Abstract
Acquisition of resistance to anti-cancer drugs is a significant obstacle to effective cancer treatment. Although several efforts have been made to overcome drug resistance in cancer cells, the detailed mechanisms have not been fully elucidated. Here, we investigated whether microRNAs (miRNAs) function as pivotal regulators in the acquisition of anti-cancer drug resistance to 5-fluorouracil (5-FU). A survey using a lentivirus library containing 572 precursor miRNAs revealed that five miRNAs promoted cell survival after 5-FU treatment in human hepatocellular carcinoma Hep3B cells. Among the five different clones, the clone expressing miR-200a-3p (Hep3B-miR-200a-3p) was further characterized as a 5-FU-resistant cell line. The cell viability and growth rate of Hep3B-miR-200a-3p cells were higher than those of control cells after 5-FU treatment. Ectopic expression of a miR-200a-3p mimic increased, while inhibition of miR-200a-3p downregulated, cell viability in response to 5-FU, doxorubicin, and CDDP (cisplatin). We also showed that dual-specificity phosphatase 6 (DUSP6) is a novel target of miR-200a-3p and regulates resistance to 5-FU. Ectopic expression of DUSP6 mitigated the pro-survival effects of miR-200a-3p. Taken together, these results lead us to propose that miR-200a-3p enhances anti-cancer drug resistance by decreasing DUSP6 expression.
Highlights
Multidrug resistance is a major factor leading to cancer treatment failure
Because acquisition of drug resistance and toxic side effects limit the clinical applications of anti-cancer drugs, several studies have attempted to define the molecular and biochemical mechanisms related to the resistant phenotypes of cancer cells.[6,7,8,9,10]
The key determinants of drug resistance still remain largely unknown. 5-Fluorouracil (5-FU) is widely used to treat a range of cancers, including colorectal, liver, and breast cancers.7,11 5-FU is known to interfere with the synthesis of the pyrimidine thymidine, a nucleoside required for DNA replication, by inhibiting thymidylate synthase, thereby leading to cell cycle arrest or cell death in cancer cells.[7]
Summary
Multidrug resistance is a major factor leading to cancer treatment failure. It is a multifactorial phenomenon that includes the reduction of cell death, an increase in DNA repair, and alterations in drug metabolism.[1,2,3,4,5] Because acquisition of drug resistance and toxic side effects limit the clinical applications of anti-cancer drugs, several studies have attempted to define the molecular and biochemical mechanisms related to the resistant phenotypes of cancer cells.[6,7,8,9,10] the key determinants of drug resistance still remain largely unknown. 5-Fluorouracil (5-FU) is widely used to treat a range of cancers, including colorectal, liver, and breast cancers.7,11 5-FU is known to interfere with the synthesis of the pyrimidine thymidine, a nucleoside required for DNA replication, by inhibiting thymidylate synthase, thereby leading to cell cycle arrest or cell death in cancer cells.[7]. It is a multifactorial phenomenon that includes the reduction of cell death, an increase in DNA repair, and alterations in drug metabolism.[1,2,3,4,5] Because acquisition of drug resistance and toxic side effects limit the clinical applications of anti-cancer drugs, several studies have attempted to define the molecular and biochemical mechanisms related to the resistant phenotypes of cancer cells.[6,7,8,9,10] the key determinants of drug resistance still remain largely unknown. MicroRNAs (miRNAs) are a conserved class of small non-coding RNAs that control gene expression by inducing mRNA degradation or by suppressing mRNA translation.[12] miRNAs execute essential regulatory roles in cancer progression as oncogenes or tumor suppressors by affecting cell growth, death, migration, and differentiation; their differential expression is linked to cancer development.[13,14,15,16] In addition, several studies have highlighted emerging roles of miRNAs in anti-cancer drug resistance.[5,6,7,8,9] Accumulating evidence suggests that the miR-200 family (miR-200a, -200b, -200c, -141 and -429) regulates the pathogenesis of several types of cancer: it plays crucial roles in cell proliferation, metastasis, epithelial-mesenchymal transition, and anti-cancer drug resistance.[17,18,19,20,21,22,23,24]
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