Cellular and Molecular Biology Laboratory (LIM 15), Neurology Department, Faculdade de Medicina (FMUSP), Universidade de Sao Paulo, Sao Paulo 01246-903, SP, Brazil.
Int J Mol Sci. 2022 Aug 23;23(17):9507. doi: 10.3390/ijms23179507.
Tumor cell infiltrative ability into surrounding brain tissue is a characteristic of diffusely infiltrative astrocytoma and is strongly associated with extracellular matrix (ECM) stiffness. Collagens are the most abundant ECM scaffolding proteins and contribute to matrix organization and stiffness. LOX family members, copper-dependent amine oxidases, participate in the collagen and elastin crosslinking that determine ECM tensile strength. Common IDH mutations in lower-grade gliomas (LGG) impact prognosis and have been associated with ECM stiffness. We analyzed the expression levels of LOX family members and matrisome-associated genes in astrocytoma stratified by malignancy grade and IDH mutation status. A progressive increase in expression of all five LOX family members according to malignancy grade was found. , , and expression correlated with matrisome gene expressions. LOXL1 correlations were detected in LGG with mutation (IDH), correlations in LGG with IDH wild type (IDH) and strong correlations in glioblastoma (GBM) were found. These increasing correlations may explain the increment of ECM stiffness and tumor aggressiveness from LGG-IDH and LGG-IDH through to GBM. The expression of the mechanosensitive transcription factor, β-catenin, also increased with malignancy grade and was correlated with and LOXL3 expression, suggesting involvement of this factor in the outside-in signaling pathway.
肿瘤细胞浸润周围脑组织的能力是弥漫性浸润性星形细胞瘤的特征，与细胞外基质（ECM）硬度密切相关。胶原是最丰富的 ECM 支架蛋白，有助于基质的组织和硬度。赖氨酰氧化酶（LOX）家族成员是铜依赖性胺氧化酶，参与决定 ECM 拉伸强度的胶原和弹性蛋白交联。低级胶质瘤（LGG）中的常见 IDH 突变影响预后，并与 ECM 硬度有关。我们分析了根据恶性程度和 IDH 突变状态分层的星形细胞瘤中 LOX 家族成员和基质相关基因的表达水平。根据恶性程度，发现所有五种 LOX 家族成员的表达均呈渐进性增加。 、 、 和 表达与基质相关基因表达相关。在具有 IDH 突变（IDH）的 LGG 中检测到 LOXL1 相关性，在具有 IDH 野生型（IDH）的 LGG 中检测到 相关性，在胶质母细胞瘤（GBM）中检测到强烈的 相关性。这些相关性的增加可能解释了从 LGG-IDH 到 LGG-IDH 再到 GBM 的 ECM 硬度和肿瘤侵袭性的增加。机械敏感性转录因子β-连环蛋白的表达也随着恶性程度的增加而增加，并与 表达和 LOXL3 表达相关，提示该因子参与了细胞外信号通路。
