Lu Ya-Nan
School of Medicine, Xuchang University, No.2111 Xinghua Road, Weidu District, Xuchang, 461000, Henan, China.
Discov Oncol. 2025 Apr 3;16(1):458. doi: 10.1007/s12672-025-02156-4.
Colorectal cancer (CRC) is a malignant digestive tumor associated with high mortality rate. Currently, 5-Fu therapy is a frequently used treatment approach for CRC. Yet, acquirement of 5-Fu resistance ultimately leads to therapeutic failure in CRC patients. LncRNA NOP14-AS1 was upregulated in cancers, but its biological functions and mechanisms in 5-Fu resistant colorectal cancer remain elusive. We discovered that NOP14-AS1 was high-expressed in colorectal tumors and cancer cells. Silencing NOP14-AS1 sensitized CRC cells to 5-Fu. By creating a 5-Fu resistant CRC cell line (HT-29 5-Fu R) and observed that expression of NOP14-AS1 was remarkedly elevated in 5-Fu resistant cells compared to parental cells. Additionally, we found that miRNA-30a-5p was a target of NOP14-AS1 and directly affected its function. miR-30a-5p overexpression sensitized CRC cells to 5-Fu treatment and targeted the glycolysis key enzyme, LDHA. Rescue experiments showed that restoring LDHA in CRC cells which were overexpressing miR-30c-5p successfully overridden 5-Fu resistance. Importantly, restoring miR-30a-5p in NOP14-AS1-overexpressing cells effectively restored 5-Fu sensitivity in HT-29 5-Fu R cells by targeting the LDHA-mediated glucose metabolism. In summary, our results revealed that lncRNA NOP14-AS1 promotes 5-Fu resistance by mediating the miR-30a-5p-LDHA axis.
结直肠癌（CRC）是一种死亡率很高的恶性消化肿瘤。目前，5-氟尿嘧啶（5-Fu）疗法是CRC常用的治疗方法。然而，获得5-Fu耐药性最终会导致CRC患者治疗失败。长链非编码RNA（lncRNA）NOP14-AS1在癌症中上调，但其在5-Fu耐药性结直肠癌中的生物学功能和机制仍不清楚。我们发现NOP14-AS1在结直肠肿瘤和癌细胞中高表达。沉默NOP14-AS1可使CRC细胞对5-Fu敏感。通过创建一个5-Fu耐药的CRC细胞系（HT-29 5-Fu R），观察到与亲代细胞相比，5-Fu耐药细胞中NOP14-AS1的表达显著升高。此外，我们发现miRNA-30a-5p是NOP14-AS1的靶标，并直接影响其功能。miR-30a-5p过表达使CRC细胞对5-Fu治疗敏感，并靶向糖酵解关键酶乳酸脱氢酶A（LDHA）。挽救实验表明，在过表达miR-30c-5p的CRC细胞中恢复LDHA可成功克服5-Fu耐药性。重要的是，在过表达NOP14-AS1的细胞中恢复miR-30a-5p可通过靶向LDHA介导的葡萄糖代谢有效恢复HT-29 5-Fu R细胞的5-Fu敏感性。总之，我们的结果表明lncRNA NOP14-AS1通过介导miR-30a-5p-LDHA轴促进5-Fu耐药性。
