Blocking lncRNA NOP14-AS1 overcomes 5-Fu resistance of colon cancer cells by modulating miR-30a-5p-LDHA-glucose metabolism pathway.

Abstract

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.