Cell cycle gene expression networks discovered using systems biology: Significance in carcinogenesis

Abstract

The early stages of carcinogenesis are linked to defects in the cell cycle. A series of cell cycle checkpoints are involved in this process. The G1/S checkpoint that serves to integrate the control of cell proliferation and differentiation is linked to carcinogenesis and the mitotic spindle checkpoint with the development of chromosomal instability. This paper presents the outcome of systems biology studies designed to evaluate if networks of covariate cell cycle gene transcripts exist in proliferative mammalian tissues including mice, rats and humans. The GeneNetwork website that contains numerous gene expression datasets from different species, sexes and tissues represents the foundational resource for these studies (www.genenetwork.org). In addition, WebGestalt, a gene ontology tool, facilitated the identification of expression networks of genes that co-vary with key cell cycle targets, especially Cdc20 and Plk1 (www.bioinfo.vanderbilt.edu/webgestalt). Cell cycle expression networks of such covariate mRNAs exist in multiple proliferative tissues including liver, lung, pituitary, adipose and lymphoid tissues among others but not in brain or retina that have low proliferative potential. Sixty-three covariate cell cycle gene transcripts (mRNAs) compose the average cell cycle network with p = e−13 to e−36. Cell cycle expression networks show species, sex and tissue variability and they are enriched in mRNA transcripts associated with mitosis many of which are associated with chromosomal instability.

Role of COL6A3 in colorectal cancer

“…For example, in the cell cycle module, the roles of Opa interacting protein 5, protein regulator of cytokinesis 1 and BUB1 mitotic checkpoint serine/threonine kinase B in cancer have been previously demonstrated ( 23 ). A number of the hub genes have well-known functions in regulating the DNA damage checkpoint, genome stability and cell cycle arrest, including checkpoint kinase 1, cyclin B2, cyclin A2 and nucleolar and spindle-associated protein 1 ( 24 ). In the cell migration/ECM module, there are many collagen encoding genes, including collagen type V α2 chain (COL5A2), collagen type VI α2 chain, COL6A3, TIMP metallopeptidase inhibitor 2 (TIMP2) and collagen type X α1 chain ( Fig.…”

Pin1 inhibition potently suppresses gastric cancer growth and blocks PI3K/AKT and Wnt/β‐catenin oncogenic pathways

“…Cellular proliferation is the result of cell cycle disorder. The cell cycle is regulated by a fine and complex network composed of check point proteins, most of which have been revealed to be Pin1‐binding substrates . For example, Pin1 modulates G1/S progression through regulation of Cyclin D1, RB, p53, p27, and Cyclin E …”

Single-Cell RNA-Seq Reveals Transcriptomic Heterogeneity and Post-Traumatic Osteoarthritis-Associated Early Molecular Changes in Mouse Articular Chondrocytes

“…Analysis of the remaining 2490 cells resulted in 10 cell clusters with distinct gene expression profiles (Figure 1B and S2A). Cell type identities were assigned based on previously published cell-type specific markers [21,[25][26][27][28][29][30][31][32][33] (Figure 1B). Cells in clusters 0, 1, 3, and 4 expressed high levels of chondrocyte markers Sox9, Col2a1, and Acan [25] and were labeled 'chondrocytes' (Figure 1C,D).…”