title: A precisely regulated gene expression cassette potently modulates metastasis and survival in multiple solid cancers.
abstract: Successful tumor development and progression involves the complex interplay of both pro- and 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 of cancer-specific genes exhibiting precise transcriptional control in solid tumors. Mining a database of tumor gene expression profiles from six different tissues, we identified 48 genes exhibiting highly restricted levels of gene expression variation in tumors (n = 270) compared to nonmalignant tissues (n = 71). Comprising genes linked to multiple cancer-related pathways, the restricted expression of this "Poised Gene Cassette" (PGC) was robustly validated across 11 independent cohorts of approximately 1,300 samples from multiple cancer types. In three separate experimental models, subtle alterations in PGC expression were consistently associated with significant differences in metastatic and invasive potential. We functionally confirmed this association in siRNA knockdown experiments of five PGC genes (p53CSV, MAP3K11, MTCH2, CPSF6, and SKIP), which either directly enhanced the invasive capacities or inhibited the proliferation of AGS cancer cells. In primary tumors, similar subtle alterations in PGC expression were also repeatedly associated with clinical outcome in multiple cohorts. Taken collectively, these findings support the existence of a common set of precisely controlled genes in solid tumors. Since inducing small activity changes in these genes may prove sufficient to potently influence various tumor phenotypes such as metastasis, targeting such precisely regulated genes may represent a promising avenue for novel anti-cancer therapies.
authors.affiliation: National Cancer Centre, Singapore, Singapore.
authors.forename: Kun
authors.initials: K
authors.lastname: Yu
authors.forename: Kumaresan
authors.initials: K
authors.lastname: Ganesan
authors.forename: Lay Keng
authors.initials: LK
authors.lastname: Tan
authors.forename: Mirtha
authors.initials: M
authors.lastname: Laban
authors.forename: Jeanie
authors.initials: J
authors.lastname: Wu
authors.forename: Xiao Dong
authors.initials: XD
authors.lastname: Zhao
authors.forename: Hongmin
authors.initials: H
authors.lastname: Li
authors.forename: Carol Ho Wing
authors.initials: CH
authors.lastname: Leung
authors.forename: Yansong
authors.initials: Y
authors.lastname: Zhu
authors.forename: Chia Lin
authors.initials: CL
authors.lastname: Wei
authors.forename: Shing Chuan
authors.initials: SC
authors.lastname: Hooi
authors.forename: Lance
authors.initials: L
authors.lastname: Miller
authors.forename: Patrick
authors.initials: P
authors.lastname: Tan
mesh_terms: D000818:Animals; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology; D019295:Computational Biology / Q000379:methods; D016208:Databases, Factual; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000503:physiopathology*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D013534:Survival; D014158:Transcription, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D034741:RNA, Small Interfering