Rhythmic regulatory molecule BLOCK alters the micro-environment of gliomas by immunosuppressing small glial cells

Glioma scleoma (GBM) is a kind of brain tumor with strong attack and high fatality rate.
A large number of pan-genome analyses showed that certain signaling paths in GBM were activated, but clinically failed to obtain efficacy from the activation of regulatory signaling paths;
analysis of tumor-like tumors found that the dry maintenance of tumor stem cells is closely related to the micro-environment of immunosuppressive tumors.
Peiwen Chen of the MD Anderson Cancer Center at the University of Texas, USA, et al., found that the complex of circadian rhythm-regulating molecules BLOCK and BMAL1 promotes the dry maintenance of GBM stem cells and activates downstream OLFML3 to promote immunosuppressive small glial cells that alter tumor microencepts, the results of which were published in the March 2020 issue of Cancer Discovery.
results of the study found: 1. CLOCK promotes tumor stem cells to maintain self-renewal capabilities and increase expression in human-sourced GBM.
the authors established human-sourced GBM stem cells in the early stages, and functional experimental screening showed that CLOCK was the most effective in promoting self-renewal of stem cells among all the screened supergeogen regulatory molecules.
the Cancer Genome Map (TCGA) database suggests that CLOCK is increasing in expression in 5% GBM and 2.8% low-grade gliomas.
in further human and mouse-sourced GBM stem cell experiments, knocking out CLOCK reduced the ability of tumor stem cells to renew themselves.
CLOCK usually forms transcription factor djures with BMAL1 to regulate circadian rhythms.
authors found that knocking out BMAL1 or using THEC/BMAL1 complex inhibitor SR9009 also inhibited the ability of tumor stem cells to renew themselves.
analysis and validation of the results show that CLOCK mainly plays a cancer-promoting role by affecting glycolipid metabolism, such as PPM1 and ACACA.
2. CLOCK enters the tumor micro-environment through small glial cells.
, the authors performed a letter analysis on knocking out BLOCK glioma stem cells and observed significantly increased interferon g/a, TNFa/NF-kB pathlines, and inflammatory responses.
And CLK high expression, mainly lead to tumor micro-environment small glial cells increase, CLOCK knocked out stem cell culture can reduce the ability of small glial cell migration, and CLK over-expression of stem cell culture can increase small glial cell migration.
, in clinical GBM samples, CLOCK or BMAL1 was positively corred with the expression of the small glial cell marker TMEM119/CX3CR1.
3. CLOCK promotes small glial cell migration by raising OLFML3.
To further explore the molecular mechanism of BLOCK's action through small glial cells, the authors first found that this phenomenon may be related to the polymeric factor OLFML3 through high-volume qRT-PCR screening, GO database aquidization analysis, and TCGA database correlation analysis.
analysis results show that OLFML3 is positively corred with the expression of small glial cell marker TMEM119/CX3CR1. Knocking out CLC or BMAL1 in
human and mouse-sourced GBM stem cells can cause a decrease in OLFML3 expression, and Chip-PCR and luciferase reports confirm that the CLOCK/BMAL1 transcription factor complex can be combined in the OLFML3 initiator region to promote its expression.
Transwell cell migration experiment found that raising OLFML3 promotes small glial cell migration.
4. Knocking out BLOCK inhibits tumor stem cell self-renewal and small glial cell migration and is beneficial to individual survival.
in mice transplanted with human-sourced GBM stem cells, the authors found significantly longer survival times in mice that knocked out stem cell BLOCK.
authors also used C57BL/6 mice transplanted with stem cell properties of CT2A cell lotus tumor experimental results show that knocking out CLC/BMAL1/OLFML3 or inhibiting CLC/BMAL1 complex can extend the survival time of lotus tumor mice.
immunoglostification analysis showed that knocking out CLOCK significantly reduced the expression of dry markers OLEG2, Nestin, and Ki67, and knocking out BLOCK or OLFML3 significantly inhibited the migration of M2 (immunosuppressive) small glial cells to tumor micro-environments.
Conclusion The authors conclude that the circadian rhythm-regulating molecule BLOCK promotes self-renewal and glycolipid metabolism of glioma stem cells, and directly increases the trending factor OLFML3 to promote the migration of immunosuppressive small glial cells to tumor micro-environments.
, CLOCK and OLFML3 could be new targets for GBM therapy.
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