SCGB1A1

Gene Summary

Gene:SCGB1A1; secretoglobin, family 1A, member 1 (uteroglobin)
Aliases: UGB, UP1, CC10, CC16, CCSP, UP-1, CCPBP
Location:11q12.3
Summary:This gene encodes a member of the secretoglobin family of small secreted proteins. The encoded protein has been implicated in numerous functions including anti-inflammation, inhibition of phospholipase A2 and the sequestering of hydrophobic ligands. Defects in this gene are associated with a susceptibility to asthma. [provided by RefSeq, May 2010]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:uteroglobin
HPRD
Source:NCBIAccessed: 27 February, 2015

Ontology:

What does this gene/protein do?
Show (14)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • RTPCR
  • Cancer RNA
  • Enzyme Inhibitors
  • Proteins
  • Gene Expression
  • Apoptosis
  • Carcinogens
  • Chromosome 11
  • Adenocarcinoma
  • Disease Models, Animal
  • Cell Proliferation
  • Tumor Markers
  • Respiratory Mucosa
  • Epithelial Cells
  • Lung Cancer
  • Immunoenzyme Techniques
  • Precancerous Conditions
  • Non-Small Cell Lung Cancer
  • Messenger RNA
  • Nitrosamines
  • Wound Healing
  • Hyperplasia
  • TP53
  • Uteroglobin
  • RT-PCR
  • DNA-Binding Proteins
  • Lung
  • Antigens, Polyomavirus Transforming
  • Pulmonary Surfactants
  • Phenotype
  • Basic Helix-Loop-Helix Transcription Factors
  • Promoter Regions
  • Western Blotting
  • Carcinoma, Neuroendocrine
  • Transcription Factors
  • Proteolipids
  • CDC2 Protein Kinase
  • Mice, Transgenic
  • Neoplastic Cell Transformation
  • Bronchi
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: SCGB1A1 (cancer-related)

Dogan I, Kawabata S, Bergbower E, et al.
SOX2 expression is an early event in a murine model of EGFR mutant lung cancer and promotes proliferation of a subset of EGFR mutant lung adenocarcinoma cell lines.
Lung Cancer. 2014; 85(1):1-6 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
OBJECTIVES: Primary and acquired resistance to EGFR TKIs in EGFR mutant lung cancer occurs primarily through secondary mutations in EGFR or Met amplification. Drug resistance can also be mediated by expression of pluripotency transcription factors, such as OCT4, SOX2 and NANOG that decrease terminal differentiation. In this study, we investigated the expression and role of SOX2 in model systems of EGFR mutant tumors.
MATERIALS AND METHODS: Immunoblotting or immunohistochemistry was used to assess expression of pluripotency transcription factors in lungs of transgenic mice or in human NSCLC cell lines. Expression of SOX2 was reduced by shRNA knockdown, and response to erlotinib and cellular proliferation were assessed.
RESULTS AND CONCLUSION: Induction of mutant EGFR in transgenic CCSP-rtTA/TetO-EGFR(L858R/T790M) mice correlated with increased OCT4 and SOX2 expression in lung tissue prior to tumor development. Established lung tumors retained SOX2 expression. To assess a role for SOX2 in tumorigenesis, a panel of NSCLC cell lines with activating EGFR mutations was assessed for SOX2 expression. Two of six cell lines with mutant EGFR showed detectable SOX2 levels, suggesting SOX2 expression did not correlate with EGFR mutation status. To assess the role of SOX2 in these cell lines, HCC827 and H1975 cells were infected with lentivirus containing SOX2 shRNA. Knockdown of SOX2 decreased proliferation in both cell lines and increased sensitivity to erlotinib in HCC827 cells. Because constitutive activation of the PI3K/Akt pathway is associated with EGFR TKI resistance, cells were treated with PI3K/AKT inhibitors and expression of SOX2 was examined. PI3K/Akt inhibitors decreased SOX2 expression in a time-dependent manner. These data suggest targeting SOX2 may provide therapeutic benefit in the subset of EGFR-mutant tumors with high constitutive levels of SOX2, and that until more direct means of inhibiting SOX2 are developed, PI3K/Akt inhibitors might be useful to inhibit SOX2 in EGFR TKI resistant tumors.

Yan C, Ding X, Wu L, et al.
Stat3 downstream gene product chitinase 3-like 1 is a potential biomarker of inflammation-induced lung cancer in multiple mouse lung tumor models and humans.
PLoS One. 2013; 8(4):e61984 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Over-activation of the signal transducers and activators of the transcription 3 (Stat3) pathway in lung alveolar type II (AT II) epithelial cells induces chronic inflammation and adenocarcinoma in the lung of CCSP-rtTA/(tetO)7-CMV-Stat3C bitransgenic mice. One of Stat3 downstream genes products, chitinase 3-like 1 (CHI3L1) protein, showed increased concentration in both bronchioalveolar lavage fluid (BALF) and blood of doxycycline-treated CCSP-rtTA/(tetO)7-CMV-Stat3C bitransgenic mice. When tested in other inflammation-induced lung cancer mouse models, the CHI3L1 protein concentration was also highly increased in BALF and blood of these models with tumors. Immunohistochemical staining showed strong staining of CHI3L1 protein around tumor areas in these mouse models. Analysis of normal objects and lung cancer patients revealed a significant elevation of CHI3L1 protein concentration in human serum samples from all categories of lung cancers. Furthermore, recombinant CHI3L protein stimulated proliferation and growth of Lewis lung cancer cells. Therefore, secretory CHI3L1 plays an important role in inflammation-induced lung cancer formation and potentially serve as a biomarker for lung cancer prediction. Based on our previous publication and this work, this is the first animal study linking overexpression of CHI3L1 to various lung tumor mouse models. These models will facilitate identification of additional biomarkers to predict and verify lung cancer under various pathogenic conditions, which normally cannot be done in humans.

Kim JM, Kim SW, Stewart R, et al.
Serotonergic and BDNF genes associated with depression 1 week and 1 year after mastectomy for breast cancer.
Psychosom Med. 2012; 74(1):8-15 [PubMed] Related Publications
OBJECTIVE: Polymorphisms of serotonin transporter (5-HTT) and brain-derived neurotrophic factor (BDNF) genes have been investigated as candidate genes for depression occurring in medical disorders. The serotonin 2a receptor (5-HTR2a) genes have been investigated as risk factors for depression but rarely in combination with medical conditions. This study aimed to investigate whether polymorphisms of interest in 5-HTT, 5-HTR2a, and BDNF genes are associated with depression after mastectomy for breast cancer.
METHODS: A total of 309 patients with breast cancer were evaluated 1 week after mastectomy, and 244 patients (79%) were followed up 1 year later. Depression (major and minor depressive disorders) was diagnosed according to DSM-IV criteria using the Mini-International Neuropsychiatric Interview and was classified into prevalent, persistent, and incident depression. Individual associations with 5-HTT gene-linked promoter region, serotonin transporter intron 2 variable number tandem repeat, 5-HTR2a 1438A/G, 5-HTR2a 102T/C, and BDNF Val66Met polymorphisms were estimated using logistic regression models, and gene-gene interactions were investigated using the generalized multifactor dimensionality reduction method.
RESULTS: At baseline, 74 patients (24%) were classified with prevalent depression, and at follow-up, 19 patients (8%) and 25 patients (10%) were classified with persistent and incident depression, respectively. The BDNF Met/Met genotype was independently associated with prevalent (odds ratio = 2.63, 95% confidence interval = 1.12-6.14) and persistent (odds ratio = 8.07, 95% confidence interval = 1.26-51.6) depression. No associations with 5-HTT and 5-HTR2a genes (all p values > .21) were found, and no significant gene-gene interactions were identified (all p values > .36).
CONCLUSIONS: Our findings support a role of BDNF, not serotonin, in the etiology of depression occurring in women with breast cancer who received a mastectomy.

