Musashi2 contributes to the maintenance of CD44v6+ liver cancer stem cells via notch1 signaling pathway

Abstract

BackgroundLiver cancer stem cells (LCSCs) contribute to hepatocellular carcinoma (HCC) development, metastasis, and drug resistance. MSI2 and Notch1 signaling are involved in the maintenance of CSCs. However, it is unknown whether MSI2 and Notch1 are involved in the maintenance of CD44v6+ LCSCs. Therefore, we investigated the clinical significance and function of MSI2 and its relationship with Notch1 signaling in the maintenance of stemness properties in CD44v6+ LCSCs.MethodsThe expression of MSI2 and CD44v6 were detected by fresh specimens and a HCC tissue microarray. The tissue microarray containing 82 HCC samples was used to analyze the correlation between CD44v6 and MSI2. CD44v6+/− cells were isolated using microbeads sorting. We explored the roles of MSI2 and Notch1 signaling in CD44v6+ LCSCs by sphere formation assay, transwell assay, clone formation assay in vitro, and xenograft tumor models in vivo. A Notch RT2 PCR Array, Co-immunoprecipitation, and RNA-immunoprecipitation were used to further investigate the molecular mechanism of MSI2 in activating Notch1 signaling.ResultsHere, we found MSI2 expression was positively correlated with high CD44v6 expression in HCC tissues, and further correlated with tumor differentiation. CD44v6+ cells isolated from HCC cell lines exhibited increased self-renewal, proliferation, migration and invasion, resistance to Sorafenib and tumorigenic capacity. Both MSI2 and Notch1 signaling were elevated in sorted CD44v6+ cells than CD44v6- cells and played essential roles in the maintenance of stemness of CD44v6+ LCSCs. Mechanically, MSI2 directly bound to Lunatic fringe (LFNG) mRNA and protein, resulting in Notch1 activation.ConclusionsOur results demonstrated that MSI2 maintained the stemness of CD44v6+ LCSCs by activating Notch1 signaling through the interaction with LFNG, which could be a potential molecular target for stem cell-targeted therapy for liver cancer.

Downregulation of SOX2-OT Prevents Hepatocellular Carcinoma Progression Through miR-143-3p/MSI2

“…Starbase and Targetscan databases predicted that there were binding sites between SOX2-OT and miR-143-3p, and between miR-143-3p and MSI2 ( Figure 3F ). MSI2 may be a potential molecular target for the treatment of HCC ( 29 ). Therefore, we speculated that miR-143-3p/MSI2 might regulate the behavior alternation of HCC cells.…”

“…Overexpression of MSI2 reversed the changes of cell malignant behaviors mediated by si-SOX2-OT#2. A study shows that MSI2 is positively correlated with high CD44v6 expression, which can promote the malignant behaviors of HCC cells ( 29 ). Collectively, our results confirmed that SOX2-OT could promote MSI2 by binding to miR-143-3p competitively, and finally promote the malignant behaviors of HCC cells.…”

Chemokine CCL20 promotes the paclitaxel resistance of CD44+CD117+ cells via the Notch1 signaling pathway in ovarian cancer

“…A common dysregulated pathway in the development of cancer is the Notch1 signaling pathway, which has been shown to play a critical role in regulating stemness, proliferation, metastasis and drug resistance of cancer ( 36 – 38 ). As shown in a previous study, the hypoxia-induced Notch/SOX2 axis was crucial for maintaining cancer stem-like cells in ovarian cancer ( 39 ).…”

RNA-sequencing reveals the expression profiles of tsRNAs and their potential carcinogenic role in cholangiocarcinoma

“…The Hippo signaling pathway are relevant to the procession of hepatocellular carcinoma(30), breast carcinoma (31), and gastric carcinoma (32), in uencing the proliferation, differentiation, and migration of tumor cells. The Notch signaling pathway is signi cant to the development of diversi ed cancers and can regulate the growth, survival, apoptosis, invasion and migration of all kinds of tumor cells, such as pancreatic carcinoma and liver cancer cells (33)(34)(35)(36). In addition, research has identi ed the relationship between tRFs and the Notch signaling pathway and shown that tRF/miR-1280 can bind with the 3'-UTR of JAG2 mRNA to decrease the synthesis of JAG2 (a ligand of Notch signaling pathway), thereby inactivating the Notch signaling pathway and reducing the proliferation and metastasis of CRC (37).…”