Nucleophosmin 1, upregulated in adenomas and cancers of the colon, inhibits p53-mediated cellular senescence

Abstract

Dysregulation of nucleophosmin 1 (NPM1) has been found in numerous solid and hematological malignancies. Our previous meta-analysis of colorectal cancer (CRC) high throughput gene expression profiling studies identified it as a consistently reported up-regulated gene in the malignant state. Our aims were to compare NPM1 expression in normal colon, adenoma and CRC, to correlate their expressions with clinico-pathological parameters, and to assess the biological role of aberrant NPM1 expression in CRC cells. NPM1 transcript levels were studied in human CRC cell lines, whereas a tissue microarray of 57 normal human colon, 40 adenoma and 185 CRC samples were used to analyze NPM1 protein expression by immunohistochemistry. CRC cell lines were subjected to transient siRNA-mediated knockdown to study NPM1's roles on cell viability and senescence. NPM1 transcript levels were 7-11-folds higher in three different human CRC cell lines compared to normal colon cells. NPM1 protein expression was found to be progressively and significantly upregulated in CRC compared to adenomas and in adenomas compared to normal mucosa. Reducing NPM1 expression by siRNA had caused a significant decrease in cell viability, a concomitant increase in cellular senescence and cell cycle arrest. Cellular senescence induced under conditions of forced NPM1 suppression could be prevented by knocking down p53. The differential expression of NPM1 along the normal colon-adenoma-carcinoma progression and its involvement in resisting p53 related senescent growth arrest in CRC cell lines implicate its role in supporting CRC tumorigenesis. What's new? Previous studies have found consistent overexpression of the multifunctional protein nucleophosmin 1 (NPM1) in various malignancies, though its status and role in colorectal cancer (CRC) have remained unclear. This report describes upregulation of NPM1 transcripts in CRC cell lines and increasing NPM1 protein expression with progression from normal colon to adenoma to CRC in a tissue microarray. Modulation of NPM1 expression in CRC cells affected cellular viability, p53-dependent senescence, and cell-cycle progression. The results suggest that NPM1 may play a fundamental role in colorectal carcinogenesis. © 2013 UICC.