Ali HR, Dawson SJ, Blows FM, et al.
Cancer stem cell markers in breast cancer: pathological, clinical and prognostic significance.
Breast Cancer Res. 2011; 13(6):R118 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
INTRODUCTION: The cancer stem cell (CSC) hypothesis states that tumours consist of a cellular hierarchy with CSCs at the apex driving tumour recurrence and metastasis. Hence, CSCs are potentially of profound clinical importance. We set out to establish the clinical relevance of breast CSC markers by profiling a large cohort of breast tumours in tissue microarrays (TMAs) using immunohistochemistry (IHC).
METHODS: We included 4, 125 patients enrolled in the SEARCH population-based study with tumours represented in TMAs and classified into molecular subtype according to a validated IHC-based five-marker scheme. IHC was used to detect CD44/CD24, ALDH1A1, aldehyde dehydrogenase family 1 member A3 (ALDH1A3) and integrin alpha-6 (ITGA6). A 'Total CSC' score representing expression of all four CSC markers was also investigated. Association with breast cancer specific survival (BCSS) at 10 years was assessed using a Cox proportional-hazards model. This study was complied with REMARK criteria.
RESULTS: In ER negative cases, multivariate analysis showed that ITGA6 was an independent prognostic factor with a time-dependent effect restricted to the first two years of follow-up (hazard ratio (HR) for 0 to 2 years follow-up, 2.4; 95% confidence interval (95% CI), 1.2 to 4.8; P = 0.009). The composite 'Total CSC' score carried independent prognostic significance in ER negative cases for the first four years of follow-up (HR for 0 to 4 years follow-up, 1.3; 95% CI, 1.1 to 1.6; P = 0.006).
CONCLUSIONS: Breast CSC markers do not identify identical subpopulations in primary tumours. Both ITGA6 and a composite Total CSC score show independent prognostic significance in ER negative disease. The use of multiple markers to identify tumours enriched for CSCs has the greatest prognostic value. In the absence of more specific markers, we propose that the effective translation of the CSC hypothesis into patient benefit will necessitate the use of a panel of markers to robustly identify tumours enriched for CSCs.

Yang YS, Yang MC, Weissler JC
Pleiomorphic adenoma gene-like 2 expression is associated with the development of lung adenocarcinoma and emphysema.
Lung Cancer. 2011; 74(1):12-24 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Previous study of transgenic mice with long-term expression of pleiomorphic adenoma gene-like 2 (PLAGL2), a surfactant protein C (SP-C) transactivator, in type II cells showed the manifestation of centrilobular emphysema in vivo. Since emphysema is an independent risk factor for bronchogenic carcinoma, we hypothesized that the mouse lungs with induced PLAGL2-expression had increased incidences in developing lung adenocarcinoma. To test the hypothesis, mouse lungs were examined for the presence of tumors. Male mice with induced PLAGL2-expression in the lungs were more vulnerable to tumorigenesis than female mice (p<0.05). Epithelial cells expressing pro-SP-C and Clara cell secretory protein (CCSP) at the terminal bronchioles and the bronchoalveolar duct junction (BADJ) were increased in the induced transgenic mice, suggesting a role of PLAGL2 in expanding SP-C expression cells. Co-expression of TTF-1, pro-SP-C and CD133 (a stem-cell marker) in cancer and distal airway epithelial cells indicated that both cells were derived from common progenitors. This result supported a common-cell-origin mechanism for the comorbid diseases - emphysema and lung cancer. Furthermore, a public lung cancer gene expression profiling database was examined to determine the relevance of PLAGL2 expression and lung adenocarcinoma in humans. Patients with high PLAGL2 expression in lung tumors were readily found. Female patients (N=218) with low PLAGL2 expression (the lowest quartile of total patients) at the early-stage of disease had better prognosis in survival. Male patients, on the other hand, had no such correlation. Generally, their survival rate was significantly poorer than of female patients. Taken together, our data suggested a pathological role of PLAGL2 in lung adenocarcinoma development and a preferable prognosis of low PLAGL2 expression in female patients.

Fukazawa T, Maeda Y, Matsuoka J, et al.
Targeting KRAS mutation-bearing lung cancer in vivo by pulmonary surfactant-adenovirus-mediated gene transfer.
Anticancer Res. 2010; 30(12):4925-35 [PubMed] Related Publications
Pulmonary surfactant has been used as a carrier to deliver a therapeutic virus to dysfunctional lung cells that reside within an intricate lung structure. To investigate whether pulmonary surfactant enhances the efficacy of intratracheal instillation of a therapeutic virus to target KRAS mutation-bearing lung cancer in vivo, we developed a recombinant adenovirus that induces cell death only in lung cancer cells and injected the adenovirus into a mouse model of KRAS mutation-positive lung cancer intratracheally with and without surfactant. A therapeutic adenovirus that induces cell death only in lung cancer cells was constructed by combining a cancer-specific human telomerase reverse transcriptase (hTERT) promoter fused to CCAAT/enhancer-binding protein alpha (CEBPα) with a modified lung-specific Clara cell-specific 10-kDa protein (CC10) promoter fused to cytotoxic adenovirus type 5 early region 1A (E1A). CEBPα is induced only in cancer cells and activates the CC10 promoter, which in turn induces cytotoxic E1A, and causes cell death only in lung cancer cells in vitro. This adenovirus was intratracheally administered to the model mice (CCSP-rtTA/Tet-op-K-Ras4bG12D bitransgenic mice) in the presence and absence of pulmonary surfactant. Intratracheally administered therapeutic adenovirus with pulmonary surfactant spread to airways, as well as to the alveolar region of the lung, and caused a reduction of lung tumors developed. The therapeutic adenovirus without pulmonary surfactant spread only to airways and was ten-fold less effective in tumor reduction. Here, we demonstrate that pulmonary surfactant is an efficient tool to intratracheally deliver a therapeutic virus to treat KRAS mutation-positive lung cancer in vivo.

