Association of chromosome 19 to lung cancer genotypes and phenotypes

Wang, Xiangdong; Zhang, Yong; Nilsson, Carol L.; Berven, Frode S.; Andrén, Per E.; Carlsohn, Elisabet; Horvatovich, Péter; Malm, Johan; Fuentes, Manuel; Végvári, Ákos; Welinder, Charlotte; Fehniger, Thomas E.; Rezeli, Melinda; Edula, Goutham; Hober, Sophia; Nishimura, Toshihide; Markó-Varga, György

doi:10.1007/s10555-015-9556-2

Cited by 26 publications

(15 citation statements)

References 69 publications

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“…FAT2 and KiSS-1R. Our results for KiSS-1R conflicted with previous reports that mRNA and protein levels of KISS1R were lower for NSCLC tissue relative to normal lung tissue [ 126 , 127 ]. KISS1R levels were assessed by reverse-transcriptase polymerase chain reaction (RT-PCR) and Western Blot (WB).…”

Section: Discussioncontrasting

confidence: 99%

Cell-surface marker discovery for lung cancer

et al. 2017

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Lung cancer is the leading cause of cancer deaths in the United States. Novel lung cancer targeted therapeutic and molecular imaging agents are needed to improve outcomes and enable personalized care. Since these agents typically cannot cross the plasma membrane while carrying cytotoxic payload or imaging contrast, discovery of cell-surface targets is a necessary initial step. Herein, we report the discovery and characterization of lung cancer cell-surface markers for use in development of targeted agents. To identify putative cell-surface markers, existing microarray gene expression data from patient specimens were analyzed to select markers with differential expression in lung cancer compared to normal lung. Greater than 200 putative cell-surface markers were identified as being overexpressed in lung cancers. Ten cell-surface markers (CA9, CA12, CXorf61, DSG3, FAT2, GPR87, KISS1R, LYPD3, SLC7A11 and TMPRSS4) were selected based on differential mRNA expression in lung tumors vs. non-neoplastic lung samples and other normal tissues, and other considerations involving known biology and targeting moieties. Protein expression was confirmed by immunohistochemistry (IHC) staining and scoring of patient tumor and normal tissue samples. As further validation, marker expression was determined in lung cancer cell lines using microarray data and Kaplan–Meier survival analyses were performed for each of the markers using patient clinical data. High expression for six of the markers (CA9, CA12, CXorf61, GPR87, LYPD3, and SLC7A11) was significantly associated with worse survival. These markers should be useful for the development of novel targeted imaging probes or therapeutics for use in personalized care of lung cancer patients.

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Section: Discussioncontrasting

confidence: 99%

Cell-surface marker discovery for lung cancer

et al. 2017

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“…We speculate that the disproportionately high frequency of alternative splicing events on chromosome 19 may be connected to the high gene density on the chromosome which could result in especially open or poised chromatin structure and accessibility to splicing factors in the poorly differentiated cells. These results are consistent with many other associations between chromosome 19 and NSCLC [32] .…”

Section: Discussionsupporting

confidence: 93%

Upregulation of RNA Processing Factors in Poorly Differentiated Lung Cancer Cells

Geles

Zhong

O'Brien

et al. 2016

Translational Oncology

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Intratumoral heterogeneity in non–small cell lung cancer (NSCLC) has been appreciated at the histological and cellular levels, but the association of less differentiated pathology with poor clinical outcome is not understood at the molecular level. Gene expression profiling of intact human tumors fails to reveal the molecular nature of functionally distinct epithelial cell subpopulations, in particular the tumor cells that fuel tumor growth, metastasis, and disease relapse. We generated primary serum-free cultures of NSCLC and then exposed them to conditions known to promote differentiation: the air-liquid interface (ALI) and serum. The transcriptional network of the primary cultures was associated with stem cells, indicating a poorly differentiated state, and worse overall survival of NSCLC patients. Strikingly, the overexpression of RNA splicing and processing factors was a prominent feature of the poorly differentiated cells and was also observed in clinical datasets. A genome-wide analysis of splice isoform expression revealed many alternative splicing events that were specific to the differentiation state of the cells, including an unexpectedly high frequency of events on chromosome 19. The poorly differentiated cells exhibited alternative splicing in many genes associated with tumor progression, as exemplified by the preferential expression of the short isoform of telomeric repeat-binding factor 1 (TERF1), also known as Pin2. Our findings demonstrate the utility of the ALI method for probing the molecular mechanisms that underlie NSCLC pathogenesis and provide novel insight into posttranscriptional mechanisms in poorly differentiated lung cancer cells.

