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1.
Am J Pathol ; 169(5): 1550-66, 2006 Nov.
Article in English | MEDLINE | ID: mdl-17071580

ABSTRACT

Gain-of-function point mutations in K-ras affect early events in pulmonary bronchioloalveolar carcinoma. We investigated altered mRNA expression on K-Ras activation in human peripheral lung epithelial cells (HPL1A) using oligonucleotide microarrays. Mutated K-Ras stably expressed in HPL1A accelerated cell growth and induced the expression of insulin-like growth factor (IGF)-binding protein (IGFBP)-4 and IGFBP-2, which modulate cell growth via IGF. Other lung epithelial cell lines (NHBE and HPL1D) revealed the same phenomena as HPL1A by mutated K-ras transgene. Lung cancer cell growth was also accelerated by mutated K-ras gene transduction, whereas IGFBP-4/2 induction was weaker compared with mutated K-Ras-expressing lung epithelial cells. To understand the differences in IGFBP-4/2 inducibility via K-Ras-activated signaling between nonneoplastic lung epithelia and lung carcinoma, we addressed the mechanisms of IGFBP-4/2 transcriptional activation. Our results revealed that Egr-1, which is induced on activation of Ras-mitogen-activated protein kinase signaling, is crucial for transactivation of IGFBP-4/2. Furthermore, IGFBP-4 and IGFBP-2 promoters were often hypermethylated in lung carcinoma, yielding low basal expression/weak induction of IGFBP-4/2. These findings suggest that continuous K-Ras activation accelerates cell growth and evokes a feedback system through IGFBP-4/2 to prevent excessive growth. Moreover, this growth regulation is disrupted in lung cancers because of promoter hypermethylation of IGFBP-4/2 genes.


Subject(s)
Cell Growth Processes , Epithelial Cells/cytology , Genes, ras/genetics , Insulin-Like Growth Factor Binding Protein 2/metabolism , Insulin-Like Growth Factor Binding Protein 4/metabolism , Lung/cytology , Point Mutation/genetics , Adenocarcinoma/pathology , DNA Methylation , Early Growth Response Protein 1/metabolism , Epithelial Cells/pathology , Gene Expression , Gene Expression Regulation , Humans , Lung/pathology , Mitogen-Activated Protein Kinases/metabolism , Phosphorylation , Promoter Regions, Genetic/genetics , Protein Binding , RNA, Messenger/genetics , RNA, Messenger/metabolism , Sequence Deletion , Transfection , Tumor Cells, Cultured
2.
Lung Cancer ; 45(3): 325-37, 2004 Sep.
Article in English | MEDLINE | ID: mdl-15301873

ABSTRACT

The expression of vascular endothelial growth factors (VEGFs) in tumors including lung cancer is considered to be associated with tumor development via capillary and lymph vessel neogenesis. Dissemination of the tumor cells to the pleura or regional lymph nodes is a critical poor prognostic factor for lung cancer patients. To investigate how VEGFs expressed in the intrathoracic infiltrating lung cancer cells participate in disease progression, we established stably VEGF-A-, VEGF-C-, VEGF-D-, VEGF-A and VEGF-C-, and VEGF-A and VEGF-D-expressing large cell lung cancer clones (TKB5/VEGF-A, TKB5/VEGF-C, TKB5/VEGF-D, TKB5/VEGF-A/C, and TKB5/VEGF-A/D), orthotopically inoculated these into the right thoracic cavity (i.t.) of nude mice, and evaluated the subsequent development of lung lesion, pleural effusion, pleural dissemination, and lymph node metastasis. While there were no significant differences either in culture or in subcutaneous tumor cell growth between the empty vector-transfected group (TKB5/empty) and each transfectant, the i.t. model demonstrated significantly different biological properties between the transfectants. TKB5/empty-inoculated mice frequently developed a large tumor on the pleura without pleural effusion, dissemination, or lymph node (LN) metastasis. In contrast, VEGF-A promoted a bloody pleural effusion (6/14), and VEGF-A and VEGF-D frequently generated pleural dissemination (11/14 and 9/11, respectively). Although both VEGF-C and VEGF-D generated LN metastasis (6/10 and 8/11, respectively), the locations of the metastasized LNs were quite different. TKB5/VEGF-C metastasized on the same side of axillary LNs as i.t. (right axillary LNs), whereas TKB5/VEGF-D metastasized to the mediastinal and left axillary and/or cervical LNs. Since the TKB5/VEGF-A/C or TKB5/VEGF-A/D co-transfectants revealed overlapping tumor progression patterns of VEGF-A and VEGF-C or VEGF-D, the metastatic LNs had abundant new capillaries and were larger than those of TKB5/VEGF-C or TKB5/VEGF-D-inoculated mice. Our results clearly demonstrate that VEGF-A secreted from intrathoracic lung cancer cells plays important roles in producing pleural effusion, dissemination, and capillary neogenesis, that VEGF-C is involved in LN metastasis, and VEGF-D in pleural dissemination and LN metastasis. It is most likely, however, that the mechanisms by which VEGF-C promotes LN metastasis are different from those of VEGF-D. The regulation of the expression of VEGFs in intrathoracic lung cancer cells might be a useful therapeutic approach to inhibiting tumor development and improving patient prognosis.


