Tianjin Key Laboratory of Early Druggability Evaluation of Innovative Drugs and Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China.
Tianjin Key Laboratory of Digestive Diseases, Department of Gastroenterology and Hepatology, Tianjin Institute of Digestive Diseases, Tianjin Medical University General Hospital, Tianjin, China.
Cancer Med. 2023 Apr;12(8):9774-9787. doi: 10.1002/cam4.5721. Epub 2023 Feb 28.
Chromosomal heterogeneity leads to the abnormal expression and mutation of tumor-specific genes. Drugs targeting oncogenes have been extensively developed. However, given the random mutation of tumor suppressor genes, the development of its targeted drugs is difficult.
Our early research revealed that artificial circular single-stranded DNA (CSSD) can restore multiple tumor suppressor genes to inhibit tumor malignant progression by adsorbing miRNA. Here, we improved CSSD to a fully closed single-stranded DNA with G quadruplex DNA secondary structure (G4-CSSD), which made G4-CSSD with higher acquisition rate and decreased degradation. The Cancer Genome Atlas (TCGA) and Human Protein Atlas database were used to predict tumour suppressor genes in colon cancer. Cellular and animal experiments were performed to validate the role of G4-CSSD in cancer cell progression.
In colon cancer, we observed the simultaneous low expressions of chloride channel accessory 1 (CLCA1), UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 6 (B3GNT6) and UDP glucuronosyltransferase family 2 member A3 (UGT2A3), which indicated an favourable prognosis. After repressing miR-590-3p with G4-CSSD590, the upregulation of CLCA1, B3GNT6 and UGT2A3 inhibited the proliferation and metastasis of colon cancer cells.
This study may provide basis for new treatment methods for colon cancer by restoration of tumor suppressor genes.
染色体异质性导致肿瘤特异性基因的异常表达和突变。针对癌基因的药物已经得到了广泛的开发。然而，鉴于肿瘤抑制基因的随机突变，其靶向药物的开发具有一定难度。
我们早期的研究表明，人工环状单链 DNA（CSSD）可以通过吸附 miRNA 来恢复多个肿瘤抑制基因，从而抑制肿瘤的恶性进展。在这里，我们将 CSSD 改进为具有 G 四链体 DNA 二级结构（G4-CSSD）的完全闭环单链 DNA，这使得 G4-CSSD 的获得率更高，降解率降低。使用癌症基因组图谱（TCGA）和人类蛋白质图谱数据库来预测结肠癌中的肿瘤抑制基因。通过细胞和动物实验来验证 G4-CSSD 在癌细胞进展中的作用。
在结肠癌中，我们观察到氯离子通道辅助因子 1（CLCA1）、UDP-N-乙酰葡糖胺：βGalβ-1,3-N-乙酰氨基葡萄糖基转移酶 6（B3GNT6）和 UDP 葡糖醛酸基转移酶家族 2 成员 A3（UGT2A3）的同时低表达，这预示着良好的预后。用 G4-CSSD590 抑制 miR-590-3p 后，CLCA1、B3GNT6 和 UGT2A3 的上调抑制了结肠癌细胞的增殖和转移。
本研究通过恢复肿瘤抑制基因，为结肠癌的新治疗方法提供了依据。
