Research IndicatorsGraph generated 28 February 2015 using data from PubMed using criteria.
Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic. Tag cloud generated 28 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).
OMIM, Johns Hopkin University
Referenced article focusing on the relationship between phenotype and genotype.
International Cancer Genome Consortium.
Summary of gene and mutations by cancer type from ICGC
Cancer Genome Anatomy Project, NCI
COSMIC, Sanger Institute
Somatic mutation information and related details
Search the Epigenomics database and view relevant gene tracks of samples.
Latest Publications: ASH1L (cancer-related)
Mouradov D, Sloggett C, Jorissen RN, et al.Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer.
Cancer Res. 2014; 74(12):3238-47 [PubMed
] Related Publications
Human colorectal cancer cell lines are used widely to investigate tumor biology, experimental therapy, and biomarkers. However, to what extent these established cell lines represent and maintain the genetic diversity of primary cancers is uncertain. In this study, we profiled 70 colorectal cancer cell lines for mutations and DNA copy number by whole-exome sequencing and SNP microarray analyses, respectively. Gene expression was defined using RNA-Seq. Cell line data were compared with those published for primary colorectal cancers in The Cancer Genome Atlas. Notably, we found that exome mutation and DNA copy-number spectra in colorectal cancer cell lines closely resembled those seen in primary colorectal tumors. Similarities included the presence of two hypermutation phenotypes, as defined by signatures for defective DNA mismatch repair and DNA polymerase ε proofreading deficiency, along with concordant mutation profiles in the broadly altered WNT, MAPK, PI3K, TGFβ, and p53 pathways. Furthermore, we documented mutations enriched in genes involved in chromatin remodeling (ARID1A, CHD6, and SRCAP) and histone methylation or acetylation (ASH1L, EP300, EP400, MLL2, MLL3, PRDM2, and TRRAP). Chromosomal instability was prevalent in nonhypermutated cases, with similar patterns of chromosomal gains and losses. Although paired cell lines derived from the same tumor exhibited considerable mutation and DNA copy-number differences, in silico simulations suggest that these differences mainly reflected a preexisting heterogeneity in the tumor cells. In conclusion, our results establish that human colorectal cancer lines are representative of the main subtypes of primary tumors at the genomic level, further validating their utility as tools to investigate colorectal cancer biology and drug responses.
Li GM, Wang YG, Pan Q, et al.RNAi screening with shRNAs against histone methylation-related genes reveals determinants of sorafenib sensitivity in hepatocellular carcinoma cells.
Int J Clin Exp Pathol. 2014; 7(3):1085-92 [PubMed
] Free Access to Full Article Related Publications
Sorafenib is the first drug currently approved to treat advanced hepatocellular carcinoma (HCC). However, very low response rate and acquired drug resistance makes rare patients benefit from sorafenib therapy, therefore it is urgent to find biomarkers for sorafenib sensitivity. Histone modifications, including histone methylation, have been demonstrated to influence the initiation and progression of HCC. It is of great interest to elicit the possibility whether histone methylation plays a role in regulation of sorafenib sensitivity. In present work, a high throughput RNAi screening with 176 shRNA pools against 88 histone methyltransferases (HMTs) and histone demethyltransferases genes was applied to HepG2 cells. Silencing of 3 genes (ASH1L, C17ORF49 and SETD4) was validated to specifically promote HepG2 cells sensitivity to sorafenib. Western blotting results showed that those 3 HMT genes knockdown alone or sorafenib treatments alone both induce AKT/ERK activation. However, combination treatment with sorafenib and silencing of C17ORF49 or SETD4 downregulated AKT phosphorylation and hence induced HCC cells death. Our work may provide potential biomarkers for sorafenib sensitivity and therapeutic combination for sorafenib treatment in HCC patients.
Song Y, Li L, Ou Y, et al.Identification of genomic alterations in oesophageal squamous cell cancer.
