Li Lin, Liu Pengwei, He Chiyi, Xu Chunfang
Departments of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, People's Republic of China.
Departments of Gastroenterology, The First Affiliated Hospital of Wannan Medical College, Wuhu, 241001, Anhui, People's Republic of China.
J Cancer Res Clin Oncol. 2023 Jan;149(1):121-134. doi: 10.1007/s00432-022-04453-9. Epub 2022 Nov 10.
Expression of the guanine nucleotide exchange factor epithelial cell transforming 2 (ECT2) is elevated in gastric cancer (GC) but its biological function in GC is poorly understood. MicroRNAs (miRNAs) have great potential as therapeutic targets for GC through their ability to modulate gene expression. In the present study, we sought to identify potential miRNA-mRNA-protein regulatory pathways that might control ECT2 expression and function in GC.
ECT2 expression was examined in clinical GC specimens by immunohistochemical staining, and protein levels were correlated with clinicopathological features and prognosis. TargetScan was used to identify potential ECT2 mRNA-complementary miRNAs, and the roles of ECT2 and miRNA-223-3p (miR-223-3p) in GC cell biology and signaling pathway activation were examined by targeted knockdown (KD) or overexpression (OE) of ECT2 and miR-223-3p in GC cell lines. A murine GC xenograft model was developed to explore the impact of ECT2 OE on tumor growth in vivo.
ECT2 expression was significantly elevated in GC specimens compared with normal gastric tissues and the level correlated positively with depth of invasion, ulceration, vascular tumor thrombus, neural invasion, and lymph node metastasis (p < 0.05). ECT2 was an independent prognostic factor for overall survival of GC patients (high ECT2 expression v.s. low ECT2 expression: χ = 29.831, p < 0.001). ECT2 KD or miR-223-3p OE markedly suppressed the proliferation, migration, and invasion of GC cells in vitro, whereas ECT2 OE had the opposite effects. ECT2 OE also promoted the growth of GC tumors in vivo. Tumor expression of Wnt2, β-catenin, and several downstream target proteins in GC cells were decreased by ECT2 KD or miR-223-3p OE but increased by ECT2 OE.
miR-223-3p regulates ECT2 expression to promote tumorigenic behavior of GC via activation of the Wnt/β-catenin signaling pathway, suggesting that ECT2 and miR-223-3p as potential therapeutic targets for GC.
鸟嘌呤核苷酸交换因子上皮细胞转化2（ECT2）在胃癌（GC）中表达升高，但其在GC中的生物学功能尚不清楚。微小RNA（miRNA）具有调节基因表达的能力，作为GC的治疗靶点具有巨大潜力。在本研究中，我们试图确定可能控制GC中ECT2表达和功能的潜在miRNA-mRNA-蛋白质调控途径。
通过免疫组织化学染色检测临床GC标本中ECT2的表达，并将蛋白水平与临床病理特征和预后相关联。使用TargetScan来识别潜在的ECT2 mRNA互补miRNA，并通过在GC细胞系中靶向敲低（KD）或过表达（OE）ECT2和miR-223-3p来研究ECT2和miR-223-3p在GC细胞生物学和信号通路激活中的作用。建立小鼠GC异种移植模型以探讨ECT2过表达对体内肿瘤生长的影响。
与正常胃组织相比，GC标本中ECT2表达显著升高，且该水平与浸润深度、溃疡、血管肿瘤血栓、神经浸润和淋巴结转移呈正相关（p < 0.05）。ECT2是GC患者总生存的独立预后因素（高ECT2表达与低ECT2表达：χ = 29.831，p < 0.001）。ECT2敲低或miR-223-3p过表达在体外显著抑制GC细胞的增殖、迁移和侵袭，而ECT2过表达则产生相反的效果。ECT2过表达还促进了体内GC肿瘤的生长。GC细胞中Wnt2、β-连环蛋白和几种下游靶蛋白的肿瘤表达通过ECT2敲低或miR-223-3p过表达而降低，但通过ECT2过表达而增加。
miR-223-3p通过激活Wnt/β-连环蛋白信号通路调节ECT2表达以促进GC的致瘤行为，提示ECT2和miR-223-3p作为GC的潜在治疗靶点。
