Overexpression of miR-203 increases the sensitivity of NSCLC A549/H460 cell lines to cisplatin by targeting Dickkopf-1
Authors: Guowei Zhang
Ruirui Cheng
Chunya Lu
Guojun Zhang
Guoqiang Zhao
Journal: Oncology Reports (2017)
Discipline: CLINICAL MEDICINE
Keywords: lung cancer; non-small cell lung cancer; NSCLC; adenocarcinoma; cisplatin resistance

Abstract:  The number of new lung cancer cases diagnosed yearly is high, and the mortality rate has not substantially declined. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and adenocarcinoma accounts for the largest proportion of NSCLC. Currently, platinum-based combined chemotherapy, particularly cisplatin (DDP) is still the main form of treatment for advanced NSCLC. However, cisplatin resistance often occurs in patients who receive chemotherapy. Previous studies offer various explanations for how miRNAs affect cisplatin resistance, but the underlying mechanism remains largely unknown. The present study was designed to focus on miR-203 and Dickkopf-1 (DKK1), investigating the potential mechanisms involved in cisplatin resistance in tissues of lung adenocarcinoma and A549/H460 cell lines. In DDP-sensitive NSCLC samples, miR-203 was expressed at a higher level when compared with this level in DDP-insensitive samples, while DKK1 mRNA was expressed at a relatively low level as indicated by qRT-PCR. Dual luciferase reporter assay revealed that DKK1 is a target gene of miR-203 in A549 and H460 cells. Upregulation of miR-203 reduced the IC50 value of cisplatin in the A549 and H460 cells by inhibiting cell growth and promoting cell apoptosis. Similar effects of tumor inhibition and cisplatin sensitization were verified in vivo. Further research showed that both overexpression of miR-203 and knockdown of DKK1 increased the sensitization to DDP with a lower IC50 value. Upon DKK1 knockdown, overexpression of miR-203 had no added effects on the sensitivity of the cells. In addition, miR-203 was unable to sensitize cells with DKK1 that lacked the 3' untranslated region (3'UTR). We conclude that miR-203 targets the 3'UTR of DKK1, and increases cisplatin sensitivity in A549/H460 cell lines. 

Retracted: No

PubPeer comments:
 At left:  Figure 5. ... nude mouse tumor xenografts derived from the A549 and H460 cells... (A) ... nude mouse xenograft tumors presented by luciferase signal detected using in vivo small animal imaging. At right:  Figure 4. Overexpression of miR-519d restricted tumor growth in vivo. (**b**) The luciferase signal of miR-519d agomir group cells was relatively weaker than the signal shown by the Blank group and the scramble group in A549 cells. (**d**) The luciferase signal of the cells in the miR-519d agomir group was significantly weaker than the signal shown by the Blank group and the scramble group in H1299 cells. From  Overexpression of miR-519d in lung adenocarcinoma inhibits cell proliferation and invasion via the association of eIF4H [(Bai et al 2017)] . ![file] Replicated mice marked with stars. , 
 #1 Fig 5(A) again. Please compare with [Right]  Fig. 1 Myricetin inhibits the proliferation of HGC-27 and SGC7901 cells....c The luciferase signal was relatively weaker in the myricetin group than in the control groups . From  Myricetin inhibits proliferation and induces apoptosis and cell cycle arrest in gastric cancer cells [(Feng et al 2015)] . Flipped horizontally for ease of comparison. ![file] One mouse displays the tumor-slowing effect of miR-203 cisplatin **and** of myricetin, though with different luciferase activity. , 
 Fig 4A, B: ![file] Two FACS plots are unexpectedly similar to plots in Fig 4A of  u03b1-Solanine Modulates the Radiosensitivity of Esophageal Cancer Cells by Inducing MicroRNA 138 Expression [(Wang et al. 2016)] ![file] ![file] Another panel from Fig 4 A B appears in Figure 4A of  The long noncoding RNA CASC2 inhibits tumorigenesis through modulating the expression of PTEN by targeting miR-18a-5p in esophageal carcinoma [(Zhang et al 2017)] . ![file] , 
 [Perhaps a systemic problem] . Journals and readers may wish to proceed with caution. ,