title: Tumor Suppressor Function of the SEMA3B Gene in Human Lung and Renal Cancers.
abstract: The SEMA3B gene is located in the 3p21.3 LUCA region, which is frequently affected in different types of cancer. The objective of our study was to expand our knowledge of the SEMA3B gene as a tumor suppressor and the mechanisms of its inactivation. In this study, several experimental approaches were used: tumor growth analyses and apoptosis assays in vitro and in SCID mice, expression and methylation assays and other. With the use of the small cell lung cancer cell line U2020 we confirmed the function of SEMA3B as a tumor suppressor, and showed that the suppression can be realized through the induction of apoptosis and, possibly, associated with the inhibition of angiogenesis. In addition, for the first time, high methylation frequencies have been observed in both intronic (32-39%) and promoter (44-52%) CpG-islands in 38 non-small cell lung carcinomas, including 16 squamous cell carcinomas (SCC) and 22 adenocarcinomas (ADC), and in 83 clear cell renal cell carcinomas (ccRCC). Correlations between the methylation frequencies of the promoter and the intronic CpG-islands of SEMA3B with tumor stage and grade have been revealed for SCC, ADC and ccRCC. The association between the decrease of the SEMA3B mRNA level and hypermethylation of the promoter and the intronic CpG-islands has been estimated in renal primary tumors (P < 0.01). Using qPCR, we observed on the average 10- and 14-fold decrease of the SEMA3B mRNA level in SCC and ADC, respectively, and a 4-fold decrease in ccRCC. The frequency of this effect was high in both lung (92-95%) and renal (84%) tumor samples. Moreover, we showed a clear difference (P < 0.05) of the SEMA3B relative mRNA levels in ADC with and without lymph node metastases. We conclude that aberrant expression and methylation of SEMA3B could be suggested as markers of lung and renal cancer progression.
authors.affiliation: Laboratory of Pathogenomics and Transcriptomics, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315, Moscow, Russia; Laboratory of Molecular Genetics of Complex Inherited Diseases, Research Center of Medical Genetics, Russian Academy of Medical Sciences, 115478, Moscow, Russia.
authors.forename: Vitaly I
authors.initials: VI
authors.lastname: Loginov
authors.affiliation: Laboratory of Structural and Functional Genomics, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russia; Department of Pathomorphology, P.A. Herzen Moscow Cancer Research Institute, Ministry of Healthcare of the Russian Federation, 125284, Moscow, Russia.
authors.forename: Alexey A
authors.initials: AA
authors.lastname: Dmitriev
authors.affiliation: Laboratory of Structural and Functional Genomics, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russia.
authors.forename: Vera N
authors.initials: VN
authors.lastname: Senchenko
authors.affiliation: Laboratory of Pathogenomics and Transcriptomics, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315, Moscow, Russia; Laboratory of Molecular Genetics of Complex Inherited Diseases, Research Center of Medical Genetics, Russian Academy of Medical Sciences, 115478, Moscow, Russia.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Pronina
authors.affiliation: Laboratory of Genetics, Federal Research Clinical Center of Federal Medical and Biological Agency of Russia, 115682, Moscow, Russia.
authors.forename: Dmitry S
authors.initials: DS
authors.lastname: Khodyrev
authors.affiliation: Laboratory of Structural and Functional Genomics, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russia; Department of Pathomorphology, P.A. Herzen Moscow Cancer Research Institute, Ministry of Healthcare of the Russian Federation, 125284, Moscow, Russia.
authors.forename: Anna V
authors.initials: AV
authors.lastname: Kudryavtseva
authors.affiliation: Laboratory of Structural and Functional Genomics, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, 119991, Moscow, Russia; Laboratory of Biotechnology, Mechnikov Research Institute for Vaccines and Sera, Russian Academy of Medical Sciences, 105064, Moscow, Russia.
authors.forename: George S
authors.initials: GS
authors.lastname: Krasnov
authors.affiliation: Department of Molecular Oncogenetics, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 03680, Kiev, Ukraine.
authors.forename: Ganna V
authors.initials: GV
authors.lastname: Gerashchenko
authors.affiliation: Department of Molecular Oncogenetics, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 03680, Kiev, Ukraine.
authors.forename: Larisa I
authors.initials: LI
authors.lastname: Chashchina
authors.affiliation: Research Institute of Clinical Oncology, N.N. Blokhin Cancer Research Center, Russian Academy of Medical Sciences, 115478, Moscow, Russia.
authors.forename: Tatiana P
authors.initials: TP
authors.lastname: Kazubskaya
authors.affiliation: Research Institute of Clinical Oncology, N.N. Blokhin Cancer Research Center, Russian Academy of Medical Sciences, 115478, Moscow, Russia.
authors.forename: Tatiana T
authors.initials: TT
authors.lastname: Kondratieva
authors.affiliation: Scientific Board, Affina Biotechnologies, 06902, Stamford, CT, USA.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Lerman
authors.affiliation: The Institute of Life Sciences, Scuola Superiore Sant'Anna, 56127, Pisa, Italy; Institute of Clinical Physiology, National Research Council, 56124, Pisa, Italy; Istituto Toscano Tumori, 56124, Pisa, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Angeloni
authors.affiliation: Laboratory of Pathogenomics and Transcriptomics, Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, 125315, Moscow, Russia; Laboratory of Molecular Genetics of Complex Inherited Diseases, Research Center of Medical Genetics, Russian Academy of Medical Sciences, 115478, Moscow, Russia; Laboratory of Post Genomic Molecular Genetic Research, Institute of Biochemical Physics, Russian Academy of Sciences, 119334, Moscow, Russia.
authors.forename: Eleonora A
authors.initials: EA
authors.lastname: Braga
authors.affiliation: Department of Molecular Oncogenetics, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, 03680, Kiev, Ukraine; Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, SE-17177, Stockholm, Sweden.
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Kashuba
mesh_terms: D000818:Animals; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D018899:CpG Islands; D019175:DNA Methylation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000235:genetics*; D016513:Mice, SCID; D018307:Neoplasms, Squamous Cell / Q000235:genetics* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D011401:Promoter Regions, Genetic; D039961:Semaphorins / Q000235:genetics*; D055752:Small Cell Lung Carcinoma / Q000235:genetics* / Q000473:pathology
chemical_list: D008562:Membrane Glycoproteins; C409766:SEMA3B protein, human; D039961:Semaphorins