Bahrami A, Folpe AL
Adult-type fibrosarcoma: A reevaluation of 163 putative cases diagnosed at a single institution over a 48-year period.
Am J Surg Pathol. 2010; 34(10):1504-13 [PubMed] Related Publications
Adult-type fibrosarcoma (FS) was once considered the most common adult sarcoma, but is now considered a diagnosis of exclusion. No recent series has critically reevaluated putative FSs to estimate their true incidence. One hundred ninety-five cases diagnosed as adult FS in somatic soft tissue were retrieved from our institutional archives for the period 1960 to 2008. Thirty-two cases with insufficient material were excluded. On the basis the morphology of the final 163 cases, immunohistochemical studies (IHC) was conducted using some combination of: wide-spectrum cytokeratin (CK), EMA, high molecular weight CK, S100, Melan A, HMB-45, CD34, TLE1, CD31, HHV8, smooth muscle actin, desmin, ALK1, CD99, Myo-D1, myogenin, c-kit, INI1, CD21, p63, calretinin, WT1, and TTF1. Fluorescence in situ hybridization analysis for SYT gene rearrangement was done in 6 putative CK-negative synovial sarcomas (SS). Revised diagnoses were based on clinical, morphologic, IHC, and molecular findings. The original group of putative FS occurred in 84 males and 79 females (median 52.5 y, range 2 to 99 y), and involved various anatomic sites. Only 26 cases met WHO criteria for FS, including 2 postradiation FS. These occurred in 16 males and 10 females (median 50 y, range 6 to 74 y), and involved the lower extremities (12 cases), head/ neck (5 cases), trunk (4 cases), upper extremities (3 case), and mediastinum/abdomen (2 cases). Clinical follow-up information was available for 24 of 26 (92%) cases, with a median of 5 years follow-up (range <1 to 35 y). Twelve patients (50%) died of locally aggressive and/or metastatic disease (median follow-up 1-year; range <1 to 8 y), 6 patients (25%) were alive without disease (median follow-up 11.5 y; range 2.5 to 35 y), and 6 patients (25%) died of other causes (median follow-up 10 y; range 9 to 18 y) (). Fluorescence in situ hybridization analysis was positive for SYT gene rearrangement in all cases tested. Non-FS (137 cases) were reclassified as: undifferentiated pleomorphic sarcoma (32 cases), SS (21 cases), solitary fibrous tumor (14 cases), myxofibrosarcoma (11 cases), malignant peripheral nerve sheath tumor (8 cases), FS dermatofibrosarcoma protuberans, and desmoplastic melanoma (4 cases each), low-grade fibromyxoid sarcoma, sarcomatoid carcinoma, desmoid-type fibromatosis, rhabdomyosarcoma, myofibroblastic sarcoma, spindle-cell liposarcoma (3 cases each), sclerosing epithelioid FS, fibroma-like epithelioid sarcoma, leiomyosarcoma, cellular fibrous histiocytoma (2 cases each), and others (17 cases). Using modern diagnostic criteria with ancillary IHC and molecular genetics, we have been able to reclassify 84% of putative FS. Exclusive of undifferentiated pleomorphic sarcoma, the distinction of which from FS is subjective, 64% of putative FS were reclassified, most commonly as monophasic SS and solitary fibrous tumor. We conclude that true FS is exceedingly rare, accounting for <1% of approximately 10,000 adult soft tissue sarcomas seen at our institution during this time period, and should be diagnosed with great caution.

Wang IC, Zhang Y, Snyder J, et al.
Increased expression of FoxM1 transcription factor in respiratory epithelium inhibits lung sacculation and causes Clara cell hyperplasia.
Dev Biol. 2010; 347(2):301-14 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Foxm1 is a member of the Forkhead Box (Fox) family of transcription factors. Foxm1 (previously called Foxm1b, HFH-11B, Trident, Win, or MPP2) is expressed in multiple cell types and plays important roles in cellular proliferation, differentiation and tumorigenesis. Genetic deletion of Foxm1 from mouse respiratory epithelium during initial stages of lung development inhibits lung maturation and causes respiratory failure after birth. However, the role of Foxm1 during postnatal lung morphogenesis remains unknown. In the present study, Foxm1 expression was detected in epithelial cells of conducting and peripheral airways and changing dynamically with lung maturation. To discern the biological role of Foxm1 in the prenatal and postnatal lung, a novel transgenic mouse line that expresses a constitutively active form of FoxM1 (FoxM1 N-terminal deletion mutant or FoxM1-ΔN) under the control of lung epithelial-specific SPC promoter was produced. Expression of the FoxM1-ΔN transgene during embryogenesis caused epithelial hyperplasia, inhibited lung sacculation and expression of the type II epithelial marker, pro-SPC. Expression of FoxM1-ΔN mutant during the postnatal period did not influence alveologenesis but caused focal airway hyperplasia and increased proliferation of Clara cells. Likewise, expression of FoxM1-ΔN mutant in conducting airways with Scgb1a1 promoter was sufficient to induce Clara cell hyperplasia. Furthermore, FoxM1-ΔN cooperated with activated K-Ras to induce lung tumor growth in vivo. Increased activity of Foxm1 altered lung sacculation, induced proliferation in the respiratory epithelium and accelerated lung tumor growth, indicating that precise regulation of Foxm1 is critical for normal lung morphogenesis and development of lung cancer.

Kurotani R, Kumaki N, Naizhen X, et al.
Secretoglobin 3A2/uteroglobin-related protein 1 is a novel marker for pulmonary carcinoma in mice and humans.
Lung Cancer. 2011; 71(1):42-8 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Secretoglobin (SCGB) 3A2, also called uteroglobin-related protein (UGRP) 1, is a downstream target for a homeodomain transcription factor NKX2-1, which is critical for the development of lung, thyroid and ventral forebrain. Both SCGB3A2 and NKX2-1 are expressed in airway epithelial cells and the latter also in alveolar Type II cells. NKX2-1 has been used clinically for diagnosis of human pulmonary tumors. Recently, the expression of SCGB3A2 was reported in human carcinomas, suggesting the use of this protein as a tumor marker. In this study, 28 lung tumors from aging B6;129 mice and nine lung adenocarcinomas from CC10TAg transgenic mice that express SV40 large T antigen under the mouse Scgb1a1 (CC10) gene promoter, were subjected to histopathological and immunohistochemical analyses for the expression of NKX2-1 and SCGB3A2. NKX2-1 was expressed in all types of tumors albeit more focally in carcinomas. In contrast, SCGB3A2 normally expressed in Clara cells, was negative in Type II cell hyperplasias and adenomas. However, it was expressed in alveolar Type II cell carcinomas and Clara cell adenocarcinomas. In these carcinomas, SCGB3A2 expression was observed in the portion of the tumor where NKX2-1 expression was reduced or almost abolished. As a comparison, the expression of SCGB3A2 and NKX2-1 from 23 human non-small cell lung carcinoma specimens was also examined. The results demonstrate that SCGB3A2 is a useful marker for diagnosis of pulmonary tumors both in mice and humans.

