Downregulation of Msi1 suppresses the growth of human colon cancer by targeting p21cip1

Abstract

Abstract. Musashi1 (Msi1), a member of the RNA-binding protein (RBP) family, is highly expressed in neural progenitor or stem cells for the maintenance of stemness as well as in various cancers. Emerging studies have demonstrated that it regulates cell processes by translational activation or suppresses specifically bound mRNA. In the present study, we initially reported remarkably increased expression of Msi1 in colon cancer tissues compared with adjacent nontumor tissues. Knockdown of Msi1 significantly suppressed the proliferation, colony formation, tumorsphere formation and the progression of implanted colon cancers, and induced cell cycle attest at G 0 /G 1 phase, along with the upregulated expression of p21 cip1 . Reporter assays using a chimeric mRNA that combined luciferase and the 3'-UTR of p21 cip1 revealed that Msi1 decreased the reporter activity through the specific motif. Thus, the current results suggested that downregulation of Msi1 could inhibit the growth of colon cancers and Msi1 may be a promising therapeutic target molecule for human colon cancers.

Increased Musashi-2 and Decreased NUMB Protein Levels Observed in Human Colorectal Cancer are reverted to Normal Levels by ATRA-Induced Cell Differentiation

“…Our results have relevance to the role of MSI-2 in human colon tumorigenesis because several studies have previously investigated MSI-1 and reported that MSI-1 is expressed in low levels in normal colonic tissue and high levels in CRCs [ 18 , 19 ]. While less is known about MSI-2, a study by Wang, et al reported that MSI-2 is overexpressed in human CRCs.…”

Structural Insight into the Recognition of r(UAG) by Musashi-1 RBD2, and Construction of a Model of Musashi-1 RBD1-2 Bound to the Minimum Target RNA

“…We also found that the amino acid residues that are involved in RNA-binding are conserved in Msi1 and its paralog, Msi2. Elevated expression of Msi1 and Msi2 has been identified in a large variety of tumors arising in the bladder, brain, breast, colon, lung, ovary, pancreas, and others [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Additionally, increased expression of Msi1 and Msi2 has been found in leukemias such as acute myelogenous leukemia and acute lymphoblastic leukemia [ 13 , 14 , 15 , 16 , 17 ].…”

“…Additionally, increased expression of Msi1 and Msi2 has been found in leukemias such as acute myelogenous leukemia and acute lymphoblastic leukemia [ 13 , 14 , 15 , 16 , 17 ]. Msi1 and Msi2 are shown to be associated with tumor initiation, progression, and drug resistance [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 25 , 26 , 36 , 37 , 38 , 39 ]. Importantly, downregulation of Msi1 and Msi2 proteins in tumors results in reduction of their tumorigenic growth [ 40 , 41 , 42 ].…”

“…Msi1 was found previously to play a key role in stem cell self-renewal through the down-regulation of numb mRNA, which encodes an inhibitor of Notch signaling, Numb; the reduction of Numb triggers an increase in Notch signaling [ 4 ]. Recently, Msi1 and Msi2 were found to be overexpressed in tumors of various organs and in leukemias [ 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 ]. Elucidation of the molecular mechanism by which Msi1 and Msi2 regulate the translation of targets is thereby important to understand how Msi1 and Msi2 are associated with tumorigenesis, and moreover, to understand how to therapeutically target Msi1 and Msi2.…”

DBC2/RhoBTB2 functions as a tumor suppressor protein via Musashi-2 ubiquitination in breast cancer

“…Although previous studies have demonstrated that MSI2 knockdown enhances p21 protein and mRNA levels, the MSI2-mediated downregulation of p21 protein levels is not entirely mediated by decreased mRNA stability. 32, 47, 48 A previous study reported that cell cycle arrest and apoptosis are induced in MSI2 knockdown cells. 39 Consistent with these findings, apoptosis was inhibited in MSI2-knockdown cells and DBC2-overexpressing cells.…”