LGR5 and Downstream Intracellular Signaling Proteins Play Critical Roles in the Cell Proliferation of Neuroblastoma, Meningioma and Pituitary Adenoma

Abstract

Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) has been reported to play critical roles in the proliferation of various cancer cells. However, the roles of LGR5 in brain tumors and the specific intracellular signaling proteins directly associated with it remain unknown. Expression of LGR5 was first measured in normal brain tissue, meningioma, and pituitary adenoma of humans. To identify the downstream signaling pathways of LGR5, siRNA-mediated knockdown of LGR5 was performed in SH-SY5Y neuroblastoma cells followed by proteomics analysis with 2-dimensional polyacrylamide gel electrophoresis (2D-PAGE). In addition, the expression of LGR5-associated proteins was evaluated in LGR5-inhibited neuroblastoma cells and in human normal brain, meningioma, and pituitary adenoma tissue. Proteomics analysis showed 12 protein spots were significantly different in expression level (more than two-fold change) and subsequently identified by peptide mass fingerprinting. A protein association network was constructed from the 12 identified proteins altered by LGR5 knockdown. Direct and indirect interactions were identified among the 12 proteins. HSP 90-beta was one of the proteins whose expression was altered by LGR5 knockdown. Likewise, we observed decreased expression of proteins in the hnRNP subfamily following LGR5 knockdown. In addition, we have for the first time identified significantly higher hnRNP family expression in meningioma and pituitary adenoma compared to normal brain tissue. Taken together, LGR5 and its downstream signaling play critical roles in neuroblastoma and brain tumors such as meningioma and pituitary adenoma.

Neural crest cells development and neuroblastoma progression: Role of Wnt signaling

“…LGR5 stimulates NB stem cell proliferation and self‐renewal by potentiating the Wnt/β‐catenin signaling (Xu et al, 2019). LGR5 inhibits Wnt/β‐catenin signaling by binding to its ligand R‐spondin which is Wnt signaling agonist and promotes NB oncogenesis (Hwang et al, 2019). The binding of Wnt ligands to LRP5 activates downstream Dsh protein that causes the breakdown of cytoplasmic degradation complex (Gsk3‐β, APC, and Axin) that earlier phosphorylated cytoplasmic β‐catenin and restricts its translocation to the nucleus (Rosenbluh et al, 2014).…”

<p>Cushing’s Disease Caused by a Pituitary Microadenoma Coexistent with a Meningioma: A Case Report and Literature Review</p>

“…12 Meanwhile, estrogen receptor positive de novo meningiomas significantly involve chromosomes 14 and 22. 13 The study by Hwang et al 14 reported that the expression levels of heterogeneous nuclear ribonucleoprotein (hnRNP) family proteins were significantly higher in pituitary adenomas and meningiomas than that in normal brain tissues. Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) and its downstream signaling pathways play an pivotal role in pituitary tumor, meningioma, and other brain tumors.…”

Arsenic Trioxide Increases Apoptosis of SK-N-BE (2) Cells Partially by Inducing GPX4-mediated Ferroptosis

“…In a study by Lorena et al[8],protein expression patterns of distant metastases in NB xenograft mouse model were identi ed by Quantitative proteomics. Hwang et al [9] found a total of 12 proteins differentially regulated after LGR5 knockdown, including Wnt/β-catenin signaling and hnRNP family, indicating that LGR5 and its downstream signaling may play a critical role in NB by hyperactivation of alternative pre-mRNA processing.…”