMT, 17 mRNA genes were up-regulated in CXCR4-positive population of A549/GR when compared to those in CXCR4 negative fraction, while 66 mRNA genes were up-regulated during TGF-β induced EMT. ITGA5, BMP7, MMP3, VIM, RGS2, ZEB2, TCF3, SNAI2, VCAN, PLEK2, WNT5A, COL3A1, SPARC and FOXC2 were doubly up-regulated during the two biological processes. Kaplan-Meier analysis indicated that the doubly up-regulated ITGA5, RGS2, SNAI2 and PLEK2 mRNA genes were related to poor overall survival in lung adenocarcinoma patients (P=9.291e-6, 0.0090, 3.81e-7 and 0.0013, respectively). In GNC analysis, SNAI2 mRNA gene but not ITGA5, RGS2 and PLEK2 was dependent on the signaling pathway of CXCR4. The molecular characteristics of drug-resistant CXCR4-positive cells have a crosstalk with EMT, which has the potential to find the marker with prognostic value on multiple signaling pathways in NSCLC.
authors: Wuxi Center for Disease Control and Prevention, Wuxi, China; Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China.
authors: Hanlu
authors: H
authors: Yin
authors: Department of Respiratory Diseases, Nanjing Chest Hospital, Nanjing, China.
authors: Yi
authors: Y
authors: Wang
authors: Department of Respiratory Diseases, Nanjing Chest Hospital, Nanjing, China.
authors: Wenping
authors: W
authors: Chen
authors: Center of Clinical Laboratory Science, Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, China.
authors: Shanliang
authors: S
authors: Zhong
authors: Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China; Department of Respiratory Diseases, Nanjing Chest Hospital, Nanjing, China; Center of Clinical Laboratory Science, Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, China. Electronic address: liuz@njmu.edu.cn.
authors: Zhian
authors: Z
authors: Liu
authors: Center of Clinical Laboratory Science, Jiangsu Cancer Hospital, Nanjing Medical University, Nanjing, China.
authors: Jianhua
authors: J
authors: Zhao
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D014408:Biomarkers, Tumor; C527276:CXCR4 protein, human; D009363:Neoplasm Proteins; D019718:Receptors, CXCR4; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1
keywords: CXCR4; Cancer stem cell; Drug resistance; Epithelial-mesenchymal transition; Non-small cell lung cancer