The Msi Family of RNA-Binding Proteins Function Redundantly as Intestinal Oncoproteins

Abstract

Members of Msi family of RNA binding proteins have recently emerged as potent oncoproteins in a range of malignancies. MSI2 is highly expressed in hematopoietic cancers where it is required for disease maintenance. In contrast to the hematopoietic system, colorectal cancers can express both Msi family members, MSI1 and MSI2. Here we demonstrate that in the intestinal epithelium, Msi1 and Msi2 have analogous oncogenic effects. Further, comparison of Msi1/2-induced gene expression programs and transcriptome-wide analyses of Msi1/2-RNA binding targets reveal significant functional overlap, including induction of the PDK-Akt-mTORC1 axis. Ultimately, we demonstrate that concomitant loss of function of both MSI family members is sufficient to abrogate the growth of human colorectal cancer cells, and Msi gene deletion inhibits tumorigenesis in several mouse models of intestinal cancer. Our findings demonstrate that MSI1 and MSI2 act as functionally redundant oncoproteins required for the ontogeny of intestinal cancers.

Suppression of intestinal tumorigenesis in Apc mutant mice upon Musashi-1 deletion

“…Our result that Msi-1 elimination leads to a reduction in polyp number in two different Apc mutant mouse lines contrasts with those from a study published during the preparation of this manuscript that showed that elimination of Msi-1 in Apc Min mice does not result in decreased polyp formation (Li et al, 2015). Rather, a ∼50% reduction in polyp number was observed only when both Msi-1 and Msi-2 were eliminated (Li et al, 2015).…”

“…4). This result is consistent with the increase in mRNA for the CBC marker Lgr5 and increased number of Lgr5-positive cells reported in mice that overexpress Msi-1 (Cambuli et al, 2015;Li et al, 2015). Taken together, these data indicate a role for Msi-1 in stem cell regulation.…”

“…These changes in proliferation and stem cell number are consistent with the opposite phenotype reported for Msi-1 overexpressing mice (Cambuli et al, 2015;Li et al, 2015). Although the Msi-1 overexpressing mice did not display changes in Wnt target gene RNA levels, Apc mRNA co-purified with Msi-1 isolated from these mice (Li et al, 2015). The expected consequence of elevated Apc and reduced β-catenin levels, reduced Wnt target gene expression and proliferation, in mice lacking Msi-1 is a reduction in the opportunity for loss of heterozygosity at the Apc locus, which is typically required for tumor initiation.…”

“…Small intestines from mice lacking Msi-1 also exhibited diminished cell proliferation, a reduced number of Lgr5-positive cells and fewer active stem cells when grown as organoids in 3D culture (Figs 1C and 4C,G,respectively). These changes in proliferation and stem cell number are consistent with the opposite phenotype reported for Msi-1 overexpressing mice (Cambuli et al, 2015;Li et al, 2015). Although the Msi-1 overexpressing mice did not display changes in Wnt target gene RNA levels, Apc mRNA co-purified with Msi-1 isolated from these mice (Li et al, 2015).…”

“…One study identified 64 Msi-1-bound mRNAs, many of which are associated with cell proliferation, differentiation, cell cycle and apoptosis (de Sousa Abreu et al, 2009). Cross-linking immunoprecipitation followed by highthroughput sequencing (CLIP-Seq) analysis of mouse intestinal epithelial cells revealed over 2200 potential Msi-1 targets (Li et al, 2015). Many human colorectal tumors display a significant increase in Msi-1 mRNA and protein compared to adjacent normal tissue Smith et al, 2015).…”