Inhibition of lncRNA-NEAT1 sensitizes 5-Fu resistant cervical cancer cells through de-repressing the microRNA-34a/LDHA axis.

Xuecheng Shao,Dan Ma,Yang Liu,Guoyan Liu,Xuehui Zheng

doi:10.1042/bsr20200533

Abstract

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.

Highlights

Cervical cancer, one of the commonly diagnosed malignancies among females, is the main leading cause of female tumor deaths around the world [1]
LncRNA-nuclear-rich transcripts 1 (NEAT1) is positively associated with cervical cancer
Since studies have reported that miR-34a could inhibits the tumorigenesis together with long noncoding RNA (lncRNA) [25,26], we focused on miR-34a as competitive endogenous RNA (ceRNA) of NEAT1

Summary

Introduction

One of the commonly diagnosed malignancies among females, is the main leading cause of female tumor deaths around the world [1]. Diagnosis and treatment of cervical cancer have been improved, the prognosis of patients still remains poor due to metastasis and chemoresistance [3,4]. 5-fluorouracil (5-Fu) is one of the systemic adjuvants and palliative chemotherapies against cervical cancers [5]. Multiple strategies including the 5-Fu-based combination with other chemotherapeutic agents have been developed to enhance the anti-tumor activity of 5-Fu [6]. Cervical cancer therapy, a fraction of patients’ response to 5-Fu gradually attenuated, resulting from the development of chemoresistance [7]. Investigating the underlying molecular mechanisms of chemoresistance is an essential task for developing novel therapeutic strategies against cervical cancer

Methods

Results

Conclusion