Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China.
BMC Cancer. 2024 Oct 10;24(1):1252. doi: 10.1186/s12885-024-12976-2.
Gliomas are the highly aggressive brain tumor and also the most devastating human tumors. The latent TGF binding proteins (LTBP) had been found to be involved in malignant biological process and could be used as potent biomarkers in several solid tumors. While the role of LTBP family in human glioma remain to be elucidated.
Normalized gene expression and corresponding clinical data of 2407 gliomas samples in public datasets were downloaded from Gliovis. Kaplan-Meier methods and Cox regression analysis was used for survival analyses.Western blot (WB) and Immunohistochemical (IHC) testing were employed to test LTBPs protein level in 154 gliomas samples. Correlation between LTBP2 expression and immune infiltration was evaluated by immunofluorescence (IF) and IHC in glioma tissues. CCK8 and flow cytometric analysis were used to detect the effect of LTBP2 on glioma cells. Orthotopic glioma- mouse models were utilized to evaluate effects in vivo.
LTBP2 mRNA level was dramatically higher in glioma samples compared with non-tumor brain tissues in XENA-TCGA_GTEx, Gill and Gravendeel datasets (all P < 0.01), and its expression positively correlated with glioma WHO grade, IDH1/2 wildtype and mesenchymal subtypes. These results were confirmed by In-house cohort which was detected by WB and IHC. We found that gliomas patients with high LTBP2 level had shorter OS than those with low LTBP2 level. LTBP2 expression significantly associated with glioma immune score (Spearman r = 0.68, P < 0.01)) and strongly correlated with infiltration degreee of macrophages both in lower grade gliomas (LGG) and GBM. Knocking down LTBP2 obviously reduced proliferation and enhanced sensitivity to temozolomide in U87 and U251 cells. Nude mice with lower expression of LTBP2 had slower tumor growth, and accompanied by less tumor-associated macrophages (TAMs) infiltration detected by IHC staining in vivo. Finally, low LTBP2 expression glioma patients who received chemotherapy survived longer than patients with high LTBP2 expression.
LTBP2 could be used as a prognostic marker, and high LTBP2 expression related to abundant TAMs infiltration and with a worse response to chemotherapy.
神经胶质瘤是高度侵袭性的脑肿瘤，也是最具破坏性的人类肿瘤。潜伏转化生长因子结合蛋白 (LTBP) 已被发现参与恶性生物学过程，并可作为几种实体肿瘤的有效生物标志物。然而，LTBP 家族在人类神经胶质瘤中的作用仍有待阐明。
从 Gliovis 下载了公共数据集 2407 个神经胶质瘤样本的归一化基因表达和相应的临床数据。采用 Kaplan-Meier 方法和 Cox 回归分析进行生存分析。Western blot (WB) 和免疫组织化学 (IHC) 检测用于检测 154 个神经胶质瘤样本中的 LTBPs 蛋白水平。通过免疫荧光 (IF) 和 IHC 在神经胶质瘤组织中评估 LTBP2 表达与免疫浸润的相关性。CCK8 和流式细胞术分析用于检测 LTBP2 对神经胶质瘤细胞的影响。建立原位神经胶质瘤-小鼠模型以评估体内作用。
与 XENA-TCGA_GTEx、Gill 和 Gravendeel 数据集的非肿瘤脑组织相比，LTBP2 mRNA 水平在神经胶质瘤样本中显著升高（均 P < 0.01），其表达与神经胶质瘤 WHO 分级、IDH1/2 野生型和间充质亚型呈正相关。这些结果通过 WB 和 IHC 检测的内部队列得到了证实。我们发现，LTBP2 水平高的神经胶质瘤患者的 OS 短于 LTBP2 水平低的患者。LTBP2 表达与神经胶质瘤免疫评分显著相关（Spearman r = 0.68，P < 0.01），并与低级别神经胶质瘤（LGG）和 GBM 中巨噬细胞的浸润程度强烈相关。敲低 LTBP2 可明显降低 U87 和 U251 细胞的增殖，并增强对替莫唑胺的敏感性。体内 IHC 染色显示，LTBP2 表达较低的裸鼠肿瘤生长较慢，肿瘤相关巨噬细胞 (TAMs) 浸润较少。最后，接受化疗的 LTBP2 低表达神经胶质瘤患者的生存期长于 LTBP2 高表达的患者。
LTBP2 可作为预后标志物，高 LTBP2 表达与丰富的 TAMs 浸润相关，对化疗反应较差。
