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Majority of Differentially Expressed Genes Are Down-Regulated During Malignant Transformation in a Four-Stage Model

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Majority of Differentially Expressed Genes Are Down-Regulated During Malignant Transformation in a Four-Stage Model Majority of differentially expressed genes are down-regulated during malignant transformation in a four-stage model Frida Danielssona, Marie Skogsa, Mikael Hussb, Elton Rexhepaja, Gillian O’Hurleyc, Daniel Klevebringa,d, Fredrik Ponténc, Annica K. B. Gade, Mathias Uhléna, and Emma Lundberga,1 aScience for Life Laboratory, Royal Institute of Technology (KTH), SE-17121 Solna, Sweden; bScience for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, SE-17121 Solna, Sweden; cScience for Life Laboratory Uppsala, Department of Immunology, Genetics and Pathology, Uppsala University, SE-75185 Uppsala, Sweden; dDepartment of Medical Epidemiology and Biostatistics, Karolinska Institutet, SE-17111 Stockholm, Sweden; and eDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-17177 Stockholm, Sweden Edited by George Klein, Karolinska Institutet, Stockholm, Sweden, and approved March 12, 2013 (received for review October 19, 2012) The transformation of normal cells to malignant, metastatic tumor with the SV40 large-T antigen, and finally made to metastasize cells is a multistep process caused by the sequential acquirement by the introduction of oncogenic H-Ras (RASG12V) (9). We of genetic changes. To identify these changes, we compared the have used this cell-line model for a genome-wide, comprehensive transcriptomes and levels and distribution of proteins in a four- analysis of the molecular mechanisms that underlie malignant stage cell model of isogenically matched normal, immortalized, transformation and metastasis, using transcriptomics and im- fl fi transformed, and metastatic human cells, using deep transcrip- muno uorescence-based protein pro ling. tome sequencing and immunofluorescence microscopy. The data Results show that ∼6% (n = 1,357) of the human protein-coding genes are differentially expressed across the stages in the model. Interest- Morphological Changes in the Four-Stage Cell Model. The mor- ingly, the majority of these genes are down-regulated, linking phologies of the four cell lines that represent the different stages malignant transformation to dedifferentiation. The up-regulated of malignancy were studied using antibodies targeting different A CELL BIOLOGY genes are mainly components that control cellular proliferation, subcellular structures (Fig. 1 ). As expected, the overall mor- phology of the primary cells is more elongated, whereas the cell whereas the down-regulated genes consist of proteins exposed fi fi morphology of the last two stages is irregular and the broblast on or secreted from the cell surface. As many of the identi ed appearance is lost. Whereas some subcellular components, such gene products control basic cellular functions that are defective as microtubules, peroxisomes, and the endoplasmic reticulum, in cancers, the data provide candidates for follow-up studies to are similar in the four cell lines, others are morphologically al- investigate their functional roles in tumor formation. When we tered. For example, the number of nucleoli is increased in the further compared the expression levels of four of the identified transformed cells, likely reflecting an increase of cellular pro- proteins in clinical cancer cohorts, similar differences were ob- liferation. In addition, the morphology of the Golgi apparatus is served between benign and cancer cells, as in the cell model. This altered, showing an aggregated perinuclear phenotype in the shows that this comprehensive demonstration of the molecular transformed cells. changes underlying malignant transformation is a relevant model To objectively evaluate and quantify differences in morphol- to study the process of tumor formation. ogy, we used automated image analysis. Based on 50 features accounting for most of the differences between the cells (Dataset S1), we show that the cells have a morphology that an automated ancer development is a multistep process where genetic fi changes are accumulated, thus progressively transforming classi er can accurately identify and distinguish between (Fig. C 1B). Nonsupervised clustering shows good agreement with BJ cells into a cancerous phenotype (1, 2). Over the last decades, = numerous investigators have studied the underlying molecular cell stage (rho 0.643). Noteworthy is that the immortalized and mechanisms for malignant transformation. This has resulted in transformed cells are more heterogeneous than the primary and metastasizing cells. many models that explain the development of a malignant phe- notype of human cells, for instance the “hallmarks of cancer” by Changes in Gene Expression. The four cell lines