Project description:Small cell lung cancer (SCLC) is a subtype of lung cancer with poor prognosis due to early dissemination and rapid growth. We here analyze gene expression profile of 23 clinical SCLC samples. EZH2 was found to be highly expressed in SCLC samples compared to 42 normal tissues including the normal lung, and other PRC2 members, SUZ12 and EED, were also highly expressed in SCLC. To obtain target genes of PRC2 in SCLC, H3K27me3 mark was mapped in three SCLC cell lines, Lu130, H209 and DMS53, and compared to normal small airway epithelial cells (SAEC). Whereas H3K27me3(+) genes in SAEC were significantly overlapped with PRC-target genes in ES cells (P=1.7x10-31), genes with H3K27me3 in SCLC cell lines but not in SAEC were not significantly overlapped with PRC-target genes in ES cells (P=0.64). These genes with H3K27me3 specifically in SCLC cell lines but not in SAEC showed decreased expression, not only in SCLC cell lines but also in clinical SCLCs, and showed enrichment of GO-terms such as plasma membrane (P=8.1x10-21) and cell adhesion (P=1.7x10-8). Introduction of JUB, a gene showing specific H3K27me3 modification and the strongest repression in the three SCLC cell lines, resulted in repression of cellular growth in DMS53. In clinical SCLC cases, lower JUB level correlated to shorter survival (P=0.002), or a set of PRC target genes (JUB, EPHB4) and marker genes of classic type SCLC (GRP, ASCL1) correlated to shorter survival (P=0.0001) and classified SCLC into two groups with distinct prognosis. Growth of SCLC cell lines was repressed when treated with 3-Deazaneplanocin A, an inhibitor against PRC2. It is suggested that high expression of PRC2 in SCLC contributed to repression of genes including non-PRC-target genes in ES cells, and that the gene repression may play a role in genesis of SCLC. Gene expression in 23 clinical SCLC samples, 42 normal tissue samples, 3 small cell lung cancer (SCLC) cell lines, and normal small airway epithelial cell (SAEC) was analyzed by Affymetrix arrays. This dataset is part of the TransQST collection.

Project description:Lung cancer is the leading cause of cancer death in the United States. Among the various subtypes of lung cancers, pulmonary neuroendocrine (NE) cancer, including small cell lung cancer (SCLC) and NE-non-small cell lung cancer (NE-NSCLC), is a particularly aggressive malignancy that is distinct from classic non–small cell lung cancer (NSCLC) in its metastatic potential and treatment response. Recently, the lineage-specific transcription factors Achaete-scute homolog 1 (ASCL1), NEUROD1, and POU2F3 have been reported to identify heterogeneity in pulmonary NE cancers. These transcription factors bind different genomic loci to regulate distinct gene programs in pulmonary NE cancers. However, the signaling pathways downstream of these transcription factors that distinguish these pulmonary NE cancer subtypes are not well characterized. Regulated protein secretion is critically involved in cell signaling and cell-cell communication events, and is known to be a hallmark associated with pulmonary NE tumors. Using a large-scale mass spectrometric approach, we performed quantitative secretomic analysis 13 cell lines including a pair of isogenic cell lines, i.e., an immortalized human bronchial epithelial cell and an ASCL1high NE NSCLC line. This panel also contained 6 additional ASCL1High and 5 NEUROD1High NE-lung cancer cell lines. From the conditioned media of the 13 cell lines, we identified and quantified 1,626 proteins. The NE-specific secretome is associated with a number of biological processes related to neurodevelopment. Further analysis of the upregulated proteins in ASCL1High subtype NE-lung cancer cells leads to the identification of IGFBP5 being a specific secreted marker for ASCL1High pulmonary NE cancer cells. Furthermore, IGFBP5 is also upregulated in the serum of a genetically modified mouse model of ASCL1High SCLC, as well as in human ASCL1High SCLC tumors. Mechanistically, ASCL1 binds to E-box elements in the IGFBP5 gene and directly regulates its transcription. Knockdown of ASCL1 in SCLC decreases IGFBP5 expression, which, in turn, leads to hyperactivation of the IGF-1R pathway. Pharmacological co-targeting of ASCL1 and IGF-1R signaling results in markedly synergistic, growth inhibitory effects in ASCL1High SCLC both in vitro and in vivo. Together, our quantitative proteomic analysis identifies a novel secreted marker and a new combination therapy for ASCL1High pulmonary NE cancer cells. In addition, we expect that the data sets will serve as an invaluable resource, providing the foundation for future mechanistic studies and biomarker discovery that helps delineate the molecular underpinnings of pulmonary NE tumors.

			Action	DRS
	20190313_HDMSE_HAR.raw.zip	Raw
	20190313_HDMSE_MRC.raw.zip	Raw
	20190313_MSE_HAR.raw.zip	Raw
	20190313_MSE_MRC.raw.zip	Raw
	20190313_UDMSE_HAR_001.raw.zip	Raw

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Label-free based DIA quantification of a lung cancer cell line and its potential application in nanomedicine.

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