A cancer-specific transcriptional signature in human neoplasia
Francesco Nicassio, … , Ian Marc Bonapace, Pier Paolo Di Fiore
Francesco Nicassio, … , Ian Marc Bonapace, Pier Paolo Di Fiore
Published November 1, 2005
Citation Information: J Clin Invest. 2005;115(11):3015-3025. https://doi.org/10.1172/JCI24862.
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Research Article Oncology

A cancer-specific transcriptional signature in human neoplasia

Abstract

The molecular anatomy of cancer cells is being explored through unbiased approaches aimed at the identification of cancer-specific transcriptional signatures. An alternative biased approach is exploitation of molecular tools capable of inducing cellular transformation. Transcriptional signatures thus identified can be readily validated in real cancers and more easily reverse-engineered into signaling pathways, given preexisting molecular knowledge. We exploited the ability of the adenovirus early region 1 A protein (E1A) oncogene to force the reentry into the cell cycle of terminally differentiated cells in order to identify and characterize genes whose expression is upregulated in this process. A subset of these genes was activated through a retinoblastoma protein/E2 viral promoter required factor–independent (pRb/E2F-independent) mechanism and was overexpressed in a fraction of human cancers. Furthermore, this overexpression correlated with tumor progression in colon cancer, and 2 of these genes predicted unfavorable prognosis in breast cancer. A proof of principle biological validation was performed on one of the genes of the signature, skeletal muscle cell reentry-induced (SKIN) gene, a previously undescribed gene. SKIN was found overexpressed in some primary tumors and tumor cell lines and was amplified in a fraction of colon adenocarcinomas. Furthermore, knockdown of SKIN caused selective growth suppression in overexpressing tumor cell lines but not in tumor lines expressing physiological levels of the transcript. Thus, SKIN is a candidate oncogene in human cancer.

Authors

Francesco Nicassio, Fabrizio Bianchi, Maria Capra, Manuela Vecchi, Stefano Confalonieri, Marco Bianchi, Deborah Pajalunga, Marco Crescenzi, Ian Marc Bonapace, Pier Paolo Di Fiore

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Figure 1

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E1A-induced genes and their classification. (A) The E1A-induced genes ar...
E1A-induced genes and their classification. (A) The E1A-induced genes are indicated by their accession numbers (acc. no.) and short names. Q–RT-PCR analysis was performed under the following conditions: (a) overexpression of E1A (not shown here; see Supplemental Table 2); (b) overexpression of the E1A mutant YH47/dl928 (YH47); (c) overexpression of E2F1 (E2F); and (d) removal of Rb (Rb–/–). Values were normalized to those obtained upon overexpression of E1A and are expressed with a color code. YH47 and E2F conditions, red/blue, > or < 35% vs. the E1A-induced condition, respectively; Rb–/– condition, red/blue, > or < 50% vs. the E1A-induced condition, respectively. Actual values are in Supplemental Table 4, and details on each experimental condition are in Supplemental Tables 5–7. Asterisks mark nonsignificant values (P > 0.05). Early and late refer to activation by E1A (actual values are in Supplemental Table 3). (B) Examples of data reported in A. The bar graphs show transcript levels (measured by Q–RT-PCR) of representative genes, as indicated. E1A-early and -late, overexpression of E1A at early and late time points; mock, dl312 adenovirus control; YH47, overexpression of the E1A mutant YH47/dl928; E2F, overexpression of E2F1; MSC-E1A, overexpression of E1A in MSCs; Rb–/–, removal of Rb; MSC prolif., proliferating myoblasts. Values are normalized to mock-infected myotubes (assumed as 1.0). Results are from a single experiment; statistical analyses on repeated experiments are indicated in Supplemental Tables 2–7.