Department of Biotechnology, Savitribai Phule Pune University, India.
Bioinformatics Centre, Savitribai Phule Pune University, India.
FEBS J. 2024 Nov;291(21):4696-4713. doi: 10.1111/febs.17253. Epub 2024 Sep 6.
Eukaryotic cells respond to stress by altering coding and non-coding gene expression programs. Alongside many approaches and regulatory mechanisms, long non-coding RNAs (lncRNA) are finding a significant place in gene regulation, suggesting an involvement in various cellular processes and pathophysiology. LncRNAs are regulated by many transcription factors, including SMAR1 and p53, which are tumor suppressor genes. SMAR1 inhibits cancer cell metastasis and invasion and is also known to inhibit apoptosis during low-dose stress in coordination with p53. Data mining analysis suggested that these tumor suppressor genes might coregulate the lncRNA RP11-431M3.1 in colon cancer cells. Importantly, RP11-431M3.1 expression was found to be negatively correlated with patient survival rates in a number of cancers. Oxidative stress occurs when an imbalance in the body is caused by reactive oxygen species (ROS). This imbalance is known to be important in the development/pathogenesis of colon cancer. We are researching the role and control of this lncRNA in HCT116 cells under conditions of oxidative stress. We observed a dose-dependent differential expression of lncRNA upon HO treatment and found that p53 and SMAR1 bind differentially to the promoter in response to the dose of stress inducer used. RP11-431M3.1 was observed to sponge miR-138 which has an important target gene, hypoxia-inducible factor (HIF1A). miR-138 was observed to bind differentially to RP11-431M3.1 and HIF1A RNA depending on the dose of oxidative stress. Furthermore, the knockdown of RP11-431M3.1 decreased the migration and proliferation of colon cancer cells. Our results suggest a previously undescribed regulatory mechanism through which RP11-431M3.1 is transcriptionally regulated by SMAR1 and p53, target HIF1A through miR-138, and highlight its potential as a therapeutic and diagnostic marker for cancer.
真核细胞通过改变编码和非编码基因表达程序来应对应激。除了许多方法和调节机制外，长链非编码 RNA（lncRNA）在基因调控中占据了重要地位，表明其参与了各种细胞过程和病理生理学过程。lncRNA 受到许多转录因子的调节，包括肿瘤抑制基因 SMAR1 和 p53。SMAR1 抑制癌细胞的转移和侵袭，并且还已知在与 p53 协同作用下，在低剂量应激时抑制细胞凋亡。数据挖掘分析表明，这些肿瘤抑制基因可能共同调节结肠癌细胞中的 lncRNA RP11-431M3.1。重要的是，在许多癌症中，RP11-431M3.1 的表达与患者的生存率呈负相关。当活性氧 (ROS) 引起体内失衡时，就会发生氧化应激。这种失衡在结肠癌的发生/发病机制中很重要。我们正在研究在氧化应激条件下该 lncRNA 在 HCT116 细胞中的作用和控制。我们观察到 HO 处理后 lncRNA 的剂量依赖性差异表达，并发现 p53 和 SMAR1 以不同的方式结合到启动子上，以响应使用的应激诱导剂的剂量。观察到 RP11-431M3.1 吸附 miR-138，后者具有重要的靶基因缺氧诱导因子 (HIF1A)。miR-138 与 RP11-431M3.1 和 HIF1A RNA 的结合因氧化应激的剂量而异。此外，RP11-431M3.1 的敲低降低了结肠癌细胞的迁移和增殖。我们的结果表明了一种以前未描述的调节机制，通过该机制，RP11-431M3.1 被 SMAR1 和 p53 转录调节，通过 miR-138 靶向 HIF1A，并强调其作为癌症治疗和诊断标志物的潜力。