Zhang X, Han B, Huang J, et al.
Prognostic significance of OCT4 expression in adenocarcinoma of the lung.
Jpn J Clin Oncol. 2010; 40(10):961-6 [PubMed] Related Publications
OBJECTIVE: The purpose of this study was to detect the presence of cancer stem-like cells with bronchioalveolar stem cells (BASCs) properties and investigate the clinicopathological role of expression of OCT4 as well as the correlation with clinical outcomes in adenocarcinoma of the lung.
METHODS: Specimens of 112 cases of Stage IB-IIIA lung adenocarcinoma after radical surgery were collected from June 1999 to June 2002. The putative cancer stem cells in tumor sections were visualized immunofluorescently by using the antibodies against three bronchioalveolar stem cells markers: surfactant protein C (SPC), Clara cell secretary protein (CCSP) and Octamer-4 (OCT4). Cancer stem-like cells with bronchioalveolar stem cell properties in human lung adenocarcinoma were subdivided into two phenotypes: OCT4(+)BASC (SPC(+)CCSP(+)OCT4(+)) and OCT4(-)BASC (SPC(+)CCSP(+)OCT4(-)).
RESULTS: Cancer cells with CCSP(+)SPC(+)BASC phenotype were detected in 107 cases, 80 cases with OCT4(+)BASC phenotype (SPC(+)CCSP(+)OCT4(+)) and 27 cases with SPC(+)CCSP(+)OCT4(-). There was a correlation between differentiation and OCT4 expression (P = 0.047). The pattern of survival curves shows the expected trend of decreasing survival with increasing stage at diagnosis (P = 0.015) and with OCT4(+)BASC expression (P = 0.019). Multivariate Cox's analysis reveals that pathological stages of TNM (P = 0.008) and bronchioalveolar stem cells phenotypes (P = 0.015) are the independent prognostic factors.
CONCLUSIONS: The cancer cells with bronchioalveolar stem cells phenotype are detectable in adenocarcinoma of the lung and the expression of self-renewal regulatory gene OCT4 in these cells indicated the worse clinical outcomes.

Quan L, Hutson A, Demant P
A locus on chromosome 8 controlling tumor regionality-a new type of tumor diversity in the mouse lung.
Int J Cancer. 2010; 126(11):2603-13 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Regional specificity of lung tumor formation has rarely been studied in mouse or human. By using crosses of strains semi-congenic for lung cancer susceptibility locus Sluc20, we have analyzed the genetic influences of Sluc20 and 5 other loci on tumor regionality in the mouse lung. We have mapped Sluc20 to a 27.92-MB proximal region of chromosome 8 and found that it controls the number and load of only those tumors that surround or are directly adjacent to the bronchi or bronchioli (peribronchial tumors). These tumors lie outside the bronchial basement membrane and tend to reach a larger size than the tumors at other locations in the lung. Similar to tumors of alveolar lineage at other locations, peribronchial tumors stain with SP-C but not CC10 antibody. The effects of Sluc20 alleles are additive because the number of peribronchial tumors in heterozygotes is intermediate. These findings show that tumor regionality in the mouse lung, which represents a novel level of lung tumor heterogeneity, is under specific genetic control. The identification of genes controlling lung tumor regionality will provide novel insights into the biology of lung tumors and potentially improve the possibilities of individualized prognosis and treatment in human lung cancer.

Qu P, Du H, Wang X, Yan C
Matrix metalloproteinase 12 overexpression in lung epithelial cells plays a key role in emphysema to lung bronchioalveolar adenocarcinoma transition.
Cancer Res. 2009; 69(18):7252-61 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Chronic obstructive pulmonary disease (COPD) and lung cancer are two diseases that are related to smoking in humans. The molecular mechanism linking these two diseases is poorly understood. Matrix metalloproteinase 12 (MMP12) is a member of the MMP family, which can be induced by smoking. Because MMP12 overexpression in epithelial cells has been reported in inflammation-triggered lung remodeling, a murine CCSP-rtTA/(tetO)(7)-MMP12 bitransgenic model was created. In this model, MMP12-Flag fusion protein overexpression and its increased enzymatic activity were observed in the lung in an inducible manner, which led to inflammatory cell infiltration and increased epithelial growth. In sequential events, spontaneous emphysema and bronchioalveolar adenocarcinoma were developed as a result of MMP12 overexpression. During this process, the concentration of interleukin-6 was steadily increased in bronchioalveolar lavage fluid, which activated the oncogenic signal transducer and activator of transcription 3 (Stat3) in alveolar type II epithelial cells. Expression of Stat3 downstream genes that are known to stimulate inflammation and tumor formation was significantly increased in the lung. When tested in humans, MMP12 up-regulation was highly associated with COPD and lung cancer in patients. Together, these studies support that MMP12 is a potent proinflammatory and oncogenic molecule. MMP12 up-regulation plays a critical role in emphysema to lung cancer transition that is facilitated by inflammation.

Wang XY, Demelash A, Kim H, et al.
Matrilysin-1 mediates bronchiolization of alveoli, a potential premalignant change in lung cancer.
Am J Pathol. 2009; 175(2):592-604 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Matrilysin-1 (also called matrix metalloproteinase-7) is expressed in injured lung and in cancer but not in normal epithelia. Bronchiolization of the alveoli (BOA), a potential precursor of lung cancer, is a histologically distinct type of metaplasia that is composed of cells resembling airway epithelium in the alveolar compartment. We demonstrate that there is increased expression of matrilysin-1 in human lesions and BOA in the CC10-human achaete-scute homolog-1 transgenic mouse model. Forced expression of the matrilysin-1 gene in immortalized human normal airway epithelial BEAS-2B and HPLD1 cells, which do not normally express matrilysin-1, promoted cellular migration, suggesting a functional link for BOA formation via bronchiolar cell migration. In addition, matrilysin-1 stimulated proliferation and inhibited Fas-induced apoptosis, while a knockdown by RNA interference decreased cell growth, migration, and increased sensitivity to apoptosis. Western blotting demonstrated increased levels of phospho-p38 and phospho-Erk1/2 kinases after matrilysin-1 expression. Gene expression analysis uncovered several genes that were related to cell growth, migration/movement, and death, which could potentially facilitate bronchiolization. In vivo, the formation of BOA lesions was reduced when CC10-human achaete-scute homolog-1 mice were crossed with matrilysin-1 null mice and was correlated with reduced matrilysin-1 expression in BOA. We conclude that matrilysin-1 may play an important role in the bronchiolization of alveoli by promoting proliferation, migration, and attenuation of apoptosis involving multiple genes in the MAP kinase pathway.

