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OLFML2A Downregulation Inhibits Glioma Proliferation Through Suppression of Wnt/β-Catenin Signaling.

ABSTRACT: Glioma is a highly heterogeneous and lethal tumor with an extremely poor prognosis. Through analysis of TCGA data, we identified that OLFML2A is a key promotor of gliomagenesis. However, the molecular function of OLFML2A and its underlying mechanism of action in glioma remain unclear. In this study, we found that OLFML2A expression was significantly upregulated in glioma specimens and positively correlated with pathological grades in glioma patients. Moreover, Kaplan-Meier survival analysis of TCGA data revealed that glioma patients with higher OLFML2A expression had shorter overall survival. Importantly, OLFML2A knockdown in glioma cells inhibited cell proliferation and promoted apoptosis. Mechanistically, OLFML2A downregulation inhibits Wnt/β-catenin signaling by upregulating amyloid precursor protein (APP) expression and reducing stabilized β-catenin levels, leading to the repression of MYC, CD44, and CSKN2A2 expression. Furthermore, OLFML2A downregulation suppressed the growth of transplanted glioma subcutaneously and intracranially by inhibiting Wnt/β-catenin pathway-dependent cell proliferation. By uncovering the oncogenic effects in human and rodent gliomas, our data support OLFML2A as a potential therapeutic target for glioma.

SUBMITTER: Ma S

PROVIDER: S-EPMC8506028 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeFAM110B is a member of the FAM110 family (family with sequence similarity 110), which is a component of the centrosome associated proteins. Previous studies have shown that FAM110B may be involved in the process of cell cycle and may play a role in carcinogenesis and tumor progression. Using an online database, we found that FAM110B may predict favorable prognosis in non-small cell lung cancer (NSCLC). Therefore, the role of FAM110B playing in NSCLC needs to be further investigated.Patients and methodsOnline databases and immunohistochemistry were used to predict the expression and prognostic value of FAM110B in NSCLC samples. Immunofluorescence staining was used to investigate the subcellular distribution of FAM110B. Western blot, MTT, colony formation, and matrigel invasion assay were used to detect the expression and the effect of FAM110B on mediating proliferation and invasion in NSCLC cell lines.ResultsIn this study, immunohistochemistry results showed that FAM110B expression significantly correlated with early TNM staging (P=0.020) and negative regional lymph node metastasis (P=0.006). Kaplan-Meier survival analysis found that the median survival time of patients with positive FAM110B expression (56.181±2.348 months) was significantly longer than those with negative FAM110B expression (47.701±2.997 months, P=0.024). Moreover, overexpression of FAM110B inhibited the proliferation and invasion of A549, H1299, and LK2 cell lines. Conversely, FAM110B RNAi exerted opposite effects in the above cell lines. Furthermore, FAM110B overexpression downregulated the active β-catenin, phosphorylation of GSK-3β (p-GSK-3β), cyclin B1, cyclin D1, MMP2, and MMP7, and upregulated the phosphorylation of β-catenin (p-β-catenin) in A549 and H1299 cells. Besides, the FAM110B-induced depressions of p-GSK-3β and active β-catenin were reversed after being treated with Wnt/β-catenin inhibitor, XAV-939.ConclusionIn summary, our results demonstrated that the overexpression of FAM110B restricts the proliferation and invasion of NSCLC cells by inhibiting Wnt/β-catenin signaling. Our study reveals the antitumor function of FAM110B in NSCLC and indicates that FAM110B is a potential therapeutic target.

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OLFML2A Downregulation Inhibits Glioma Proliferation Through Suppression of Wnt/β-Catenin Signaling.

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