Nature. 2014; 509(7498):91-5 [PubMed
] Related Publications
Oesophageal cancer is one of the most aggressive cancers and is the sixth leading cause of cancer death worldwide. Approximately 70% of global oesophageal cancer cases occur in China, with oesophageal squamous cell carcinoma (ESCC) being the histopathological form in the vast majority of cases (>90%). Currently, there are limited clinical approaches for the early diagnosis and treatment of ESCC, resulting in a 10% five-year survival rate for patients. However, the full repertoire of genomic events leading to the pathogenesis of ESCC remains unclear. Here we describe a comprehensive genomic analysis of 158 ESCC cases, as part of the International Cancer Genome Consortium research project. We conducted whole-genome sequencing in 17 ESCC cases and whole-exome sequencing in 71 cases, of which 53 cases, plus an additional 70 ESCC cases not used in the whole-genome and whole-exome sequencing, were subjected to array comparative genomic hybridization analysis. We identified eight significantly mutated genes, of which six are well known tumour-associated genes (TP53, RB1, CDKN2A, PIK3CA, NOTCH1, NFE2L2), and two have not previously been described in ESCC (ADAM29 and FAM135B). Notably, FAM135B is identified as a novel cancer-implicated gene as assayed for its ability to promote malignancy of ESCC cells. Additionally, MIR548K, a microRNA encoded in the amplified 11q13.3-13.4 region, is characterized as a novel oncogene, and functional assays demonstrate that MIR548K enhances malignant phenotypes of ESCC cells. Moreover, we have found that several important histone regulator genes (MLL2 (also called KMT2D), ASH1L, MLL3 (KMT2C), SETD1B, CREBBP and EP300) are frequently altered in ESCC. Pathway assessment reveals that somatic aberrations are mainly involved in the Wnt, cell cycle and Notch pathways. Genomic analyses suggest that ESCC and head and neck squamous cell carcinoma share some common pathogenic mechanisms, and ESCC development is associated with alcohol drinking. This study has explored novel biological markers and tumorigenic pathways that would greatly improve therapeutic strategies for ESCC.
Secretogranin III (SGC3) belongs to the granin family and is highly expressed in endocrine and neural tissues. The human SCG3 promoter has not yet been characterized. We identified that a 0.5-kb DNA fragment upstream of the SCG3 gene can selectively drive transgene expression in neuroblastoma cell lines. The strength of transgene expression was further increased, with specificity maintained, by addition of the human achaete-scute complex homolog 1 (ASH1) enhancer. We developed an oncolytic serotype 5-based adenovirus, in which the SCG3 promoter and ASH1 enhancer drive E1A gene expression. The virus was further modified with a cell-penetrating peptide (Tat-PTD) in the viral capsid, which we have previously shown results in increased adenovirus transduction efficiency of many neuroblastoma cell lines. The virus, Ad5PTD(ASH1-SCG3-E1A), shows selective and efficient killing of neuroblastoma cell lines in vitro, including cisplatin-, etoposide-, and doxorubicin-insensitive neuroblastoma cells. Furthermore, it delays tumor growth and thereby prolonged survival for nude mice harboring subcutaneous human neuroblastoma xenograft. In conclusion, we report a novel oncolytic adenovirus with potential use for neuroblastoma therapy.
Lung cancer is a highly heterogeneous disease in terms of both underlying genetic lesions and response to therapeutic treatments. We performed deep whole-genome sequencing and transcriptome sequencing on 19 lung cancer cell lines and three lung tumor/normal pairs. Overall, our data show that cell line models exhibit similar mutation spectra to human tumor samples. Smoker and never-smoker cancer samples exhibit distinguishable patterns of mutations. A number of epigenetic regulators, including KDM6A, ASH1L, SMARCA4, and ATAD2, are frequently altered by mutations or copy number changes. A systematic survey of splice-site mutations identified 106 splice site mutations associated with cancer specific aberrant splicing, including mutations in several known cancer-related genes. RAC1b, an isoform of the RAC1 GTPase that includes one additional exon, was found to be preferentially up-regulated in lung cancer. We further show that its expression is significantly associated with sensitivity to a MAP2K (MEK) inhibitor PD-0325901. Taken together, these data present a comprehensive genomic landscape of a large number of lung cancer samples and further demonstrate that cancer-specific alternative splicing is a widespread phenomenon that has potential utility as therapeutic biomarkers. The detailed characterizations of the lung cancer cell lines also provide genomic context to the vast amount of experimental data gathered for these lines over the decades, and represent highly valuable resources for cancer biology.
