Department of General Surgery, The Fourth Affiliated Hospital of Harbin Medical University, No. 37, Yiyuan Street, Nangang District, 150001, Harbin, Heilongjiang, People's Republic of China.
Dig Dis Sci. 2024 Apr;69(4):1182-1199. doi: 10.1007/s10620-024-08312-0. Epub 2024 Feb 15.
Coiled-coil domain-containing protein 178 (CCDC178) has been revealed to exert metastasis-promoting properties in hepatocellular carcinoma, whereas its function in gastric cancer (GC) has not been fully understood.
We evaluated its role in GC and the molecular mechanism.
The differentially expressed genes in datasets related to GC metastasis were intersected with survival-related genes in GC, followed by prognostic significance prediction. Loss- and gain-of-function assays were conducted to examine the involvement of CCDC178, Homeobox protein BarH-like 1 (BARX1), and the extracellular signal-regulated kinase (ERK) pathway in GC cell malignant phenotype and the polarization of tumor-associated macrophages (TAM). The corresponding functions were verified in the in vivo animal experiment.
High CCDC178 expression predicted a poor prognosis for GC patients, and CCDC178 correlated significantly with macrophage infiltration in GC tissues. CCDC178 activated the ERK pathway in GC. Silencing of CCDC178 reduced the colony formation, migratory and invasive potential of GC cells, and the M2-like polarization of TAM, which was reversed by TBHQ (an ERK activator). BARX1 bound to the promoter region of CCDC178, thus inducing its transcriptional level. Silencing of BARX1 suppressed the M2-type polarization of TAM in vitro and in vivo, and CCDC178 mitigated the repressing role of BARX1 knockdown.
BARX1 activates the transcription of CCDC178 to induce the ERK pathway, thereby supporting macrophage recruitment and M2-like polarization in GC.
卷曲螺旋结构域蛋白 178（CCDC178）已被证实具有促进肝细胞癌转移的特性，但其在胃癌（GC）中的作用尚未完全阐明。
评估其在 GC 中的作用及其分子机制。
将与 GC 转移相关的数据集的差异表达基因与 GC 中的生存相关基因进行交集，然后预测其预后意义。通过缺失和获得功能实验，研究 CCDC178、同源盒蛋白 BarH-like 1（BARX1）和细胞外信号调节激酶（ERK）通路在 GC 细胞恶性表型和肿瘤相关巨噬细胞（TAM）极化中的作用。在体内动物实验中验证了相应的功能。
高 CCDC178 表达预示 GC 患者预后不良，CCDC178 与 GC 组织中的巨噬细胞浸润显著相关。CCDC178 在 GC 中激活 ERK 通路。沉默 CCDC178 降低了 GC 细胞的集落形成、迁移和侵袭能力，以及 TAM 的 M2 样极化，而 TBHQ（一种 ERK 激活剂）则逆转了这一现象。BARX1 与 CCDC178 的启动子区域结合，从而诱导其转录水平。BARX1 沉默抑制了 TAM 在体外和体内的 M2 型极化，而 CCDC178 减轻了 BARX1 敲低的抑制作用。
BARX1 激活 CCDC178 的转录，从而诱导 ERK 通路，支持 GC 中巨噬细胞募集和 M2 样极化。
