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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.

SUBMITTER: Yu K

PROVIDER: S-EPMC2444049 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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A precisely regulated gene expression cassette potently modulates metastasis and survival in multiple solid cancers.

Yu Kun K Ganesan Kumaresan K Tan Lay Keng LK Laban Mirtha M Wu Jeanie J Zhao Xiao Dong XD Li Hongmin H Leung Carol Ho Wing CH Zhu Yansong Y Wei Chia Lin CL Hooi Shing Chuan SC Miller Lance L Tan Patrick P

PLoS genetics 20080718 7

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 ...[more]

PMID: 18636107

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Project description:Successful carcinogenesis involves the integration of both pro- and anti-oncogenic pathways. We postulated that genes critical for balancing these opposing pathways are likely to be precisely controlled in tumors, since even subtle alterations in their activity might cause substantial alterations in tumor growth and survival. Using a novel genomic approach, we identified a 48-gene âPoised Gene Cassetteâ (PGC) showing tight regulation specifically in human cancers but not in corresponding nonmalignant tissues. We show, using a wide variety of in vitro and in vivo approaches, that small alterations in PGC expression are consistently associated with significant differences in experimental metastasis and patient survival, and we demonstrate a direct functional role for five PGC genes (p53CSV, MAP3K11, MTCH2, CPSF6 and SKIP) in cancer invasion. Our findings support the existence of a novel class of ultrasensitive genes that may regulate various cancer-associated phenotypes such as metastasis. Such precisely controlled genes could represent appealing drug targets, since even partial alterations in their activity should prove sufficient to induce potent effects on tumors. Besides cancer, our analytical approach is quite generalizable and likely to be applicable to other disease conditions. Experiment Overall Design: Primary human tumor and adjacent normal tissues were obtained from the Tissue Repository of the National Cancer Centre of Singapore (NCCS). Appropriate institutional approvals were obtained from the NCCS Tissue Repository and Ethics Committees. In the operating theater, morphologically visible tumor and adjacent matched normal tissues were removed by surgery and examined by a surgical pathologist to confirm the presence of cancer cells by cryosections. The tissue samples were divided into discrete aliquots, flash frozen and subsequently stored in liquid nitrogen. The detailed information regarding samples is available in Supplementary Information S1. The training set used in this study comprises 341 samples (270 tumors and 71 matched normals) from patients with breast, colon, liver, lung, oesophagal and thyroid cancer (Tissue Type/Tumor/Normal : Lung/18/12, Thyroid/35/16, Liver/9/8, Oesophagus/16/13, Colon/9/9, Breast/183/13.)

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A precisely regulated gene expression cassette potently modulates metastasis and survival in multiple solid cancers.

Publications

A precisely regulated gene expression cassette potently modulates metastasis and survival in multiple solid cancers.

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