Our previous data suggested that the human basic helix-loop-helix transcription factor achaete-scute homologue-1 (hASH1) may stimulate both proliferation and migration in the lung. In the CNS, cyclin-dependent kinase 5 (Cdk5) and its activator p35 are important for neuronal migration that is regulated by basic helix-loop-helix transcription factors. Cdk5/p35 may also play a role in carcinogenesis. In this study, we found that the neuronal activator p35 was commonly expressed in primary human lung cancers. Cdk5 and p35 were also expressed by several human lung cancer cell lines and coupled with migration and invasion. When the kinase activity was inhibited by the Cdk5 inhibitor roscovitine or dominant-negative (dn) Cdk5, the migration of lung cancer cells was reduced. In neuroendocrine cells expressing hASH1, such as a pulmonary carcinoid cell line, knocking down the gene expression by short hairpin RNA reduced the levels of Cdk5/p35, nuclear p35 protein, and migration. Furthermore, expression of hASH1 in lung adenocarcinoma cells normally lacking hASH1 increased p35/Cdk5 activity and enhanced cellular migration. We were also able to show that p35 was a direct target for hASH1. In conclusion, induction of Cdk5 activity is a novel mechanism through which hASH1 may regulate migration in lung carcinogenesis.
Nishikawa E, Osada H, Okazaki Y, et al.miR-375 is activated by ASH1 and inhibits YAP1 in a lineage-dependent manner in lung cancer.
Cancer Res. 2011; 71(19):6165-73 [PubMed
] Related Publications
Lung cancers with neuroendocrine (NE) features are often very aggressive but the underlying molecular mechanisms remain elusive. The transcription factor ASH1/ASCL1 is a master regulator of pulmonary NE cell development that is involved in the pathogenesis of lung cancers with NE features (NE-lung cancers). Here we report the definition of the microRNA miR-375 as a key downstream effector of ASH1 function in NE-lung cancer cells. miR-375 was markedly induced by ASH1 in lung cancer cells where it was sufficient to induce NE differentiation. miR-375 upregulation was a prerequisite for ASH1-mediated induction of NE features. The transcriptional coactivator YAP1 was determined to be a direct target of miR-375. YAP1 showed a negative correlation with miR-375 in a panel of lung cancer cell lines and growth inhibitory activities in NE-lung cancer cells. Our results elucidate an ASH1 effector axis in NE-lung cancers that is functionally pivotal in controlling NE features and the alleviation from YAP1-mediated growth inhibition.
Miki M, Ball DW, Linnoila RIInsights into the achaete-scute homolog-1 gene (hASH1) in normal and neoplastic human lung.
Lung Cancer. 2012; 75(1):58-65 [PubMed
] Related Publications
Achaete-scute homolog-1 (ASH1) is pivotal for the development of pulmonary neuroendocrine (NE) cells. We examined human ASH1 (hASH1) expression across a comprehensive panel of human lung cancer cell lines, primary human lung tumors and normal fetal and post-natal lungs. While hASH1 was a cardinal feature of NE carcinomas, a subgroup of non-NE lung cancers also exhibited expression of this factor. Twenty lung cancer cell lines out of 33 were positive for hASH1 mRNA by reverse transcription PCR, including 6/6 small cell carcinomas (SCLC), 5/5 carcinoids, 6/7 non-SCLC with NE features, and 3/14 other non-SCLC. Among human primary tumors, 2/2 SCLC, 5/5 pulmonary carcinoids, and 10/41 non-SCLC (only 4 of which had NE features) were positive for hASH1 by immunohistochemistry and RNA-RNA in situ hybridization. In normal human fetal lung, the expression of hASH1 and the neural marker synaptophysin was highly concordant in neuroepithelial bodies and solitary NE cells, while the rest of the epithelium was negative. In childhood and adulthood, the markers became progressively discordant, with a majority of hASH1-immunoreactive foci (69%) being negative for synaptophysin in adults, potentially representing dormant NE cell progenitors. We conclude that hASH1 provides an early indication of NE program in human lung.