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“…It has been shown that dysregulated expression of LTBP isoforms are related to the onset of various carcinomas. [12][13][14][15][16][17] In addition, LTBP-4 is also associated with fibrosis-related disease, which is unique within those isoforms. A recent study showed that LTBP-4 exerted distinct functions by causing autosomal recessive cutis laxa type 1C in mice.…”

mentioning

confidence: 99%

Increased expression of latent TGF-β-binding protein 4 affects the fibrotic process in scleroderma by TGF-β/SMAD signaling

Liu

Wang

et al. 2017

Laboratory Investigation

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Scleroderma is a fibrosis-related disorder characterized by cutaneous and internal organ fibrosis, and excessive collagen deposition in extracellular matrix (ECM) is a major cause of fibrosis. Transforming growth factor-β (TGF-β)/SMAD signaling has a central role in the pathogenesis of fibrosis by inducing abnormal collagen accumulation in ECM, and latent TGF-β-binding protein 4 (LTBP-4) affects the secretion of latent TGF-β to ECM. A previous study indicated that bleomycin (BLM) treatment increased LTBP-4 expression in lung fibroblasts of Thy-1 knockout mice with lung fibrosis, and LTBP-4 further promoted TGF-β bioavailability as well as SMAD3 phosphorylation. However, the expression and function of LTBP-4 in human scleroderma remain unclear. We aimed to investigate the potential role of LTBP-4 in scleroderma through clinical, in vivo and in vitro studies. LTBP-4 and TGF-β expressions were significantly upregulated in systemic scleroderma (SSc) patients' plasma compared with normal controls (LTBP-4, 1,215±100.2 vs 542.8±41.7 ng/ml, P<0.0001; TGF-β, 1.5±0.2 vs 0.7±0.1 ng/ml, P=0.0031), while no significant difference was found between localized scleroderma (LSc) and normal controls. The plasma concentrations of LTBP-4 and TGF-β were even higher in SSc patients with lung fibrosis (LTBP-4, 1462± 137.3 vs 892.8±113.4 ng/ml, P=0.0037; TGF-β, 2.0±0.4 vs 0.9±0.2 ng/ml, P=0.0212) and esophagus involvement (1390±134.4 vs 940.7±127.0 ng/ml, P=0.0269; TGF-β, 1.9±0.3 vs 0.9±0.2 ng/ml, P=0.0426). The area under receiver operating characteristics (ROC) curve of LTBP-4 was 0.86. Immunohistochemistry measurement also demonstrated a higher LTBP-4 expression in sclerotic skin tissue of LSc and SSc compared with normal controls. More positive fibroblasts were also found in BLM-induced scleroderma mouse model than the saline-treated group. In in vitro studies, knockdown of LTBP-4 in SSc skin fibroblasts prominently reduced downstream COL1A1, COL1A2, and COL3A1 mRNA level by 84%, 82%, and 43%, respectively, and other fibrosis-related genes' expression were also decreased. Furthermore, extracellular TGF-β level and the SMAD2/3 phosphorylation were inhibited through LTBP-4 knockdown treatment, suggesting that the knockdown of LTBP-4 reduced the collagen expression through TGF-β/SMAD signaling pathway. Taken together, these data suggest that LTBP-4 affects fibrotic process in scleroderma, and the high expression of LTBP-4 in SSc plasma may serve as a clinical biomarker in diagnosing this disease. In addition, this study also lays the theoretical foundation for targeting LTBP-4 as treatment of scleroderma.

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Association of chromosome 19 to lung cancer genotypes and phenotypes

Cited by 26 publications

References 69 publications

Cell-surface marker discovery for lung cancer

Cell-surface marker discovery for lung cancer

Upregulation of RNA Processing Factors in Poorly Differentiated Lung Cancer Cells

Increased expression of latent TGF-β-binding protein 4 affects the fibrotic process in scleroderma by TGF-β/SMAD signaling

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