Department of Gastroenterology, Yantai Affiliated Hospital of Binzhou Medical University, 717 Jinbu Street, Muping District, Yantai, 264100, Shandong, People's Republic of China.
Department of Digestive Endoscopy Room, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, 264100, Shandong, People's Republic of China.
Dig Dis Sci. 2022 Sep;67(9):4444-4457. doi: 10.1007/s10620-021-07287-6. Epub 2021 Nov 19.
Troponin C-1 (TNNC1) has been previously characterized as an oncogenic gene.
This study aimed to reveal the roles of TNNC1 in gastric cancer and the potential underlying mechanisms.
TNNC1 siRNAs and TNNC1 overexpression plasmid were used to alter its expression in AGS, MKN45, and HGC-27 cells. CCK-8 assay, colony formation, EdU assay, flow cytometry, transwell assay, and scratch test were conducted to measure the phenotype changes. In vivo effects of TNNC1 silence were confirmed by using a xenograft mouse model. Bioinformatics analysis was conducted to screen out the transcription factor and downstream signaling of TNNC1.
TNNC1 was highly expressed in gastric cancer tissues and cell lines, and its expression was associated with poor prognosis. TNNC1 silence suppressed the proliferation, migration, and invasion of AGS and MKN45 cells. However, TNNC1 silence induced apoptosis by mediating the cleavage of caspase-3 and caspase-9. Overexpression of TNNC1 in HGC-27 cells led to the contrary effects. The anti-tumor effects of TNNC1 silence were also confirmed in a xenograft animal model. E2F1 was validated as an upstream transcription factor of TNNC1. Effects of TNNC1 silence on AGS cell migration and invasion were attenuated by E2F1 overexpression. Besides, TGF-β/Smad was a downstream signaling pathway of TNNC1. The anti-tumor impacts of TNNC1 silence were weaken by SB431542 (a specific inhibitor of TGF-β signaling) while accelerated by TGF-β.
TNNC1 activated by E2F1 functioned as an oncogenic gene through regulating TGF-β/Smad signaling. TNNC1 was suggested as a potential molecular drug target of gastric cancer.
肌钙蛋白 C-1（TNNC1）先前被认为是一种致癌基因。
本研究旨在揭示 TNNC1 在胃癌中的作用及其潜在的机制。
使用 TNNC1 siRNA 和 TNNC1 过表达质粒改变 AGS、MKN45 和 HGC-27 细胞中的表达。通过 CCK-8 测定、集落形成、EdU 测定、流式细胞术、Transwell 测定和划痕试验来测量表型变化。通过异种移植小鼠模型证实 TNNC1 沉默的体内效应。进行生物信息学分析筛选 TNNC1 的转录因子和下游信号。
TNNC1 在胃癌组织和细胞系中高表达，其表达与预后不良相关。TNNC1 沉默抑制 AGS 和 MKN45 细胞的增殖、迁移和侵袭。然而，TNNC1 沉默通过介导 caspase-3 和 caspase-9 的切割诱导细胞凋亡。在 HGC-27 细胞中过表达 TNNC1 则导致相反的效果。TNNC1 沉默在异种移植动物模型中也得到了证实。E2F1 被验证为 TNNC1 的上游转录因子。E2F1 过表达减弱了 TNNC1 沉默对 AGS 细胞迁移和侵袭的影响。此外，TGF-β/Smad 是 TNNC1 的下游信号通路。TGF-β 信号的特异性抑制剂 SB431542 削弱了 TNNC1 沉默的抗肿瘤作用，而 TGF-β 则加速了该作用。
E2F1 激活的 TNNC1 通过调节 TGF-β/Smad 信号发挥致癌基因的作用。TNNC1 被认为是胃癌潜在的分子药物靶点。