Osada H, Tomida S, Yatabe Y, et al.Roles of achaete-scute homologue 1 in DKK1 and E-cadherin repression and neuroendocrine differentiation in lung cancer.
Cancer Res. 2008; 68(6):1647-55 [PubMed
] Related Publications
The proneural basic-helix-loop-helix protein achaete-scute homologue 1 (ASH1) is expressed in a very limited spectrum of normal and cancerous cells in a lineage-specific manner, including normal pulmonary neuroendocrine cells and lung cancer cells with neuroendocrine features. Our previous results indicated that ASH1 may play a crucial role in the growth and survival of lung cancers with neuroendocrine features, which prompted us to investigate the molecular function of ASH1 in relation to its involvement in carcinogenic processes. Herein, we report for the first time that ASH1 functions as a dual transcription factor by activating neuroendocrine differentiation markers and also repressing putative tumor suppressors. This protein was found to inactivate DKK1 and DKK3, negative regulators of Wnt/beta-catenin signaling, E-cadherin, and integrin beta1 through ASH1-mediated deacetylation and repressive trimethylation of lysine 27 (H3K27me3) of histone H3 in the promoter regions of DKK1 and E-cadherin. In addition, ASH1-transduced A549 adenocarcinoma cells exhibited markedly altered morphology characteristics compared with lung cancer cells with neuroendocrine features both in vitro and in vivo and also grew faster in vivo. Our results provide important clues for a better understanding of the molecular and cellular biological roles of ASH1 in the process of carcinogenesis of lung cancers with neuroendocrine features and warrant future investigations to shed light on the lineage-specific dependency of this transcription factor with dual functions.
Skawran B, Steinemann D, Weigmann A, et al.Gene expression profiling in hepatocellular carcinoma: upregulation of genes in amplified chromosome regions.
Mod Pathol. 2008; 21(5):505-16 [PubMed
] Related Publications
Cytogenetics of hepatocellular carcinoma and adenoma have revealed gains of chromosome 1q as a significant differentiating factor. However, no studies are available comparing these amplification events with gene expression. Therefore, gene expression profiling was performed on tumours cytogenetically well characterized by array-based comparative genomic hybridisation. For this approach analysis was carried out on 24 hepatocellular carcinoma and 8 hepatocellular adenoma cytogenetically characterised by array-based comparative genomic hybridisation. Expression profiles of mRNA were determined using a genome-wide microarray containing 43,000 spots. Hierarchical clustering analysis branched all hepatocellular adenoma from hepatocellular carcinoma. Significance analysis of microarray demonstrated 722 dysregulated genes in hepatocellular carcinoma. Gene set enrichment analysis detected groups of upregulated genes located in chromosome bands 1q22-42 seen also as the most frequently gained regions by comparative genomic hybridisation. Comparison of significance analysis of microarray and gene set enrichment analysis narrowed down the number of dysregulated genes to 18, with 7 genes localised on 1q22 (SCAMP3, IQGAP3, PYGO2, GPATC4, ASH1L, APOA1BP, and CCT3). In hepatocellular adenoma 26 genes in bands 11p15, 11q12, and 12p13 were upregulated. However, the respective chromosome bands were not gained in hepatocellular adenoma. Expression analysis and comparative genomic hybridisation identified an upregulation of genes in amplified regions of 1q. These results may serve to further narrow down the number of candidate driver genes in hepatocarcinogenesis.
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.
Hayes DC, Secrist H, Bangur CS, et al.Multigene real-time PCR detection of circulating tumor cells in peripheral blood of lung cancer patients.
Anticancer Res. 2006 Mar-Apr; 26(2B):1567-75 [PubMed
] Related Publications
BACKGROUND: CLCA2, HMGB3, L587S and ASH1 were identified in lung cancer tissues using genetic subtraction, microarray and quantitative PCR, and found to be specific and complementary for detection of non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC).
MATERIALS AND METHODS: A real-time RT-PCR assay, simultaneously detecting four genes, was developed and tested on lung cancer specimens.
