This article is the original of the Translational Medicine Network, **Please indicate the source
Author: Jerry
Reading guide:CD133 is widely used as a marker for isolating tumor-initiating cells in a variety of tumors. However, the relationship between CD133N-glycosylation and stem cell properties is unclear.
Recently, a research team from Fudan University published a study titled "Loss of -1,2-mannosidase man1c1 promotes tumorigenesis of intrahepatic cholangiocarcinoma through enhancing CD133-fip200 interaction" in the journal Cell Reports**, In this study, the researchers found that the level of 1,2-mannosylated CD133 in intrahepatic cholangiocarcinoma (ICCA) tissue correlated with the level of the stemness gene. 1,2-Mannose-modified CD133+ cells have the characteristics of tumor-initiating cells. CD133 1,2-mannosylated is a functional marker of ICCA-initiating cells.
Background:
Tumor-initiating cells (TICS) are closely related to tumor initiation, metastasis, and metastasis. As a result, TICS is considered to be the most promising tumor target. To date, the identification of TICSs has been primarily based on surface markings. CD133 is a pentatransmembrane glycoprotein that has been widely used as a marker for the isolation of TICS, including liver cancer, glioma, and colon cancer. CD133 is expressed in both stem cells and differentiated cells. Accumulating evidence suggests that the surface N-glycan structure of CD133 is associated with stem cell properties. During the differentiation of cancer stem cells, the N-glycan structure on the surface of CD133 changes. Hypoxia enhances glycosylation of CD133 in glioma stem cells. In addition, altering the glycosylation of CD133 can affect its stability or function. The N-glycosylation complex promotes CD133 secretion by enhancing the interaction of CD133 with TSG101. Hypoxia-induced glycosyltransferase 8 domain 1 (GLT8D1) promotes glioma stem cell maintenance by inhibiting CD133 degradation. However, the relationship between the N-glycan structure of CD133 and stem cell properties is unclear.
Intrahepatic cholangiocarcinoma (ICCA) is the second most common type of liver cancer. The 5-year survival rate for ICCA is 9%. ICCA remains a tricky disease due to its high rate. ICCA has been associated with overweight, obesity, and chronic liver disease, including cirrhosis and/or viral hepatitis. The molecular mechanisms of ICCA must be explored in order to develop new strategies. Identification of markers in ICCA-initiating cells may contribute to the development of ICCA targeting**. Although CD133 expression is associated with ICCA metastasis and low viability, the role of CD133 in identifying ICCA-initiating cells is unclear.
Research Progress
The researchers evaluated the expression signature of MAN1C1 in ICCA. Immunohistochemical analysis showed that MAN1C1 was expressed in various normal tissues. In the TCGA dataset, the expression of MAN1C1 was significantly reduced in a subset of tumor samples, including cholangiocarcinoma. Low expression of MAN1C1 is associated with poor prognosis in various cancers. Thus, low MAN1C1 expression is associated with cancer progression.
Next, the researchers evaluated whether -1,2-man contributes to the properties of ICCA-initiated cells. Cancer stem cells (CSCs) are mainly found in microenvironments with low glucose or nutrient storage. Ectopically expressing Flag-tagged MAN1C1 significantly reduced spheroid formation in -1,2-MAN+CD133+ cells under low-glucose conditions in passages 1-2. Limiting dilution assays are widely used to determine stem cell frequency.
Through in vitro limiting dilution experiments, the researchers found that MAN1C1 overexpression inhibited stem cell activity in CD133+-1,2-MAN+ cells. Ectopic expression of MAN1C1 inhibits the tumor initiation ability of CD133+-1,2-MAN+ cells and improves the survival rate of tumor mice. In conclusion, inhibition of -1,2-MAN modification by Man1C1 overexpression inhibited the self-renewal and tumorigenesis of ICCA-initiated cells.
Inhibition of -1,2-MAN by overexpression of MAN1C1 inhibits tumorigenesis in ICCA-initiated cells.
FIP200 is required for autophagosome formation in mammalian cells. In the setting of nutrient deprivation or hypoxia, autophagy maintains self-renewal of the TIC. Effect of -1,2-Man on ICCA-initiated autophagy. The conversion of LC3-I to LC3-II is used as an indicator of autophagy activation. Man1C1 overexpression significantly reduces the ratio of LC3-II to LC3-I in CD133+-1,2-MAN+ cells. When autophagy is activated, GFP-linked LC3 (GFP-LC3) is concentrated in the autophagic vacuole to form punctate green fluorescence. Ectopic expression of MAN1C1 reduces the formation of GFP-LC3 dots. Overall, MAN1C1 reduces autophagy in ICCA-initiated cells.
1,2-MAN enhances the self-renewal and tumorigenesis ability of ICCA-initiated cells by upregulating the autophagy gene FIP200.
Next, the researchers evaluated the role of FIP200 in MAN1C1-reduced autophagy. The ectopic expression of FIP200 blocks the negative effect of MAN1C1 on autophagy in CD133+-1,2-MAN+ cells, and the inhibitory effect of MAN1C1 overexpression on CD133+-1,2-MAN+ cell self-renewal is partially rescued by FIP200 overexpression. Overexpression of Fip200 reverses the inhibitory effect of MAN1C1 on CD133+ 1,2-MAN+ cells. In summary, 1,2-MAN enhances the self-renewal and tumorigenesis ability of intrahepatic cholangiocarcinoma initiating cells by upregulating the expression of FIP200.
Conclusions of the study
In summary, CD133-1,2-glycosylation is a functional marker for ICCA-initiated cells, providing a more specific marker for TIC. This discovery provides a relationship between the N-glycan structure of CD133 and stem cell properties and provides a novel strategy to eliminate ICCA-initiated cells.
References: Note: This article aims to introduce the progress of medical research and cannot be used as a reference for ** scheme. If you need health guidance, please go to a regular hospital.
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