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 3

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Class D genes in human tumors. (A) The overexpression of class D genes w...
Class D genes in human tumors. (A) The overexpression of class D genes was tested by ISH on TMAs. The color code indicates the percentage of tumors in which overexpression was detected (actual numbers are reported in Supplemental Table 10). White, 0–20%; blue, 21–40%; green, 41–60%; orange, 61–80%; red, 81–100%. In almost all cases (with the exception of TRPC4AP and SF3B1 in normal colon; see Figure 4), normal counterparts (not reported here) showed low or undetectable levels of expression (≤ 1 on our scale; see Methods). Asterisks mark significant values (P < 0.05) of overexpression in tumors vs. normal counterparts. In some cases (uterus, melanoma [melan.], brain), statistical analysis could not be performed due to lack of normal tissues (see Supplemental Table 10 for further details). Eight other genes (from classes A–C, LBR, XTP1, MGC22679, K1594, C3orf4, CML66, K0648, and FLJ37562) showed no overexpression (not shown). Two additional class B genes (Np95 and Nasp) showed elevated mRNA levels in both tumors and proliferating cells of the normal counterparts, thus not fulfilling the criteria for overexpression (see text). (B) Examples of data reported in A. N, normal tissue; T, tumor. Top row, bright fields (histology); bottom row, dark fields (transcripts appear as bright dots). Original magnification, ×10. (C) Tumor and normal samples from colon and breast carcinoma patients were analyzed for levels of expression of SKIN by ISH (black bars) and Q–RT-PCR (white bars), respectively. Q–RT-PCR data are normalized to colon case 1N (assumed as 1.0). Data show good correlation between the 2 methods.