A Precisely Regulated Gene Expression Cassette Potently Modulates Metastasis and Survival in Multiple Solid Cancers

• DOI: 10.1371/journal.pgen.1000129
• Publication Date: 2008-07-17T22:35:49Z
• Authors: Kun Yu; Kumaresan Ganesan; Lay Keng Tan; Mirtha Laban; Jeanie Wu; Xiao Dong Zhao; Hongmin Li; Carol Ho Wing Leung; Yansong Zhu; Chia Lin Wei; Shing Chuan Hooi; Lance Miller; Patrick Tan
• Keywords: 0301 basic medicine; 570; Databases, Factual; Survival; Transcription, Genetic; 610; Mice, Nude; QH426-470; Sensitivity and Specificity; Cohort Studies; Mice; 03 medical and health sciences; Neoplasms; Genetics; Animals; Humans; Neoplasm Metastasis; RNA, Small Interfering; Oligonucleotide Array Sequence Analysis; 0303 health sciences; Gene Expression Profiling; Computational Biology; Reproducibility of Results; Xenograft Model Antitumor Assays; 3. Good health; Gene Expression Regulation, Neoplastic; Colonic Neoplasms; Research Article

Successful tumor development and progression involves the complex interplay of both pro- anti-oncogenic signaling pathways. Genetic components balancing these opposing activities are likely to require tight regulation, because even subtle alterations in their expression may disrupt this balance with major consequences for various cancer-associated phenotypes. Here, we describe a cassette cancer-specific genes exhibiting precise transcriptional control solid tumors. Mining database gene profiles from six different tissues, identified 48 highly restricted levels variation tumors (n = 270) compared nonmalignant tissues 71). Comprising linked multiple cancer-related pathways, "Poised Gene Cassette" (PGC) was robustly validated across 11 independent cohorts approximately 1,300 samples cancer types. In three separate experimental models, PGC were consistently associated significant differences metastatic invasive potential. We functionally confirmed association siRNA knockdown experiments five (p53CSV, MAP3K11, MTCH2, CPSF6, SKIP), which either directly enhanced capacities or inhibited proliferation AGS cells. primary tumors, similar also repeatedly clinical outcome cohorts. Taken collectively, findings support existence common set precisely controlled Since inducing small activity changes prove sufficient potently influence phenotypes such as metastasis, targeting regulated represent promising avenue novel anti-cancer therapies.