CHRDL1 Regulates Stemness in Glioma Stem-like Cells

Abstract

Glioblastoma (GBM) still presents as one of the most aggressive tumours in the brain, which despite enormous research efforts, remains incurable today. As many theories evolve around the persistent recurrence of this malignancy, the assumption of a small population of cells with a stem-like phenotype remains a key driver of its infiltrative nature. In this article, we research Chordin-like 1 (CHRDL1), a secreted protein, as a potential key regulator of the glioma stem-like cell (GSC) phenotype. It has been shown that CHRDL1 antagonizes the function of bone morphogenic protein 4 (BMP4), which induces GSC differentiation and, hence, reduces tumorigenicity. We, therefore, employed two previously described GSCs spheroid cultures and depleted them of CHRDL1 using the stable transduction of a CHRDL1-targeting shRNA. We show with in vitro cell-based assays (MTT, limiting dilution, and sphere formation assays), Western blots, irradiation procedures, and quantitative real-time PCR that the depletion of the secreted BMP4 antagonist CHRDL1 prominently decreases functional and molecular stemness traits resulting in enhanced radiation sensitivity. As a result, we postulate CHRDL1 as an enforcer of stemness in GSCs and find additional evidence that high CHRDL1 expression might also serve as a marker protein to determine BMP4 susceptibility.

BMP antagonist CHRDL2 enhances the cancer stem cell phenotype and increases chemotherapy resistance in Colorectal Cancer

“…Some well-studied BMP antagonists include Noggin, which has been implicated in promoting skin and breast cancer tumorigenesis, and the Gremlins (GREM1 and 2), with repression of GREM1 shown to inhibit tumour cell proliferation. The Chordin family of proteins have also been implicated in CRC, including Chordin, Chordin-like 1 (CHRDL1) and Chordin-like 2 (CHRDL2) [21][22][23][24]. One of the best studied BMP antagonists, Noggin, has previously been shown to inhibit BMP signalling in a mouse model, resulting in the formation of numerous ectopic crypts perpendicular to the crypt-villus axis [12].…”

Effect of CHRDL1 on angiogenesis and metastasis of colorectal cancer cells via TGF‐β/VEGF pathway

“…The functionality of BMPs is antagonized by adhering CHRDL1 to BMP4, 5, and 6 and thus preventing them from interacting with receptors 8,9 . It changes the progeny of neural stem cells from gliogenesis to neurogenesis and aids the development of neural stem cells into neurons in the brain 10–12 . It might be important for the development of the embryonic skeleton and the dorsoventral axis.…”

“…8,9 It changes the progeny of neural stem cells from gliogenesis to neurogenesis and aids the development of neural stem cells into neurons in the brain. [10][11][12] It might be important for the development of the embryonic skeleton and the dorsoventral axis. By controlling BMP4 in endothelial cells, it may also play a significant part in regulating retinal angiogenesis.…”