Subject(s)
Carcinoma, Non-Small-Cell Lung/physiopathology , Gene Expression Regulation, Neoplastic , Lung Neoplasms/physiopathology , Lymphatic Metastasis , Pleural Neoplasms/secondary , Vascular Endothelial Growth Factors/biosynthesis , Animals , Cell Division , Disease Progression , Immunohistochemistry , Male , Mice , Mice, Nude , Neoplasms, Experimental , Prognosis , Tumor Cells, Cultured , Vascular Endothelial Growth Factors/pharmacology
3.
Pathol Int ; 53(1): 58-65, 2003 Jan.
Article in English | MEDLINE | ID: mdl-12558872

ABSTRACT

We report an extremely rare case of primary lung cancer showing various histological elements diagnosed as the collision of an adenosquamous carcinoma and a large cell neuroendocrine carcinoma by loss of heterozygosity (LOH) analysis of the human androgen receptor (AR) and phosphoglycerate kinase (PGK-1) genes. The tumor exhibited a tiny ground-glass opaque shadow suggesting atypical adenomatous hyperplasia 18 months prior to surgery. However, the tumor grew rapidly, and the resected tumor consisted of two closely located nodules. The larger nodule was composed of well-differentiated adenocarcinomatous and moderately to poorly differentiated squamous cell carcinomatous elements, while the smaller nodule consisted of a large cell neuroendocrine carcinomatous element with partial squamoid differentiation having focal continuity with the adenocarcinomatous element. Both the adenocarcinomatous and squamous cell carcinomatous elements revealed transitional features and LOH of AR and PGK-1 genes, while the large cell neuroendocrine carcinomatous element showed a monoclonal pattern but possessed both alleles of AR and PGK-1 genes. From these clinical and pathological results, the parental cell of the large cell neuroendocrine carcinomatous element was considered to be different from that of the adenosquamous carcinomatous element.


Subject(s)
Carcinoma, Adenosquamous/secondary , Carcinoma, Neuroendocrine/secondary , Lung Neoplasms/pathology , Neoplasms, Multiple Primary/pathology , Amino Acid Sequence , Base Sequence , Carcinoma, Adenosquamous/genetics , Carcinoma, Adenosquamous/surgery , Carcinoma, Neuroendocrine/genetics , Carcinoma, Neuroendocrine/surgery , Clone Cells , DNA Primers , DNA, Neoplasm/analysis , Fatal Outcome , Female , Genome, Human , Humans , Loss of Heterozygosity , Lung Neoplasms/genetics , Lung Neoplasms/surgery , Male , Middle Aged , Molecular Sequence Data , Neoplasms, Multiple Primary/genetics , Neoplasms, Multiple Primary/surgery , Phosphoglycerate Kinase/analysis , Phosphoglycerate Kinase/genetics , Polymerase Chain Reaction , Polymorphism, Restriction Fragment Length , Receptors, Androgen/analysis , Receptors, Androgen/genetics
4.
Am J Pathol ; 161(1): 291-300, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12107114

ABSTRACT

Small cell lung cancer (SCLC) and neuroblastoma (NB), the most aggressive adult and infant neuroendocrine cancers, respectively, are immunologically characterized by a severe reduction in major histocompatibility complex (MHC) that is indispensable for anti-tumor immunity. We had reported that the severe reduction of MHC in SCLC was caused by a deficient interferon (IFN)-gamma-inducible expression of class II transactivator (CIITA) that is known as a very important transcription factor for IFN-gamma-inducible class II and class I MHC expression (Yazawa T, Kamma H, Fujiwara M, Matsui M, Horiguchi H, Satoh H, Fujimoto M, Yokohama K, Ogata T: Lack of class II transactivator causes severe deficiency of HLA-DR expression in small cell lung cancer. J Pathol 1999, 187:191-199). Here, we demonstrate that the reduction of MHC in NB was also caused by a deficient IFN-gamma-inducible expression of CIITA and that the deficiency in SCLC and NB was caused by similar mechanisms. Human achaete-scute complex homologue (HASH)-1, L-myc, and N-myc, which are specifically overexpressed in SCLC and NB, bound to the E-box in CIITA promoter IV and reduced the transcriptional activity. Anti-sense oligonucleotide experiments revealed that overexpressed L-myc and N-myc lie upstream in the regulatory pathway of HASH-1 expression. The expression of HASH-1 was also up-regulated by IFN-gamma. Our results suggest that SCLC and NB have complicated mechanisms of IFN-gamma-inducible CIITA transcription deficiency through the overexpressed HASH-1, L-myc, and N-myc. These complicated mechanisms may play an important role in the escape from anti-tumor immunity.


Subject(s)
Carcinoma, Small Cell/genetics , Lung Neoplasms/genetics , Neuroblastoma/genetics , Nuclear Proteins , Trans-Activators/genetics , Transcription, Genetic , Basic Helix-Loop-Helix Transcription Factors , Carcinoma, Small Cell/immunology , Carcinoma, Small Cell/metabolism , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/pharmacology , Humans , Interferon-gamma/pharmacology , Lung Neoplasms/immunology , Lung Neoplasms/metabolism , Major Histocompatibility Complex/immunology , Neuroblastoma/immunology , Neuroblastoma/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Proto-Oncogene Proteins c-myc/pharmacology , Transcription Factors/metabolism , Transcription Factors/pharmacology , Transcription, Genetic/drug effects , Tumor Cells, Cultured/drug effects
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