Identification of Novel Deregulated RNA Metabolism-Related Genes in Non-Small Cell Lung Cancer

Valles, Iñaki; Pajares, María J.; Segura, Víctor; Guruceaga, Elizabeth; Gómez‐Román, Javier; Blanco, David; Tamura, Akiko; Montuenga, Luis M.; Pı́o, Rubén

doi:10.1371/journal.pone.0042086

Cited by 48 publications

(47 citation statements)

References 72 publications

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“…S2 C and D). Consistent with their ability to mediate a cancer-specific function, MRPL3 is overexpressed in nonsmall cell lung cancers (14) and MALAT1 in non-small cell lung cancers and hepatocellular carcinomas (15, 16). Although we have not examined the mechanism by which these genes promote metastasis, MRPL3 promotes the translation of mRNAs encoding mitochondrial enzymes (17) and the biogenesis of miRNA-like small RNAs (miRNAs) (18), and MALAT1 is involved in alternative splicing (19) and transcriptional activation of growth-control genes (20).…”

Section: Significancementioning

confidence: 95%

Forward genetic screens in mice uncover mediators and suppressors of metastatic reactivation

Gao

Chakraborty²,

Lee-Lim³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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We have developed a screening platform for the isolation of genetic entities involved in metastatic reactivation. Retroviral libraries of cDNAs from fully metastatic breast-cancer cells or pooled microRNAs were transduced into breast-cancer cells that become dormant upon infiltrating the lung. Upon inoculation in the tail vein of mice, the cells that had acquired the ability to undergo reactivation generated metastatic lesions. Integrated retroviral vectors were recovered from these lesions, sequenced, and subjected to a second round of validation. By using this strategy, we isolated canonical genes and microRNAs that mediate metastatic reactivation in the lung. To identify genes that oppose reactivation, we screened an expression library encoding shRNAs, and we identified target genes that encode potential enforcers of dormancy. Our screening strategy enables the identification and rapid biological validation of single genetic entities that are necessary to maintain dormancy or to induce reactivation. This technology should facilitate the elucidation of the molecular underpinnings of these processes.forward genetic screens | metastatic reactivation | cDNA library screen | shRNA library screen | microRNA library screen T he majority of cancer-related deaths are caused by metastatic relapse (1). The process through which cancer cells acquire metastatic capacity is complex. Unrestrained proliferation, resistance to proapoptotic insults, and invasion through tissue boundaries are not sufficient for metastasis. To colonize distant organs, cancer cells must also adapt to the local microenvironment of the target organ and finally outgrow (2, 3). Mathematical modeling of clinical data and experiments in mouse models suggest that cancer cells disseminating from prevalent cancers, such as those of the breast and prostate, undergo an extended period of dormancy at premetastatic sites (4). Insights into the mechanisms that enable disseminated cancer cells to survive during dormancy and then outgrow into life-threatening lesions may lead to the identification of novel therapeutic targets for the prevention or treatment of metastatic disease.Advances in genomics and mouse modeling have fostered a renaissance of studies on metastasis (2, 3). Current approaches to the study of metastasis can be divided in two categories. In the first, genetic methods are used to modify the function of a candidate gene in intact mice or in cells that are subsequently transplanted in mice (5, 6). In the second, genomic methods, such as DNA microarray analysis or array comparative genomic hybridization (aCGH), are used to identify a restricted number of candidate genes, which are then tested in appropriate mouse models (7,8). Although these approaches have been extremely successful, they are very laborious and do not necessarily yield biologically potent mediators of metastasis. Functional genetic screens can lead to the rapid identification of strong mediators of a selectable phenotype (9, 10). In agreement with this notion, recent studies have ...

