title: Quantitative Secretomic Analysis Identifies Extracellular Protein Factors That Modulate the Metastatic Phenotype of Non-Small Cell Lung Cancer.
abstract: Lung cancer is the leading cause of cancer-related deaths for men and women in the United States, with non-small cell lung cancer (NSCLC) representing 85% of all diagnoses. Late stage detection, metastatic disease and lack of actionable biomarkers contribute to the high mortality rate. Proteins in the extracellular space are known to be critically involved in regulating every stage of the pathogenesis of lung cancer. To investigate the mechanism by which secreted proteins contribute to the pathogenesis of NSCLC, we performed quantitative secretomic analysis of two isogenic NSCLC cell lines (NCI-H1993 and NCI-H2073) and an immortalized human bronchial epithelial cell line (HBEC3-KT) as control. H1993 was derived from a chemo-naïve metastatic tumor, while H2073 was derived from the primary tumor after etoposide/cisplatin therapy. From the conditioned media of these three cell lines, we identified and quantified 2713 proteins, including a series of proteins involved in regulating inflammatory response, programmed cell death and cell motion. Gene Ontology (GO) analysis indicates that a number of proteins overexpressed in H1993 media are involved in biological processes related to cancer metastasis, including cell motion, cell-cell adhesion and cell migration. RNA interference (RNAi)-mediated knock down of a number of these proteins, including SULT2B1, CEACAM5, SPRR3, AGR2, S100P, and S100A14, leads to dramatically reduced migration of these cells. In addition, meta-analysis of survival data indicates NSCLC patients whose tumors express higher levels of several of these secreted proteins, including SULT2B1, CEACAM5, SPRR3, S100P, and S100A14, have a worse prognosis. Collectively, our results provide a potential molecular link between deregulated secretome and NSCLC cell migration/metastasis. In addition, the identification of these aberrantly secreted proteins might facilitate the development of biomarkers for early detection of this devastating disease.
authors.affiliation: Department of Biochemistry and ‡Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Pharmacology and Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas 75235, United States.
authors.forename: Rongkuan
authors.initials: R
authors.lastname: Hu
authors.affiliation: Department of Biochemistry and ‡Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Pharmacology and Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas 75235, United States.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Huffman
authors.affiliation: Department of Biochemistry and ‡Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Pharmacology and Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas 75235, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Chu
authors.affiliation: Department of Biochemistry and ‡Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Pharmacology and Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas 75235, United States.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and ‡Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Pharmacology and Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas 75235, United States.
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.affiliation: Department of Biochemistry and ‡Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Pharmacology and Internal Medicine, University of Texas Southwestern Medical Center , Dallas, Texas 75235, United States.
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Yu
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002465:Cell Movement; D002853:Chromatography, Liquid; D005110:Extracellular Space / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D063990:Gene Ontology; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009362:Neoplasm Metastasis; D010641:Phenotype; D011379:Prognosis; D020543:Proteome / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D053719:Tandem Mass Spectrometry; D014162:Transfection
chemical_list: D014408:Biomarkers, Tumor; D020543:Proteome; D034741:RNA, Small Interfering
keywords: metastasis; non-small cell lung cancer; proteomics and mass spectrometry; secretome