Zeng Y, Yang Z, Xu JG, et al.
Differentially expressed genes from the glioblastoma cell line SHG-44 treated with all-trans retinoic acid in vitro.
J Clin Neurosci. 2009; 16(2):285-94 [PubMed] Related Publications
Morphology, immunocytochemistry, growth curve assay, and flow cytometry were used to investigate the effects of all-trans retinoic acid (RA) on cell proliferation, cell cycle progression and differentiation of the astrocytoma cell line SHG-44 from glioblastoma multiforme (World Health Organization grade IV). The differentially expressed genes from RA-treated and normal SHG-44 were identified by cDNA microarray after the cell line SHG-44 was treated with 10muM RA for 3 days. Validation of some differentially expressed genes was performed by Northern Blot analysis. The expression of glial fibrillary acidic protein (GFAP) was markedly increased in RA-treated SHG-44 cells. Other changes included a short shuttle shape, small nucleus, decreased karyoplasm proportion, the formation of increased thin cytoplasmic processes, reduced cell growth and a 15% increase in G0/G1 phase cell populations. In addition, 42 known genes were identified with altered expression in our cDNA microarray. There was stable down-regulation of MDM2 and UGB as well as overexpression of SOD2, CSTB, and G3BP when RA-treated SHG-44 was compared with normal SHG-44. RA simultaneously suppressed the proliferation of SHG-44 cells significantly as well as induced differentiation and altered gene expression.

Girnun GD, Chen L, Silvaggi J, et al.
Regression of drug-resistant lung cancer by the combination of rosiglitazone and carboplatin.
Clin Cancer Res. 2008; 14(20):6478-86 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
PURPOSE: Current therapy for lung cancer involves multimodality therapies. However, many patients are either refractory to therapy or develop drug resistance. KRAS and epidermal growth factor receptor (EGFR) mutations represent some of the most common mutations in lung cancer, and many studies have shown the importance of these mutations in both carcinogenesis and chemoresistance. Genetically engineered murine models of mutant EGFR and KRAS have been developed that more accurately recapitulate human lung cancer. Recently, using cell-based experiments, we showed that platinum-based drugs and the antidiabetic drug rosiglitazone (PPARgamma ligand) interact synergistically to reduce cancer cell and tumor growth. Here, we directly determined the efficacy of the PPARgamma/carboplatin combination in these more relevant models of drug resistant non-small cell lung cancer.
EXPERIMENTAL DESIGN: Tumorigenesis was induced by activation of either mutant KRAS or EGFR. Mice then received either rosiglitazone or carboplatin monotherapy, or a combination of both drugs. Change in tumor burden, pathology, and evidence of apoptosis and cell growth were assessed.
RESULTS: Tumor burden remained unchanged or increased in the mice after monotherapy with either rosiglitazone or carboplatin. In striking contrast, we observed significant tumor shrinkage in mice treated with these drugs in combination. Immunohistochemical analyses showed that this synergy was mediated via both increased apoptosis and decreased proliferation. Importantly, this synergy between carboplatin and rosiglitazone did not increase systemic toxicity.
CONCLUSIONS: These data show that the PPARgamma ligand/carboplatin combination is a new therapy worthy of clinical investigation in lung cancers, including those cancers that show primary resistance to platinum therapy or acquired resistance to targeted therapy.

Dakir EL H, Feigenbaum L, Linnoila RI
Constitutive expression of human keratin 14 gene in mouse lung induces premalignant lesions and squamous differentiation.
Carcinogenesis. 2008; 29(12):2377-84 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Squamous cell carcinoma accounts for 20% of all human lung cancers and is strongly linked to cigarette smoking. It develops through premalignant changes that are characterized by high levels of keratin 14 (K14) expression in the airway epithelium and evolve through basal cell hyperplasia, squamous metaplasia and dysplasia to carcinoma in situ and invasive carcinoma. In order to explore the impact of K14 in the pulmonary epithelium that normally lacks both squamous differentiation and K14 expression, human keratin 14 gene hK14 was constitutively expressed in mouse airway progenitor cells using a mouse Clara cell specific 10 kDa protein (CC10) promoter. While the lungs of CC10-hK14 transgenic mice developed normally, we detected increased expression of K14 and the molecular markers of squamous differentiation program such as involucrin, loricrin, small proline-rich protein 1A, transglutaminase 1 and cholesterol sulfotransferase 2B1. In contrast, wild-type lungs were negative. Aging CC10-hK14 mice revealed multifocal airway cell hyperplasia, occasional squamous metaplasia and their lung tumors displayed evidence for multidirectional differentiation. We conclude that constitutive expression of hK14 initiates squamous differentiation program in the mouse lung, but fails to promote squamous maturation. Our study provides a novel model for assessing the mechanisms of premalignant lesions in vivo by modifying differentiation and proliferation of airway progenitor cells.

Qu P, Roberts J, Li Y, et al.
Stat3 downstream genes serve as biomarkers in human lung carcinomas and chronic obstructive pulmonary disease.
Lung Cancer. 2009; 63(3):341-7 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Smoking causes lung cancer and chronic obstructive pulmonary disease (COPD) that impose severe health problem to humans. Both diseases are related to each other and can be induced by chronic inflammation in the lung. To identify the molecular mechanism for lung cancer formation, a CCSP-rtTA/(teto)(7)Stat3C bitransgenic model was generated recently. In this model, persistent activation of the Stat3 signaling pathway induced pulmonary inflammation and adenocarcinoma formation in the lung. A group of Stat3 downstream genes were identified by Affymetrix GeneChip microarray analysis that can be used as biomarkers for lung cancer diagnosis and prognosis. To determine which human lung cancers are related to the Stat3 pathway, multiple Stat3 downstream genes were screened in human lung cancers (adenocarcinomas and squamous cell carcinomas) and lung tissue with COPD. In both cancer and COPD, the Stat3 gene was up-regulated. A panel of Stat3-up-regulated downstream genes in mice was up-regulated in human adenocarcinomas, but not in human squamous cell carcinomas. This panel of genes was also modestly up-regulated in lung tissue with COPD from patients with a history of smoking and not up-regulated in those without histories of smoking. Several Stat3-down-regulated downstream genes also showed differential expression patterns in carcinoma and COPD. These studies support a concept that Stat3 is a potent oncogenic molecule that plays a role in formation of lung adenocarcinomas in both mice and humans. The carcinogenesis of adenocarcinoma and squamous cell carcinoma is mediated by different molecular mechanisms and pathways in vivo. Stat3 and its downstream genes can serve as biomarkers for lung adenocarcinoma and COPD diagnosis and prognosis in mice and humans.

Li Y, Du H, Qin Y, et al.
Activation of the signal transducers and activators of the transcription 3 pathway in alveolar epithelial cells induces inflammation and adenocarcinomas in mouse lung.
Cancer Res. 2007; 67(18):8494-503 [PubMed] Related Publications
The lung is an organ for host defense to clear up pathogens through innate and adaptive immunity. This process involves up-regulation of proinflammatory cytokines and chemokines that lead to activation of the signal transducers and activators of the transcription 3 (Stat3) signaling pathway. Overexpression of Stat3C in alveolar type II epithelial cells of CCSP-rtTA/(tetO)(7)-Stat3C bitransgenic mice leads to severe pulmonary inflammation, including immune cell infiltration and up-regulation of proinflammatory cytokines and chemokines in the lung. As a consequence, spontaneous lung bronchoalveolar adenocarcinoma was observed in bitransgenic mice. Aberrantly expressed genes in the bitransgenic model were identified and served as biomarkers for human bronchoalveolar adenocarcinoma. During tumorigenesis, genes that are critical to epithelial cell proliferation in lung development were reactivated. Therefore, Stat3 is a potent proinflammatory molecule that directly causes spontaneous lung cancer in vivo.

