Glycosylation of Cancer Stem Cells: Function in Stemness, Tumorigenesis, and Metastasis

Barkeer, Srikanth; Chugh, Seema; Batra, Surinder K.; Ponnusamy, Moorthy P.

doi:10.1016/j.neo.2018.06.001

Cited by 89 publications

(63 citation statements)

References 134 publications

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“…These results confirm that O -GFs GALNT3 and B3GNT3 are involved in the maintenance of stemness in PCSCs by altering the CSC markers. Similar to our observation, numerous studies have shown the significant involvement of GFs in the regulation of stemness of many cancers [ 25 ]. GALNT1 has been reported to regulate stemness in bladder CSCs through activating SHH signaling and inducing gli1 expression [ 55 ].…”

Section: Discussionsupporting

confidence: 92%

“…De-regulated mucin expression (MUC1, MUC4, MUC5AC, MUC16; majorly O -linked glycoprotein) has been implicated in PC development, metastasis, and chemoresistance [ 16 , 20 – 24 ]. However, there are limited studies on the role of glycosylation in stemness of PCSCs [ 25 ]. One study, for example, demonstrated the enrichment of fucosylation in gemcitabine-resistant and CD44 + CD24 + CSC-like populations in PC [ 26 ].…”

Section: Introductionmentioning

confidence: 99%

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Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells

et al. 2018

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BackgroundGlycosylation plays a critical role in the aggressiveness of pancreatic cancer (PC). Emerging evidences indicate significant involvement of cancer stem cells (CSCs) in PC aggressiveness. However, the importance of glycosylation in pancreatic cancer stem cells (PCSCs) is yet to be addressed. Hence, we evaluated the potential role of glycosylation in maintenance of stemness of PCSCs.MethodsEffect of glycosylation specific inhibitors on growth and PCSCs of PC cells was assessed by MTT assay and Side Population (SP) analysis. Isolated PCSCs/SP were characterized using molecular and functional assays. Expression of tumor-associated carbohydrate antigens (TACAs) was analyzed in PCSCs by western blotting. Effect of tunicamycin on PCSCs was analyzed by tumorsphere, clonogenicity, migration assay and immunoblotting for CSCs markers. The differential expression of glycogenes in PCSCs compared to non-CSCs were determined by RT-qPCR, immunoblotting and immunofluorescence. Co-expression of GALNT3 and B3GNT3 with CD44v6 was assessed in progression stages of KrasG12D; Pdx-1-Cre (KC) and KrasG12D; p53R172H; Pdx-1-Cre (KPC) tumors by immunofluorescence. Transient and CRISPR/Cas9 silencing of GALNT3 and B3GNT3 was performed to examine their effect on CSCs maintenance.ResultsInhibition of glycosylation decreased growth and CSCs/SP in PC cells. PCSCs overexpressed CSC markers (CD44v6, ESA, SOX2, SOX9 and ABCG2), exhibited global expressional variation of TACAs and showed higher self-renewal potential. Specifically, N-glycosylation inhibition, significantly decreased tumorsphere formation, migration, and clonogenicity of PCSCs, as well as hypo-glycosylated CD44v6 and ESA. Of note, glycosyltransferases (GFs), GALNT3 and B3GNT3, were significantly overexpressed in PCSCs and co-expressed with CD44v6 at advanced PDAC stages in KC and KPC tumors. Further, GALNT3 and B3GNT3 knockdown led to a decrease in the expression of cell surface markers (CD44v6 and ESA) and self-renewal markers (SOX2 and OCT3/4) in PCSCs. Interestingly, CD44v6 was modified with sialyl Lewis a in PCSCs. Finally, CRISPR/Cas9-mediated GALNT3 KO significantly decreased self-renewal, clonogenicity, and migratory capacity in PCSCs.ConclusionsTaken together, for the first time, our study showed the importance of glycosylation in mediating growth, stemness, and maintenance of PCSCs. These results indicate that elevated GALNT3 and B3GNT3 expression in PCSCs regulate stemness through modulating CSC markers.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5074-2) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells

et al. 2018

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“…[ 22 ] Besides, in EMT process, cancer stem cell features were acquired in cancer cells, resulting in drug resistance and anti-cancer therapies. [ 23 ] In presented study, we found that cetuximab inhibition the expression of E-cadherin and MMPs, further inhibit the degradation of ECM and EMT, resulting in inhibition of cellular invasion ability. And inhibition of ITGB1 enhance the anti-tumor effect of cetuximab, decreased the expression of MMPs and E-cadherin.…”

Section: Discussionmentioning

confidence: 83%

Inhibition of ITGB1 enhance the anti-tumor effect of cetuximab in colorectal cancer cell

Yang

Wang

et al. 2020

Medicine

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“…Thus, given the diversity of molecules found in it, ascites is a stimulus that could alter various biological processes, among which, fucosylation may be included. Typically, fucosylation and sialylation are terminal carbohydrate chain-modifications of glycoproteins (which means that fucose and sialyl are frequently located at the end of the carbohydrate chain) [9,10]. Fucosylation and sialylation mediate biological functions and have also been implicated in cancer [9,11,12].…”

Section: Introductionmentioning

confidence: 99%

Ascites from Ovarian Cancer Induces Novel Fucosylated Proteins

Alberto-Aguilar

Hernández‐Ramírez

Osorio-Trujillo

et al. 2019

Cancer Microenvironment

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Ovarian cancer is considered to be the most lethal type of gynecological cancer. During the advanced stages of ovarian cancer, an accumulation of ascites is observed. Fucosylation has been classified as an abnormal post-translational modification that is present in many diseases, including ovarian cancer. Ovarian cancer cells that are cultured with ascites stimulation change their morphology; concomitantly, the fucosylation process is altered. However, it is not known which fucosylated proteins are modified. The goal of this work was to identify the differentially fucosylated proteins that are expressed by ovarian cancer cell lines that are cultured with ovarian cancer patients' ascites. Aleuria aurantia lectin was used to detect fucosylation, and some changes were observed, especially in the cell membrane. Affinity chromatography and mass spectrometry (MALDI-TOF) were used to identify 6 fucosylated proteins. Four proteins (Intermediate filament family orphan 1 [IFFO1], PHD finger protein 20-like protein 1 [PHF20L1], immunoglobulin gamma 1 heavy chain variable region partial [IGHV1-2], and Zinc finger protein 224 [ZNF224]) were obtained from cell cultures stimulated with ascites, and the other two proteins (Peregrin [BRPF1] and Dystrobrevin alpha [DTNA]) were obtained under normal culture conditions. The fucosylated state of some of these proteins was further analyzed. The experimental results show that the ascites of ovarian cancer patients modulated the fucosylation process. The PHD finger protein 20-like protein 1, Zinc finger protein 224 and Peregrin proteins colocalize with fucosylation at different levels.

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Glycosylation of Cancer Stem Cells: Function in Stemness, Tumorigenesis, and Metastasis

Cited by 89 publications

References 134 publications

Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells

Novel role of O-glycosyltransferases GALNT3 and B3GNT3 in the self-renewal of pancreatic cancer stem cells

Inhibition of ITGB1 enhance the anti-tumor effect of cetuximab in colorectal cancer cell

Ascites from Ovarian Cancer Induces Novel Fucosylated Proteins

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