RESULTS: Twenty-two out of 24 adenocarcinomas, 18/18 squamous, 4/5 large cell, 2/2 small cell and 2/2 bronchoalveolar/neuroendocrine cancer tissue samples tested positive. Specificity was demonstrated by evaluation of 194 other tumor and corresponding normal tissues. Circulating tumor cells in the peripheral blood of 49/108 lung cancer patient samples tested positive, and general correlations of multigene expression signals to disease status were observed. Changes in multigene expression during treatment and disease recurrence in individual patients could be detected.
CONCLUSION: These data indicate the diagnostic and prognostic utility of a multigene real-time RT-PCR assay to detect tumor cells in the peripheral blood of lung cancer patients.
Carraresi L, Martinelli R, Vannoni A, et al.Establishment and characterization of murine small cell lung carcinoma cell lines derived from HPV-16 E6/E7 transgenic mice.
Cancer Lett. 2006; 231(1):65-73 [PubMed
] Related Publications
We have established two murine cell lines derived from Small Cell Lung Carcinomas (SCLCs) developed by HPV-E6/E7 transgenic mice. These cells named PPAP-9 and PPAP-10 were isolated from mice bearing tumors, 9 and 10 months old, respectively. The cells, 5 microm in diameter, express HPV oncoproteins and sustain tumor formation after subcutaneous injection in syngenic mice. A detailed analysis indicated the epithelial origin and the neuroendocrine differentiation of these cells. We showed by confocal immunofluorescence the expression of the epithelial marker cytokeratin 5, whose gene promoter was used to direct the expression of HPV E6/E. Cells express several neuroendocrine markers such as CGRP, MAP-2, Ash1, CgrA, Scg2. The neuroendocrine differentiation of these cells was further confirmed by electron microscopy demonstrating neuropeptides secreting granules in their cytoplasm. Furthermore, in agreement with the altered expression observed in the majority of human SCLC we showed in these cells the absence of both p53 and pRB and a dramatic reduction in the expression of Caveolin-1.
Osada H, Tatematsu Y, Yatabe Y, et al.ASH1 gene is a specific therapeutic target for lung cancers with neuroendocrine features.
Cancer Res. 2005; 65(23):10680-5 [PubMed
] Related Publications
Lung cancers with neuroendocrine features are usually aggressive, although the underlying molecular mechanisms largely remain to be determined. The basic helix-loop-helix protein, achaete-scute complex-like 1/achaete-scute homologue 1 (ASH1), is expressed in normal fetal pulmonary neuroendocrine cells and lung cancers with neuroendocrine elements and is suggested to be involved in lung carcinogenesis. In the present study, we show inhibition of ASH1 expression by plasmid-based RNA interference (RNAi) to significantly suppress growth of lung cancer cells with ASH1 expression through G2-M cell cycle arrest and accumulation of sub-G1 populations, possibly linked to cleavage of caspase-9 and caspase-7. However, lung cancer cell lines without ASH1 expression and immortalized normal BEAS2B bronchial epithelial cells were not affected. The RNAi-resistant mutant ASH1 clearly induced rescue from G2-M arrest, suggesting a target-specific effect of RNAi. An ASH1-RNAi adenovirus was also established and significantly inhibited not only in vitro cell proliferation but also in vivo xenograft growth of ASH1-positive NCI-H460 cells. Elevated levels of apoptosis were also observed in NCI-H460 xenografts with the ASH1-RNAi adenovirus. The present study therefore suggests that ASH1 plays a crucial role in lung cancer development and may be an effective therapeutic target in lung cancers with neuroendocrine features.
Kazanjian A, Wallis D, Au N, et al.Growth factor independence-1 is expressed in primary human neuroendocrine lung carcinomas and mediates the differentiation of murine pulmonary neuroendocrine cells.
