We showed that Msi proteins can translationally repress in the basal state suggests that Notch pathway activity is high in and required for the entry into the mesenchymal state, consistent with previous studies (Zavadil et al

We showed that Msi proteins can translationally repress in the basal state suggests that Notch pathway activity is high in and required for the entry into the mesenchymal state, consistent with previous studies (Zavadil et al., 2004; Dickson et al., 2007). compartments but are mostly absent from differentiated tissues. is a marker of neural stem cells (NSCs) (Sakakibara et al., 1996) and is also expressed in stem cells in the gut (Kayahara et al., 2003) and epithelial cells in the mammary gland (Colitti and Farinacci, 2009), Tuberculosis inhibitor 1 while is expressed in hematopoietic stem cells (HSCs) (Kharas et al., 2010). This expression pattern led to the proposal that Msi proteins generally mark the epithelial stem cell state across distinct tissues (Okano et al., 2005), with HSCs being an exception. is not expressed in the normal adult brain outside a minority of adult NSCs but is induced in glioblastoma (Muto et Tuberculosis inhibitor 1 al., 2012). Msi proteins affect cell proliferation in several cancer types. In glioma and medulloblastoma cell lines, knockdown of reduced the colony-forming capacity of these cells and reduced their tumorigenic growth in a xenograft assay in mice (Muto et al., 2012). Msi expression correlates with HER2 expression in breast cancer cell lines, and knockdown of Msi proteins resulted in decreased proliferation (Wang et al., 2010). These observations, together with the cell-type specific expression of Msi proteins in normal development, suggested that Msi proteins might function as regulators of cell state, with potential relevance to cancer. Msi proteins have been proposed to act as translational repressors of mRNAsand sometimes as activators (MacNicol et al., 2011)when bound to mRNA 3 UTRs, and were speculated to affect pre-mRNA processing in (Nakamura et al., 1994; Okano et al., 2002). However, no conclusive genome-wide evidence for either role has been reported for the mammalian Msi family. Here, we aimed to investigate the roles of these proteins in human cancers and to gain a better understanding of their genome-wide effects on the transcriptome using mouse models. Results Msi genes are frequently overexpressed in multiple human cancers To obtain a broad view of the role Msis might play in human cancer, we surveyed the expression and mutation profiles of Msi genes in primary tumors Tuberculosis inhibitor 1 using genomic and RNA sequencing (RNA-Seq) data from The Cancer Genome Atlas (TCGA) (Cancer Genome Atlas Network., 2012). To determine whether Msi genes are generally upregulated in human cancers, we analyzed RNA-Seq data from five cancer types for which matched tumor-control pairs were available. In these matched designs, a pair of RNA samples was obtained in parallel from a single patient’s tumor and healthy tissue-matched biopsy, thus minimizing the contribution of individual genetic variation to expression differences. We observed that was upregulated in at least 50% of breast and prostate tumors (Figure 1A, top). Overall, or were significantly upregulated in matched tumor-control pairs for 3 of the 5 cancer types, compared to control pairs. Kidney tumors showed the opposite expression pattern, with and downregulated in a majority of tumors and rarely upregulated, and in thyroid cancer neither nor showed a strong bias towards up- or down-regulation (Figure 1A, top). In breast tumors, a bimodal distribution of expression was observed, with a roughly even Mouse monoclonal to FAK split between up- and down-regulation of Tuberculosis inhibitor 1 upregulation might be specific to a subtype of breast tumors. The bimodality of expression was not seen when comparing control pairs, so Tuberculosis inhibitor 1 is not explained by general variability in levels (Figure 1A, bottom, solid vs dotted lines). Open in a separate window Figure 1. Msi genes are frequently overexpressed in breast, lung, and prostate cancer but downregulated in kidney cancer.(A) Top: percentage of.