Li Xiangyong, Zhao Haibin, Zhou Xijian, Song Lei
Department of Hematology and Oncology, The 101st Hospital of the People's Liberation Army, Wuxi, Jiangsu 214044, P.R. China.
Department of Pathology, The 101st Hospital of the People's Liberation Army, Wuxi, Jiangsu 214044, P.R. China.
Mol Med Rep. 2015 Jan;11(1):577-82. doi: 10.3892/mmr.2014.2726. Epub 2014 Oct 21.
5-Fluorouracil (5-FU) chemotherapy is widely used in the treatment of advanced colon cancer. However, the development of resistance to 5-FU is a significant obstacle to successful treatment. MicroRNA-34a (miR-34a) has been reported to be downregulated in a number of tumor types and has also been shown to act as a tumor suppressor. However, the mechanisms underlying the biological effects of miR-34a in chemoresistance remain unclear. The present study showed that the expression of miR-34a is downregulated in 5-FU-resistant colon cancer cells. In addition, 5-FU-resistant colon cancer cells exhibited upregulation of lactate dehydrogenase A (LDHA) expression and activity compared with parental cells. Furthermore, LDHA was shown to be a direct target of miR-34a. Overexpression of miR-34a reduced the expression of LDHA, probably through binding to the 3' untranslated region, leading to the re-sensitization of 5-FU-resistant cancer cells to 5-FU. Additionally, overexpression of LDHA rendered colon cancer cells resistant to 5-FU, suggesting that the miR-34a-induced sensitization to 5-FU is mediated through the inhibition of LDHA. In conclusion, the current study showed that miR-34a is involved in sensitivity to 5-FU in part through its effects on LDHA expression. This indicates that miR-34a‑mediated inhibition of glucose metabolism may be a therapeutic target in patients with chemoresistant colon cancer.
5-氟尿嘧啶（5-FU）化疗广泛应用于晚期结肠癌的治疗。然而，对5-FU产生耐药性是成功治疗的一个重大障碍。据报道，微小RNA-34a（miR-34a）在多种肿瘤类型中表达下调，并且还被证明具有肿瘤抑制作用。然而，miR-34a在化疗耐药中的生物学效应的潜在机制仍不清楚。本研究表明，miR-34a在5-FU耐药的结肠癌细胞中表达下调。此外，与亲本细胞相比，5-FU耐药的结肠癌细胞中乳酸脱氢酶A（LDHA）的表达和活性上调。此外，LDHA被证明是miR-34a的直接靶点。miR-34a的过表达降低了LDHA的表达，可能是通过与3'非翻译区结合，导致5-FU耐药癌细胞对5-FU重新敏感。此外，LDHA的过表达使结肠癌细胞对5-FU产生耐药性，这表明miR-34a诱导的对5-FU的敏感性是通过抑制LDHA介导的。总之，本研究表明，miR-34a部分通过其对LDHA表达的影响参与对5-FU的敏感性。这表明miR-34a介导的葡萄糖代谢抑制可能是化疗耐药结肠癌患者的一个治疗靶点。
