Cervical cancer is one of the most diagnosed malignancies among females. The 5-fluorouracil (5-Fu) is a widely used chemotherapeutic agent against diverse cancers. Despite the initially encouraging progresses, a fraction of cervical cancer patients developed 5-Fu resistance. We detected that nuclear-rich transcripts 1 (NEAT1) was significantly up-regulated in cervical cancer tissues and cell lines. Moreover, NEAT1 was positively associated with 5-Fu resistance. Furthermore, expression of NEAT1 was significantly up-regulated in 5-Fu resistant CaSki cervical cancer cells. Knocking down NEAT1 by shRNA dramatically promoted the sensitivity of 5-Fu resistant CaSki cells. We observed a negative correlation between long noncoding RNA (lncRNA)-NEAT1 and miR-34a in cervical cancer patient tissues. Overexpression of miR-34a significantly sensitized 5-Fu resistant cells. Bioinformatics analysis uncovered that NEAT1 functions as a competitive endogenous RNA (ceRNA) of miR-34a in cervical cancer cells via sponging it at multiple sites to suppress expression of miR-34a. This negative association between NEAT1 and miR-34a was further verified in cervical cancer tissues. We found the 5-Fu resistant cells displayed significantly increased glycolysis rate. Overexpression of miR-34a suppressed cellular glycolysis rate and sensitized 5-Fu resistant cells through direct targeting the 3'-untranslated region (UTR) of LDHA, a glycolysis key enzyme. Importantly, knocking down NEAT1 successfully down-regulated LDHA expressions and glycolysis rate of cervical cancer cells by up-regulating miR-34a, a process could be further rescued by miR-34a inhibition. Finally, we demonstrated inhibition of NEAT1 significantly sensitized cervical cancer cells to 5-Fu through the miR-34a/LDHA pathway. In summary, the present study suggests a new molecular mechanism for the NEAT1-mediated 5-Fu resistance via the miR-34a/LDHA-glycolysis axis.
Keywords: 5-Fu resistance; Warburg effect; cervical cancer; lncRNA-NEAT1; miR–34a.
© 2021 The Author(s).