长链非编码 RNA LINC01606 通过 SCD1-Wnt/β-catenin-TFE3 反馈回路信号促进结肠癌细胞干性来保护其免于铁死亡。
Long noncoding RNA LINC01606 protects colon cancer cells from ferroptotic cell death and promotes stemness by SCD1-Wnt/β-catenin-TFE3 feedback loop signalling.
机构信息
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Gastrointestinal Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China.
出版信息
Clin Transl Med. 2022 Apr;12(4):e752. doi: 10.1002/ctm2.752.
BACKGROUND
Ferroptosis is principally caused by iron catalytic activity and intracellular lipid peroxidation. Long noncoding RNAs (lncRNAs) play crucial roles in tumorigenesis. However, the potential interplay between lncRNA LINC01606 and ferroptosis in colon cancer remains elusive.
METHODS
The expression level of LNC01606 in colon cancer tissue was detected by quantitative real-time polymerase chain reaction. The functional role of LNC01606 was investigated by gain- and loss-of-function assays both in vitro and in vivo. The LINC01606-SCD1-Wnt/β-catenin-TFE3 axis were screened and validated by DNA/RNA pull down, gas chromatography-mass spectrometry, RNA immunoprecipitation and dual-luciferase reporter.
RESULTS
The expression of lncRNA LINC01606 was frequently upregulated in human colon cancer and strongly associated with a poor prognosis. LINC01606 functioned as an oncogene and promotes colon cancer cell growth, invasion and stemness both in vitro and in vivo. Moreover, LINC01606 protected colon cancer cells from ferroptosis by decreasing the concentration of iron, lipid reactive oxygen species, mitochondrial superoxide and increasing mitochondrial membrane potential. Mechanistically, LINC01606 enhanced the expression of stearoyl-CoA desaturase 1 (SCD1), serving as a competing endogenous RNA to modulate miR-423-5p expression, subsequently activating the canonical Wnt/β-catenin signaling, and transcription factor binding to IGHM enhancer 3 (TFE3) increased LINC01606 transcription after recruitment to the promoter regions of LINC01606. Furthermore, we confirmed that upregulated LINC01606 and Wnt/β-catenin formed a positive feedback regulatory loop, further inhibiting ferroptosis and enhancing stemness.
CONCLUSIONS
LINC01606 functions as an oncogene to facilitate tumor cell stemness, proliferation and inhibit ferroptosis and is a promising therapeutic target for colon cancer.
背景
铁死亡主要由铁催化活性和细胞内脂质过氧化引起。长链非编码 RNA（lncRNA）在肿瘤发生中发挥关键作用。然而，lncRNA LINC01606 与结肠癌中铁死亡之间的潜在相互作用仍不清楚。
方法
通过定量实时聚合酶链反应检测结肠癌组织中 LINC01606 的表达水平。通过体外和体内的增益和失能实验研究 LINC01606 的功能作用。通过 DNA/RNA 下拉、气相色谱-质谱联用、RNA 免疫沉淀和双荧光素酶报告基因检测筛选和验证 LINC01606-SCD1-Wnt/β-catenin-TFE3 轴。
结果
lncRNA LINC01606 在人类结肠癌中经常上调，且与不良预后密切相关。LINC01606 作为癌基因，在体外和体内均促进结肠癌细胞的生长、侵袭和干性。此外，LINC01606 通过降低铁、脂质活性氧、线粒体超氧化物和增加线粒体膜电位来减少铁死亡对结肠癌细胞的保护。机制上，LINC01606 增强了硬脂酰辅酶 A 去饱和酶 1（SCD1）的表达，作为竞争内源性 RNA 来调节 miR-423-5p 的表达，随后激活经典的 Wnt/β-catenin 信号通路，转录因子结合 IGHM 增强子 3（TFE3）在募集到 LINC01606 启动子区域后增加 LINC01606 的转录。此外，我们证实上调的 LINC01606 和 Wnt/β-catenin 形成正反馈调节环路，进一步抑制铁死亡并增强干性。
结论
LINC01606 作为一种癌基因，促进肿瘤细胞干性、增殖，抑制铁死亡，是结肠癌有前途的治疗靶点。
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