microRNA-200a-3p increases 5-fluorouracil resistance by regulating dual specificity phosphatase 6 expression

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.

Higher intratumor than peritumor expression of DUSP6/MKP-3 is associated with recurrence after curative resection of hepatocellular carcinoma / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The MAPK phosphatases (MKPs) are a family of dual-specificity phosphatases (DUSPs) that can dephosphorylate both phosphothreonine and phosphotyrosine residues, thus inactivating MAPK signaling. DUSP6 is a cytoplasmic MKP that can inactivate ERK. DUSP6 has been implicated in the development of some tumors. The aim of this research was to investigate the expression of DUSP6 in hepatocellular carcinoma (HCC) and the correlation of DUSP6 with mitogen-activated protein kinases (MAPKs), clinicopathological characteristics, and prognosis.</p><p><b>METHODS</b>Tissues from 305 patients who had undergone hepatectomy for HCC was used in this study. The expression of DUSP6, p-ERK, p-JNK, and p-p38α was determined using tissue microarrays for immunohistochemical analysis. The prognostic value of DUSP6 and other clinicopathological factors were evaluated.</p><p><b>RESULTS</b>The expression of DUSP6 was significantly higher in the tumor tissue when compared to the peritumor or normal liver tissue (P < 0.001). Tumor DUSP6 expression was significantly associated with disease-free survival (DFS) (P = 0.013). Tumor DUSP6 expression was an independent prognostic factor for DFS (Hazard ratio = 1.635, P = 0.006).</p><p><b>CONCLUSIONS</b>DUSP6 is over expressed in tumor tissue compared to peritumor or normal liver tissue. Higher expression of DUSP6 in tumor tissue, than in peritumor tissue, is associated with the recurrence after curative resection of HCC, and the relative tumor DUSP6 expression has good power to predict the recurrence of HCC.</p>