TPX2andAURKApromote 20q amplicon-driven colorectal adenoma to carcinoma progression

Abstract

Background and objective Progression of a colorectal adenoma to invasive cancer occurs in a minority of adenomas and is the most crucial step in colorectal cancer pathogenesis. In the majority of cases, this is associated with gain of a substantial part of chromosome 20q, indicating that multiple genes on the 20q amplicon may drive carcinogenesis. The aim of this study was to identify genes located on the 20q amplicon that promote progression of colorectal adenoma to carcinoma. Design Functional assays were performed for 32 candidate driver genes for which a positive correlation between 20q DNA copy number and mRNA expression had been demonstrated. Effects of gene knockdown on cell viability, anchorage-independent growth, and invasion were analysed in colorectal cancer cell lines with 20q gain. Colorectal tumour protein expression was examined by immunohistochemical staining of tissue microarrays. Results TPX2, AURKA, CSE1L, DIDO1, HM13, TCFL5, SLC17A9, RBM39 and PRPF6 affected cell viability and/or anchorage-independent growth. Chromosome 20q DNA copy number status correlated significantly with TPX2 and AURKA protein levels in a series of colorectal adenomas and carcinomas. Moreover, downmodulation of TPX2 and AURKA was shown to inhibit invasion. Conclusion These data identify TPX2 (20q11) and AURKA (20q13.2) as two genes located on distinct regions of chromosome 20q that promote 20q amplicon-driven progression of colorectal adenoma to carcinoma. Therefore the selection advantage imposed by 20q gain in tumour progression is achieved by gain-of-function of multiple cancer-related genes—knowledge that can be translated into novel tests for early diagnosis of progressive adenomas.

CSE1L, DIDO1 and RBM39 in colorectal adenoma to carcinoma progression

“…Usually, large fragments of the 20q arm are amplified as a whole, suggesting a role of multiple 20q genes on CRC progression. Recently, we confirmed by functional analyses that multiple genes on chromosome 20q contribute to cancer processes [9]. AURKA and TPX2 were identified as genes that promote 20q gain-driven colorectal adenoma-to-carcinoma progression.…”

“…The 20q amplicon harbors multiple genes that contribute to CRC carcinogenesis as indicated by the large part of the chromosome arm that is generally amplified in CRC. We recently identified AURKA and TPX2 as major contributors to 20q gain associated CRC progession [9]. In the same study CSE1L, DI-DO1 and RBM39 were also found to contribute to several cancer-related biological processes such as cell viability and anchorage-independent growth.…”

“…Disruption of DIDO1 has been reported to result in chromosomal instability by a defective mitotic checkpoint [41], while overexpression of DIDO1 also induces chromosomal instability as observed by asymmetric divisions leading to the occurrence of lagging chromosomes [42]. Like DIDO1, inhibition of the expression of other genes with a role in chromosomal instability, such as AURKA and TPX2, also reduced anchorage-independent growth [9].…”

“…Other genes that contribute to chromosomal instability (e.g. AURKA and TPX2) have been described as playing a major role in colorectal adenomato-carcinoma progression [9,39].…”

Mining, Validation, and Clinical Significance of Colorectal Cancer (CRC)-Associated lncRNAs

“…Five microarrays were selected, which included CRC cases, colorectal adenoma cases, and normal tissues. CRC commonly arises from normal colorectal tissue that develops into adenomas [28]. Of 142 differentially expressed lncRNAs, 15 candidates were selected.…”