Serglycin activates pro-tumorigenic signaling and controls glioblastoma cell stemness, differentiation and invasive potential
© 2020 The Authors..
Despite the functional role of serglycin as an intracellular proteoglycan, a variety of malignant cells depends on its expression and constitutive secretion to advance their aggressive behavior. Serglycin arose to be a biomarker for glioblastoma, which is the deadliest and most treatment-resistant form of brain tumor, but its role in this disease is not fully elucidated. In our study we suppressed the endogenous levels of serglycin in LN-18 glioblastoma cells to decipher its involvement in their malignant phenotype. Serglycin suppressed LN-18 (LN-18shSRGN) glioblastoma cells underwent astrocytic differentiation characterized by induced expression of GFAP, SPARCL-1 and SNAIL, with simultaneous loss of their stemness capacity. In particular, LN-18shSRGN cells presented decreased expression of glioma stem cell-related genes and ALDH1 activity, accompanied by reduced colony formation ability. Moreover, the suppression of serglycin in LN-18shSRGN cells retarded the proliferative and migratory rate, the invasive potential in vitro and the tumor burden in vivo. The lack of serglycin in LN-18shSRGN cells was followed by G2 arrest, with subsequent reduction of the expression of cell-cycle regulators. LN-18shSRGN cells also exhibited impaired expression and activity of proteolytic enzymes such as MMPs, TIMPs and uPA, both in vitro and in vivo. Moreover, suppression of serglycin in LN-18shSRGN cells eliminated the activation of pro-tumorigenic signal transduction. Of note, LN-18shSRGN cells displayed lower expression and secretion levels of IL-6, IL-8 and CXCR-2. Concomitant, serglycin suppressed LN-18shSRGN cells demonstrated repressed phosphorylation of ERK1/2, p38, SRC and STAT-3, which together with PI3K/AKT and IL-8/CXCR-2 signaling control LN-18 glioblastoma cell aggressiveness. Collectively, the absence of serglycin favors an astrocytic fate switch and a less aggressive phenotype, characterized by loss of pluripotency, block of the cell cycle, reduced ability for ECM proteolysis and pro-tumorigenic signaling attenuation.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2020 |
|---|---|
| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:6-7 |
|---|---|
| Enthalten in: |
Matrix biology plus - 6-7(2020) vom: 02. Mai, Seite 100033 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Manou, Dimitra [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Revised 30.03.2024 published: Electronic-eCollection Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.1016/j.mbplus.2020.100033 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM32103662X |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM32103662X | ||
| 003 | DE-627 | ||
| 005 | 20240331000012.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2020 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.mbplus.2020.100033 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1357.xml |
| 035 | |a (DE-627)NLM32103662X | ||
| 035 | |a (NLM)33543029 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Manou, Dimitra |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Serglycin activates pro-tumorigenic signaling and controls glioblastoma cell stemness, differentiation and invasive potential |
| 264 | 1 | |c 2020 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 30.03.2024 | ||
| 500 | |a published: Electronic-eCollection | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2020 The Authors. | ||
| 520 | |a Despite the functional role of serglycin as an intracellular proteoglycan, a variety of malignant cells depends on its expression and constitutive secretion to advance their aggressive behavior. Serglycin arose to be a biomarker for glioblastoma, which is the deadliest and most treatment-resistant form of brain tumor, but its role in this disease is not fully elucidated. In our study we suppressed the endogenous levels of serglycin in LN-18 glioblastoma cells to decipher its involvement in their malignant phenotype. Serglycin suppressed LN-18 (LN-18shSRGN) glioblastoma cells underwent astrocytic differentiation characterized by induced expression of GFAP, SPARCL-1 and SNAIL, with simultaneous loss of their stemness capacity. In particular, LN-18shSRGN cells presented decreased expression of glioma stem cell-related genes and ALDH1 activity, accompanied by reduced colony formation ability. Moreover, the suppression of serglycin in LN-18shSRGN cells retarded the proliferative and migratory rate, the invasive potential in vitro and the tumor burden in vivo. The lack of serglycin in LN-18shSRGN cells was followed by G2 arrest, with subsequent reduction of the expression of cell-cycle regulators. LN-18shSRGN cells also exhibited impaired expression and activity of proteolytic enzymes such as MMPs, TIMPs and uPA, both in vitro and in vivo. Moreover, suppression of serglycin in LN-18shSRGN cells eliminated the activation of pro-tumorigenic signal transduction. Of note, LN-18shSRGN cells displayed lower expression and secretion levels of IL-6, IL-8 and CXCR-2. Concomitant, serglycin suppressed LN-18shSRGN cells demonstrated repressed phosphorylation of ERK1/2, p38, SRC and STAT-3, which together with PI3K/AKT and IL-8/CXCR-2 signaling control LN-18 glioblastoma cell aggressiveness. Collectively, the absence of serglycin favors an astrocytic fate switch and a less aggressive phenotype, characterized by loss of pluripotency, block of the cell cycle, reduced ability for ECM proteolysis and pro-tumorigenic signaling attenuation | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ALDH1, aldehyde dehydrogenase 1 | |
| 650 | 4 | |a Astrocytic differentiation | |
| 650 | 4 | |a CXCR, C-X-C chemokine receptor | |
| 650 | 4 | |a ECM, extracellular matrix | |
| 650 | 4 | |a EMT, epithelial to mesenchymal transition | |
| 650 | 4 | |a ERK, extracellular-signal-regulated kinase | |
| 650 | 4 | |a GFAP, glial fibrillary acid protein | |
| 650 | 4 | |a Glioblastoma | |
| 650 | 4 | |a IL, interleukin | |
| 650 | 4 | |a Interleukins | |
| 650 | 4 | |a MAPK, mitogen-activated protein kinase | |
| 650 | 4 | |a MMPs, metalloproteinases | |
| 650 | 4 | |a PGs, proteoglycans | |
| 650 | 4 | |a PI3K, phosphoinositide 3-kinase | |
| 650 | 4 | |a Proteoglycans | |
| 650 | 4 | |a Proteolytic enzymes | |
| 650 | 4 | |a SRGN, serglycin | |
| 650 | 4 | |a STAT-3, signal transducer and activator of transcription 3 | |
| 650 | 4 | |a Serglycin | |
| 650 | 4 | |a Signaling | |
| 650 | 4 | |a Stemness | |
| 650 | 4 | |a TIMPs, tissue inhibitors of metalloproteinases | |
| 650 | 4 | |a uPA, urokinase plasminogen activator | |
| 700 | 1 | |a Bouris, Panagiotis |e verfasserin |4 aut | |
| 700 | 1 | |a Kletsas, Dimitris |e verfasserin |4 aut | |
| 700 | 1 | |a Götte, Martin |e verfasserin |4 aut | |
| 700 | 1 | |a Greve, Burkhard |e verfasserin |4 aut | |
| 700 | 1 | |a Moustakas, Aristidis |e verfasserin |4 aut | |
| 700 | 1 | |a Karamanos, Nikos K |e verfasserin |4 aut | |
| 700 | 1 | |a Theocharis, Achilleas D |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Matrix biology plus |d 2019 |g 6-7(2020) vom: 02. Mai, Seite 100033 |w (DE-627)NLM321036336 |x 2590-0285 |7 nnns |
| 773 | 1 | 8 | |g volume:6-7 |g year:2020 |g day:02 |g month:05 |g pages:100033 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1016/j.mbplus.2020.100033 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 6-7 |j 2020 |b 02 |c 05 |h 100033 | ||