Inhibition of lncRNA-NEAT1 sensitizes 5-Fu resistant cervical cancer cells through de-repressing the microRNA-34a/LDHA axis.
Inhibition of lncRNA-NEAT1 sensitizes 5-Fu resistant cervical cancer cells through de-repressing the microRNA-34a/LDHA axis.
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DOI：
10.1042/bsr20200533
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发表时间：
2021-07-30
影响因子：
4
通讯作者：
Liu G
中科院分区：
文献类型：
--
作者：
Shao X;Zheng X;Ma D;Liu Y;Liu G
宫颈癌是女性中最常见的恶性肿瘤之一。5-氟尿嘧啶（5-Fu）是一种广泛使用的化疗药物，用于治疗多种癌症。尽管最初取得了令人鼓舞的进展，但一部分宫颈癌患者出现了5-Fu耐药。我们检测到富含核转录物1（NEAT 1）在宫颈癌组织和细胞系中显著上调。NEAT 1与5-Fu耐药呈正相关。此外，NEAT 1的表达在5-Fu耐药的CaSki宫颈癌细胞中显著上调。通过shRNA敲低NEAT 1显著提高了5-Fu耐药CaSki细胞的敏感性。我们观察到宫颈癌患者组织中长链非编码RNA（lncRNA）-NEAT 1和miR-34 a之间呈负相关。过表达miR-34 a可显著增敏5-Fu耐药细胞。生物信息学分析发现，NEAT 1在宫颈癌细胞中作为miR-34 a的竞争性内源性RNA（ceRNA），通过在多个位点吸附而抑制miR-34 a的表达。NEAT 1和miR-34 a之间的这种负相关性在宫颈癌组织中得到进一步证实。我们发现5-Fu耐药细胞的糖酵解速率显著增加。过表达miR-34 a可抑制细胞糖酵解速率，并通过直接靶向糖酵解关键酶LDHA的3′-非翻译区（UTR）致敏5-Fu耐药细胞。重要的是，敲低NEAT 1通过上调miR-34 a成功下调宫颈癌细胞的LDHA表达和糖酵解速率，这一过程可以通过miR-34 a抑制进一步挽救。最后，我们证明了NEAT 1的抑制通过miR-34 a/LDHA通路显著地使宫颈癌细胞对5-Fu敏感。综上所述，本研究提示NEAT 1介导的5-Fu耐药可能通过miR-34 a/LDHA-糖酵解轴发挥作用。
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.