Wang XY, Dakir el H, Naizhen X, et al.
Achaete-scute homolog-1 linked to remodeling and preneoplasia of pulmonary epithelium.
Lab Invest. 2007; 87(6):527-39 [PubMed] Related Publications
The basic helix-loop-helix protein achaete-scute homolog-1 (ASH1) is involved in lung neuroendocrine (NE) differentiation and tumor promotion in SV40 transgenic mice. Constitutive expression of human ASH-1 (hASH1) in mouse lung results in hyperplasia and remodeling that mimics bronchiolization of alveoli (BOA), a potentially premalignant lesion of human lung carcinomas. We now show that this is due to sustained cellular proliferation in terminal bronchioles and resistance to apoptosis. Throughout the airway epithelium the expression of anti-apoptotic Bcl-2 and c-Myb was increased and Akt/mTOR pathway activated. Moreover, the expression of matrix metalloproteases (MMPs) including MMP7 was specifically enhanced at the bronchiolo-alveolar duct junction and BOA suggesting that MMPs play a key role in this microenvironment during remodeling. We also detected MMP7 in 70% of human BOA lesions. Knockdown of hASH1 gene in human lung cancer cells in vitro suppressed growth by increasing apoptosis. We also show that forced expression of hASH1 in immortalized human bronchial epithelial cells decreases apoptosis. We conclude that the impact of hASH1 is not limited to cells with NE phenotype. Rather, constitutive expression of hASH1 in lung epithelium promotes remodeling through multiple pathways that are commonly activated during lung carcinogenesis. The collective results suggest a novel model of BOA formation via hASH1-induced suppression of the apoptotic pathway. Our study yields a promising new preclinical tool for chemoprevention of peripheral lung carcinomas.

Henry LR, Lee HO, Lee JS, et al.
Clinical implications of fibroblast activation protein in patients with colon cancer.
Clin Cancer Res. 2007; 13(6):1736-41 [PubMed] Related Publications
PURPOSE: Human fibroblast activation protein (FAP)/seprase is a 97-kDa surface glycoprotein expressed on tumor associated fibroblasts in the majority of epithelial cancers including colon adenocarcinomas. FAP overexpression in human tumor cells has been shown to promote tumor growth in animal models, and clinical trials targeting FAP enzymatic activity have been initiated. The primary objective of this study was to evaluate the clinical significance of stromal FAP in human colon cancers by immunohistochemisty.
EXPERIMENTAL DESIGN: Sections of paraffin-embedded resected primary human colon cancer specimens from 1996 through 2001 within the Fox Chase Cancer Center tumor bank were stained with D8 antibody directed against FAP/seprase. Xenotransplanted human colorectal tumors in mice were examined similarly for stromal FAP in tumors of different sizes. Overall percentage of stromal FAP staining of the primary tumor was assessed semiquantitatively (0, 1+, 2+, 3+) and staining intensity was also graded (none, weak, intermediate, strong). Survival time and time to recurrence data were analyzed using Kaplan-Meier plots, log-rank tests, and Cox proportional hazards models.
RESULTS: One hundred thirty-eight patients with resected specimens were available for study (mean follow-up, 1,050 days) with 6 (4%) stage I, 52 (38%) stage II, 43 (31%) stage III, and 37 (27%) stage IV patients. FAP was detected in >93% of specimens. Semiquantitative staining was scored as 1+ in 28 (20%), 2+ in 52 (38%), and 3+ in 49 (35%). FAP staining intensity was graded as weak in 45 (33%), intermediate in 48 (35%), and dark in 36 (26%). Stromal FAP was found to correlate inversely with tumor stage (semiquantitative, P = 0.01; intensity, P = 0.009) and with tumor size of the tumor xenograft model (correlation coefficient, -0.61; P = 0.047), suggesting that stromal FAP may have a greater role in the early development of tumors. Furthermore, greater stromal FAP for patients with known metastatic disease was associated with a decreased survival.
CONCLUSION: Our data indicate that patients whose colon tumors have high levels of stromal FAP are more likely to have aggressive disease progression and potential development of metastases or recurrence. This study affirms the rationale for ongoing clinical investigations using FAP as a therapeutic target to disrupt FAP-driven tumor progression in patients with metastatic disease. It also suggests that the effects of FAP inhibition should be investigated in earlier-stage tumors, given its high levels and potential effect earlier in the course of the disease.

Park KS, Korfhagen TR, Bruno MD, et al.
SPDEF regulates goblet cell hyperplasia in the airway epithelium.
J Clin Invest. 2007; 117(4):978-88 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Goblet cell hyperplasia and mucous hypersecretion contribute to the pathogenesis of chronic pulmonary diseases including cystic fibrosis, asthma, and chronic obstructive pulmonary disease. In the present work, mouse SAM pointed domain-containing ETS transcription factor (SPDEF) mRNA and protein were detected in subsets of epithelial cells lining the trachea, bronchi, and tracheal glands. SPDEF interacted with the C-terminal domain of thyroid transcription factor 1, activating transcription of genes expressed selectively in airway epithelial cells, including Sftpa, Scgb1a1, Foxj1, and Sox17. Expression of Spdef in the respiratory epithelium of adult transgenic mice caused goblet cell hyperplasia, inducing both acidic and neutral mucins in vivo, and stainined for both acidic and neutral mucins in vivo. SPDEF expression was increased at sites of goblet cell hyperplasia caused by IL-13 and dust mite allergen in a process that was dependent upon STAT-6. SPDEF was induced following intratracheal allergen exposure and after Th2 cytokine stimulation and was sufficient to cause goblet cell differentiation of Clara cells in vivo.

Zhong S, Xu Y, Zhang Z
Construction of eukaryotic expression vector of human CC10 gene and expression of CC10 protein in lung adenocarcinoma A549 cell line.
J Huazhong Univ Sci Technolog Med Sci. 2005; 25(5):505-7 [PubMed] Related Publications
A mammalian expression plasmid pcDNA3. 1-hCC10 was constructed and identified, then CC10 protein expression in A549 lung cancer cell line was detected. A 273 bp cDNA fragment was amplified from the total RNA of normal lung tissue by using RT-PCR and cloned into expression plasmid cDNA3. 1, and the recombinant plasmid was identified by employing double digestion restriction enzymes Hind III and BamH I and the cDNA sequence was assayed by the Sanger dideoxy-mediated chain termination method. The segment was then transfected into the A549 lung cancer cell line. The protein expression of CC10 was detected by immunofluorescence and Western blot. Our results showed that the cDNA fragment included the entire coding region (273 bp). The recombinant eukaryotic cell expression vector of pcDNA3. 1-hCC10 was successfully constructed, and the sequence of the insert was identical to the published sequence. A549 cells line transfected with the pcDNA3. 1-hCC10 expressed high level of CC10 protein. The recombinant plasmid cDNA3. 1-hCC10 may serve as an effective tool for the study of tumorogenesis and tumor treatment.