Cancer Res. 2004; 64(19):6874-82 [PubMed
] Related Publications
Human small cell lung cancers might be derived from pulmonary cells with a neuroendocrine phenotype. They are driven to proliferate by autocrine and paracrine neuropeptide growth factor stimulation. The molecular basis of the neuroendocrine phenotype of lung carcinomas is relatively unknown. The Achaete-Scute Homologue-1 (ASH1) transcription factor is critically required for the formation of pulmonary neuroendocrine cells and is a marker for human small cell lung cancers. The Drosophila orthologues of ASH1 (Achaete and Scute) and the growth factor independence-1 (GFI1) oncoprotein (Senseless) genetically interact to inhibit Notch signaling and specify fly sensory organ development. Here, we show that GFI1, as with ASH1, is expressed in neuroendocrine lung cancer cell lines and that GFI1 in lung cancer cell lines functions as a DNA-binding transcriptional repressor protein. Forced expression of GFI1 potentiates tumor formation of small-cell lung carcinoma cells. In primary human lung cancer specimens, GFI1 expression strongly correlates with expression of ASH1, the neuroendocrine growth factor gastrin-releasing peptide, and neuroendocrine markers synaptophysin and chromogranin A (P < 0.0000001). GFI1 colocalizes with chromogranin A and calcitonin-gene-related peptide in embryonic and adult murine pulmonary neuroendocrine cells. In addition, mice with a mutation in GFI1 display abnormal development of pulmonary neuroendocrine cells, indicating that GFI1 is important for neuroendocrine differentiation.
Ferretti E, Di Stefano D, Zazzeroni F, et al.Human pituitary tumours express the bHLH transcription factors NeuroD1 and ASH1.
J Endocrinol Invest. 2003; 26(10):957-65 [PubMed
] Related Publications
Among the transcription factors involved in pituitary ontogenesis and physiology, basic helix-loop-helix (bHLH) have been poorly studied. Members of bHLH family include NeuroD1 and ASH1, both involved in neuroendocrine differentiation. We evaluated their mRNA expression patterns, by semi-quantitative RT-PCR analysis (sq-RT-PCR) and/or Northern blot, in a series of 33 pituitary adenomas (PA), anterior pituitaries, and pituitary cell lines. Immunohistochemistry for NeuroD1 was also performed in 25 PA. Low levels of NeuroD1 were observed in normal pituitaries and in the somatomammotroph cell lines GH3/GH4C1, contrasting with high levels in corticotroph AtT20 cells. NeuroD1 mRNA was widely expressed in PA (82%), with measurable levels found especially in those derived from Pit-1 independent lineages, i.e. corticotroph (5/5) and clinically non-secreting (CNS) adenomas (9/11). According to sq-RT-PCR analysis, overexpression of NeuroD1 compared to normal pituitaries was frequent. Variable nuclear NeuroD1 immunopositivity was also present in about 70% of studied cases. ASH1 mRNA was widely detected in normal pituitaries, in all tumour cell lines and in most PA (84%), with measurable levels in corticotroph (5/5) and CNS (9/11) adenomas, and in a significant subset of PA derived from Pit-1 dependent lineages (9/16). We conclude that: a) NeuroD1 is differentially expressed in PA and its possible ontogenetic and/or pathogenetic implications in non-corticotroph PA are discussed; b) ASH1 is a neuroendocrine marker whose expression is largely conserved in normal and neoplastic pituitary cells.
Borges M, Linnoila RI, van de Velde HJ, et al.An achaete-scute homologue essential for neuroendocrine differentiation in the lung.
Nature. 1997; 386(6627):852-5 [PubMed
] Related Publications
In Drosophila and in vertebrates, the achaete-scute family of basic helix-loop-helix transcription factors plays a critical developmental role in neuronal commitment and differentiation. Relatively little is known, however, about the transcriptional control of neural features in cells outside a neuronal context. A minority of normal bronchial epithelial cells and many lung cancers, especially small-cell lung cancer, exhibit a neuroendocrine phenotype that may reflect a common precursor cell population. We show here that human achaete-scute homologue-1 (hASH1) is selectively expressed in normal fetal pulmonary neuroendocrine cells, as well as in the diverse range of lung cancers with neuroendocrine features. Strikingly, newborn mice bearing a disruption of the ASH1 gene have no detectable pulmonary neuroendocrine cells. Depletion of this transcription factor from lung cancer cells by antisense oligonucleotides results in a significant decrease in the expression of neuroendrocrine markers. Thus, a homologue of Drosophila neural fate determination genes seems to be necessary for progression of lung epithelial cells through a neuroendocrine differentiation pathway that is a feature of small-cell lung cancer, the most lethal form of human lung cancer.