were cultivated and Hanahan and Weinberg (3, 4). mRNA was isolated for RNA sequencing (RNA-seq). The With new technologies for deep sequencing, novel opportu- number of genes with detectable transcripts is similar in the nities to study the underlying molecular events leading to cancers different cell types (Fig. 2A), varying between 12,074 and 12,493 have emerged. A large number of investigations have analyzed using a false discovery rate (FDR) of 1%. Spearman correlations mutations occurring in tumors, such as the analysis of mRNA between duplicate samples are high (0.97–0.98, S2) and the ge- expression, microRNA expression, and DNA copy number in a netic elements introduced into the cells were confirmed (see large number of tumors in the Cancer Genome Atlas (5). Simi- legend to Fig. 2). The bioinformatics analysis identified a total of larly, the Human Protein Atlas project (6) studies human cancers 1,357 differentially expressed genes: 214 between the primary using a proteome-wide collection of antibodies, resulting in pub- licly available immunohistochemistry images covering 20 different human cancer types. Author contributions: E.L. designed research; F.D., M.S., G.O., and E.L. performed re- An interesting approach to studying the molecular mecha- search; M.H., E.R., D.K., and A.K.B.G. contributed new reagents/analytic tools; F.D., M.H., nisms underlying cancer is to use an isogenically matched cell E.R., D.K., and F.P. analyzed data; and F.D., M.U., and E.L. wrote the paper. model in which normal cells are progressively transformed into The authors declare no conflict of interest. malignant cells. There are several studies where genetic elements This article is a PNAS Direct Submission. such as oncogenes have been introduced to different types of Data deposition: The RNA-seq data reported in this paper have been deposited in the cells in an accumulative order as an attempt to mimic the natural National Center for Biotechnology Information Sequence Read Archive (accession no. steps of transformation (7, 8). One such cell model is the four- SRP019968). stage model based on BJ fibroblasts developed by the Weinberg 1To whom correspondence should be addressed. E-mail: [email protected]. fi group, in which primary broblast cells were immortalized with This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. telomerase reverse transcriptase (TERT), further transformed 1073/pnas.1216436110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1216436110 PNAS Early Edition | 1of6 Downloaded by guest on September 28, 2021 Primary Immortalized Transformed Metastasizing expressed genes in relation to all detected genes. Here, extra- BJ BJ hTERT BJ hTERT Large-T BJ hTERT Large-T Ras cellular proteins and proteins in the plasma membrane are highly A enriched, whereas ribosomal and mitochondrial proteins are not. To further distinguish between differences among up- and down- regulated proteins, these groups were analyzed separately in terms Microtubules of GO biological process. The large group of down-regulated genes (80%) relates to a diverse set of functions, such as extra- B cellular matrix production, cell adhesion, cell migration, growth factor binding, and angiogenesis. A minority (20%) of the dif- ferentially expressed genes are up-regulated and highly enriched for functions that control cellular proliferation, such as DNA Peroxisomes replication, mitotic spindle, and cell-cycle control (Dataset S3, C validated by independent method in Dataset S4). Molecular Consequences of Cell Immortalization. Telomerase re- verse transcriptase is the catalytic subunit of the enzyme telo- Mitochondria merase and is expressed in most cancers (10). The RNA-seq D analysis revealed that immortalization of the fibroblasts by in- troduction of TERT resulted in 214 differentially expressed genes (Dataset S2). The cytosolic isozymes aldehyde dehydrogenase 1 (ALDH1A1) and erythrocyte membrane protein band 4.1-like-3 Nucleolus (EPB41L3) are detected only in primary cells, and are completely absent upon immortalization [ALDH1A1: fragments per kilobase E of exon model per million fragments mapped (FPKM) 255 to 0; EPB41L3: FPKM 14 to 0]. Immunofluorescence (IF) analysis shows that whereas both the ALDH1A1 and EPB41L3 proteins reticulum show cytoplasmic localization in the primary BJ cells, they are Endoplasmic absent in the subsequent stages of the model (Fig. 3 A and B). F Beyond alcohol metabolism, the role of ALDH1A1 is not yet understood. There are studies that report ALDH1A1 expression as a favorable prognostic factor in ovarian (11) and pancreatic cancer (12). However, contradicting data also show that positive Golgi apparatus cells have increased invasive and metastatic capabilities (13) and that ALDH1A1 expression is correlated with poor survival in G breast cancer (14). Primary 0.15 Immortalized Regarding up-regulated genes, epiregulin
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