Ji H, Houghton AM, Mariani TJ, et al.
K-ras activation generates an inflammatory response in lung tumors.
Oncogene. 2006; 25(14):2105-12 [PubMed] Related Publications
Activating mutations in K-ras are one of the most common genetic alterations in human lung cancer. To dissect the role of K-ras activation in bronchial epithelial cells during lung tumorigenesis, we created a model of lung adenocarcinoma by generating a conditional mutant mouse with both Clara cell secretory protein (CC10)-Cre recombinase and the Lox-Stop-Lox K-ras(G12D) alleles. The activation of K-ras mutant allele in CC10 positive cells resulted in a progressive phenotype characterized by cellular atypia, adenoma and ultimately adenocarcinoma. Surprisingly, K-ras activation in the bronchiolar epithelium is associated with a robust inflammatory response characterized by an abundant infiltration of alveolar macrophages and neutrophils. These mice displayed early mortality in the setting of this pulmonary inflammatory response with a median survival of 8 weeks. Bronchoalveolar lavage fluid from these mutant mice contained the MIP-2, KC, MCP-1 and LIX chemokines that increased significantly with age. Cell lines derived from these tumors directly produced MIP-2, LIX and KC. This model demonstrates that K-ras activation in the lung induces the elaboration of inflammatory chemokines and provides an excellent means to further study the complex interactions between inflammatory cells, chemokines and tumor progression.

Yamamoto O, Takahashi H, Hirasawa M, et al.
Surfactant protein gene expressions for detection of lung carcinoma cells in peripheral blood.
Respir Med. 2005; 99(9):1164-74 [PubMed] Related Publications
BACKGROUND: Inflow of tumor cells to circulation is an essential step for metastasis of primary tumors. To know its state may contribute to therapeutic strategy. However, methodology to detect lung carcinoma cells floating in peripheral blood has not been established. Pulmonary surfactant protein (SP)-A, SP-C and Clara cells-10 kd protein (CC10) are specific to the lung and often expressed in primary lung carcinomas. We evaluated the worth of these gene expressions for the detection of carcinoma cells in peripheral blood.
METHODS: The expressions in 5 ml of venous blood were tested by RT-PCR. Ninety-nine patients with non-small cell lung carcinoma (NSCLC) and 17 with small cell lung carcinoma (SCLC) were compared to 13 with secondary lung tumor, 48 with non-malignant respiratory diseases and 19 healthy volunteers.
RESULTS: The mRNA expressions of SP-A and SP-C were completely specific to NSCLC when compared to SCLC and secondary lung tumors. All of the healthy volunteers and patients with non-malignant respiratory diseases showed negative for these mRNA expressions, except for one sample. The positive rate of SP-A, SP-C and CC10 mRNA in patients with NSCLC was 33.3%, 14.1%, 3.3%, respectively. The rates of SP-A and SP-C mRNA were higher than that (11.1%) in CEA mRNA. The increased positive rate of mRNA of SP-A and SP-C was significantly dependent on the clinical stage and the existence of distant metastasis.
CONCLUSION: These results demonstrate that the detection of mRNA of SP-A and SP-C would give clinicians valuable information suggesting the presence of blood-floating carcinoma cells as a step toward metastasis.

Ushigome M, Ubagai T, Fukuda H, et al.
Up-regulation of hnRNP A1 gene in sporadic human colorectal cancers.
Int J Oncol. 2005; 26(3):635-40 [PubMed] Related Publications
We have previously reported that the heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1), a major hnRNP, binds to G-rich repetitive sequences and quadruplex (G4') structures in DNA, including the 5'-TTAGGG-3' telomere repeat and 5'-GGCAG-3' short-tandem-repeat. DNA synthesis arrest at the (GGG) sites within these repeats in vitro was retrieved by the addition of the hnRNP A1 protein or its N-terminal proteolytic product, UP1, in a dose-dependent manner. Therefore, functional perturbation of hnRNP A1 may abrogate the genomic stability of telomere repeats and other G-rich sequences, independent of its major role in transcriptional and translational regulation. In the present study, we conducted genetic and expression analysis of the hnRNP A1 gene in sporadic human colorectal cancers to clarify its possible involvement in human carcinogenesis. Of 30 lesions, one harbored a mutation at the -11 position from the translation initiation site, but none in the coding region. A single nucleotide polymorphism, an A or G-allele, was found in the 5' upstream promoter region of the gene. Quantitative gene expression analysis revealed that 60% (18/30) of cases showed over-expression of hnRNP A1 in cancer tissues by 2-fold or greater, compared to their normal colon tissues, with values of 78, 64 and 40% for clinicopathological stages II, III and IV, respectively. Although the biological consequences of hnRNP A1 overexpression in colorectal cancers remain to be clarified, it could contribute to maintenance of telomere repeats in cancer cells with enhanced cell proliferation. Alternatively, since the variations in the stoichiometry of hnRNP family proteins are considered to affect cell-specific gene expression, quantitative alteration of hnRNP A1 could result in facilitation of transformation of colon epithelial cells as a consequence of transcriptional and translational perturbation.

Roper JM, Gehen SC, Staversky RJ, et al.
Loss of Gadd45a does not modify the pulmonary response to oxidative stress.
Am J Physiol Lung Cell Mol Physiol. 2005; 288(4):L663-71 [PubMed] Related Publications
It is well established that exposure to high levels of oxygen (hyperoxia) injures and kills microvascular endothelial and alveolar type I epithelial cells. In contrast, significant death of airway and type II epithelial cells is not observed at mortality, suggesting that these cell types may express genes that protect against oxidative stress and damage. During a search for genes induced by hyperoxia, we previously reported that airway and alveolar type II epithelial cells uniquely express the growth arrest and DNA damage (Gadd)45a gene. Because Gadd45a has been implicated in protection against genotoxic stress, adult Gadd45a (+/+) and Gadd45a (-/-) mice were exposed to hyperoxia to investigate whether it protected epithelial cells against oxidative stress. During hyperoxia, Gadd45a deficiency did not affect loss of airway epithelial expression of Clara cell secretory protein or type II epithelial cell expression of pro-surfactant protein C. Likewise, Gadd45a deficiency did not alter recruitment of inflammatory cells, edema, or overall mortality. Consistent with Gadd45a not affecting the oxidative stress response, p21(Cip1/WAF1) and heme oxygenase-1 were comparably induced in Gadd45a (+/+) and Gadd45a (-/-) mice. Additionally, Gadd45a deficiency did not affect oxidative DNA damage or apoptosis as assessed by oxidized guanine and terminal deoxyneucleotidyl transferase-mediated dUTP nick-end labeling staining. Overexpression of Gadd45a in human lung adenocarcinoma cells did not affect viability or survival during exposure, whereas it was protective against UV-radiation. We conclude that increased tolerance of airway and type II epithelial cells to hyperoxia is not attributed solely to expression of Gadd45a.