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Section: Significancementioning

confidence: 95%

Forward genetic screens in mice uncover mediators and suppressors of metastatic reactivation

Gao

Chakraborty²,

Lee-Lim³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…The study protocol was approved by the Institutional Ethical Committee and all patients gave written informed consent. RNA extraction was performed as previously described (26).…”

Section: Biological Materialsmentioning

confidence: 99%

Identification of Alternative Splicing Events Regulated by the Oncogenic Factor SRSF1 in Lung Cancer

et al. 2014

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Abnormal alternative splicing has been associated with cancer. Genome-wide microarrays can be used to detect differential splicing events. In this study, we have developed ExonPointer, an algorithm that uses data from exon and junction probes to identify annotated cassette exons. We used the algorithm to profile differential splicing events in lung adenocarcinoma A549 cells after downregulation of the oncogenic serine/arginine-rich splicing factor 1 (SRSF1). Data were generated using two different microarray platforms. The PCR-based validation rate of the top 20 ranked genes was 60% and 100%. Functional enrichment analyses found a substantial number of splicing events in genes related to RNA metabolism. These analyses also identified genes associated with cancer and developmental and hereditary disorders, as well as biologic processes such as cell division, apoptosis, and proliferation. Most of the top 20 ranked genes were validated in other adenocarcinoma and squamous cell lung cancer cells, with validation rates of 80% to 95% and 70% to 75%, respectively. Moreover, the analysis allowed us to identify four genes, ATP11C, IQCB1, TUBD1, and proline-rich coiled-coil 2C (PRRC2C), with a significantly different pattern of alternative splicing in primary non-small cell lung tumors compared with normal lung tissue. In the case of PRRC2C, SRSF1 downregulation led to the skipping of an exon overexpressed in primary lung tumors. Specific siRNA downregulation of the exon-containing variant significantly reduced cell growth. In conclusion, using a novel analytical tool, we have identified new splicing events regulated by the oncogenic splicing factor SRSF1 in lung cancer. Cancer Res; 74(4); 1105-15. Ó2013 AACR.

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“…In relation to its role in cancer, a significant loss of ADAR2-editing activity in astrocytomas (Cenci et al 2008;Tomaselli et al 2013) and malignant gliomas (Maas et al 2001) has been observed. Also, low levels of ADAR2 mRNA in primary cell culture from lung cancer (Valles et al 2012) and hepatocellular carcinoma cells (Chan et al 2014) have been detected. Conversely, ADAR2 is upregulated in various carcinomas and sarcoma cell lines (Flanagan et al 2009).…”

Section: Taf15mentioning

confidence: 99%

RNA-binding proteins as molecular links between cancer and neurodegeneration

et al. 2014

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For many years, epidemiological studies have suggested an association between cancer and neurodegenerative disorders-two disease processes that seemingly have little in common. Although these two disease processes share disruptions in a wide range of cellular pathways, including cell survival, cell death and the cell cycle, the end result is very divergent: uncontrolled cell survival and proliferation in cancer and progressive neuronal cell death in neurodegeneration. Despite the clinical data connecting these two disease processes, little is known about the molecular links between them. Among the mechanisms affected in cancer and neurodegenerative diseases, alterations in RNA metabolism are obtaining significant attention given the critical role for RNA transcription, maturation, transport, stability, degradation and translation in normal cellular function. RNA-binding proteins (RBPs) are integral to each stage of RNA metabolism through their participation in the formation of ribonucleoprotein complexes (RNPs). RBPs have a broad range of functions including posttranscriptional regulation of mRNA stability, splicing, editing and translation, mRNA export and localization, mRNA polyadenylation and miRNA biogenesis, ultimately impacting the expression of every single gene in the cell. In this review, we examine the evidence for RBPs as being key a molecular linkages between cancer and neurodegeneration.

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Identification of Novel Deregulated RNA Metabolism-Related Genes in Non-Small Cell Lung Cancer

Cited by 48 publications

References 72 publications

Forward genetic screens in mice uncover mediators and suppressors of metastatic reactivation

Forward genetic screens in mice uncover mediators and suppressors of metastatic reactivation

Identification of Alternative Splicing Events Regulated by the Oncogenic Factor SRSF1 in Lung Cancer

RNA-binding proteins as molecular links between cancer and neurodegeneration

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