Xin B, Platzer P, Fink SP, et al.
Colon cancer secreted protein-2 (CCSP-2), a novel candidate serological marker of colon neoplasia.
Oncogene. 2005; 24(4):724-31 [PubMed] Related Publications
Cancers of the colon and rectum are the second leading cause of cancer death among adult Americans. When detected at early stages, colon cancer is highly curable. Colonoscopy, an effective but invasive screening test, has been limited in its public acceptance. The goal of this study was to identify novel serum markers of colon cancers and precancerous colon adenomas as potential candidates for noninvasive detection of early colon neoplasms. Employing expression microarrays, we identified colon cancer secreted protein-2 (CCSP-2) as a novel transcript whose expression is generally absent in normal colon and other normal body tissues, but that is induced an average of 78-fold in Stage II, III, and IV colon cancers, as well as in colon adenomas and colon cancer cell lines. These findings were validated by real-time PCR analysis in an independent panel of colon cancer cases. Moreover, CCSP-2 was shown to encode a secreted protein that circulates stably and is detectable in the blood of mice bearing human cancer xenografts transfected with epitope-tagged CCSP-2. As a novel secreted protein that is markedly induced in colon adenomas and cancers, CCSP-2 is a novel candidate for development as a diagnostic serum marker of early stage colon cancer.

Park JS, Young Yoon S, Kim JM, et al.
Identification of novel genes associated with the response to 5-FU treatment in gastric cancer cell lines using a cDNA microarray.
Cancer Lett. 2004; 214(1):19-33 [PubMed] Related Publications
The 5-Fluorouracil (5-FU) is an anticancer drug that is widely used in the treatment of cancer. To identify novel genes associated with 5-FU in gastric cancer, the time-dependent expression profiling of genes in response to 5-FU was examined in 5-FU sensitive and/or resistant gastric cancer cell lines using a 'KUGI 14 K cDNA chip' containing 14,081 unigenes obtained from human gastric cancer cell lines and tissues. By this analysis, we obtained 13 genes which are directly associated with sensitivity or resistance to 5-FU. Of these genes, 11 were found to be commonly up-regulated only in the 5-FU sensitive cell lines, and 2 were oppositely regulated in both of 5-FU sensitive and resistant cell lines. These genes were determined to be involved in cell surface, apoptosis, cell cycle and signal transduction. Of these genes, the expression levels of ZFP100, 4F2hc, FLJ11021, CSTF3, PPP1R14A, DDB2, C6orf139, CDKN1A, HOXC11 and FLJ38860 were confirmed by semi-quantitative RT-PCR. In addition, seven genes containing RRMI, UP1 and K-EST0037597 were found to be commonly up-regulated in both cell lines. In addition, the expression of genes such as TP, OPRT, TS and DPD, which have been previously known to be involved in 5-FU metabolism, were examined in both of 5-FU sensitive and resistant cell lines. These results provide not only predictive biomarkers for 5-FU sensitivity or resistance to human gastric cancer, but also a new molecular basis for understanding the mechanism of cellular cytoxicity to 5-FU.

Shijubo N, Kawabata I, Sato N, Itoh Y
Clinical aspects of Clara cell 10-kDa protein/ uteroglobin (secretoglobin 1A1).
Curr Pharm Des. 2003; 9(14):1139-49 [PubMed] Related Publications
Clara cell 10-kDa protein (CC10)/ uteroglobin (UG) is a nonglycoprotein with a molecular mass of 16 kilodaltons, which is produced by mucosal epithelial cells in the lung (Clara cells), uterus and prostate. Like other low molecular weigh proteins it is catabolized in renal proximal tubules. Structurally it is a homodimer of subunits of 70 amino acids covalently bound in an antiparallel manner. It belongs to secretogobin (SCGB) family and is assigned as subgroup 1A1. The function of the protein so far elucidated is immunoregulatory and anti-inflammatory in innate immunity. The knockout mouse of UG gene resulted in aggravation of inflammation by allergic and hyperoxic stimuli. It also showed very similar pathological features with human IgA nephropathy. The value is changed in the lung fluid and serum of various inflammatory and allergic lung diseases. Several kinds of single nucleotide polymorphisms (SNPs) in human CC10/UG gene were recently discovered; Adenine allele accumulation in G38A SNP has possible association with asthma and IgA nephropathy, being paralleled with disease severity of IgA nephropathy. Its expression is enhanced by some transcriptional factors induced by cytokines such as interferon-gamma. For cancer cells, the protein functions as an antagonist of neoplastic phenotype. CC10/UG forms one of intra- and intercellular regulators involved in inflammation and malignant transformation in the respiratory and urogenital fields.

Yao R, Wang Y, Lubet RA, You M
Differential gene expression in chemically induced mouse lung adenomas.
Neoplasia. 2003 Jan-Feb; 5(1):41-52 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Because of similarities in histopathology and tumor progression stages between mouse and human lung adenocarcinomas, the mouse lung tumor model with lung adenomas as the endpoint has been used extensively to evaluate the efficacy of putative lung cancer chemopreventive agents. In this study, a competitive cDNA library screening (CCLS) was employed to determine changes in the expression of mRNA in chemically induced lung adenomas compared with paired normal lung tissues. A total of 2555 clones having altered expression in tumors were observed following competitive hybridization between normal lung and lung adenomas after primary screening of over 160,000 clones from a mouse lung cDNA library. Among the 755 clones confirmed by dot blot hybridization, 240 clones were underexpressed, whereas 515 clones were overexpressed in tumors. Sixty-five clones with the most frequently altered expression in six individual tumors were confirmed by semiquantitative RT-PCR. When examining the 58 known genes, 39 clones had increased expression and 19 had decreased expression, whereas the 7 novel genes showed overexpression. A high percentage (>60%) of overexpressed or underexpressed genes was observed in at least two or three of the lesions. Reproducibly overexpressed genes included ERK-1, JAK-1, surfactant proteins A, B, and C, NFAT1, alpha-1 protease inhibitor, helix-loop-helix ubiquitous kinase (CHUK), alpha-adaptin, alpha-1 PI2, thioether S-methyltransferase, and CYP2C40. Reproducibly underexpressed genes included paroxanase, ALDH II, CC10, von Ebner salivary gland protein, and alpha- and beta-globin. In addition, CCLS identified several novel genes or genes not previously associated with lung carcinogenesis, including a hypothetical protein (FLJ11240) and a guanine nucleotide exchange factor homologue. This study shows the efficacy of this methodology for identifying genes with altered expression. These genes may prove to be helpful in our understanding of the genetic basis of lung carcinogenesis and in developing biomarkers for lung cancer chemoprevention studies in mice.

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