RETRACTED: The miR 495-UBE2C-ABCG2/ERCC1 axis reverses cisplatin resistance by downregulating drug resistance genes in cisplatin-resistant non-small cell lung cancer cells
Authors: Juanjuan Dai
Yan Wu
Kaikai Gong
Sichuan Xi
Jing Du
Lijuan Yang
Dan Jin
Jiwei Guo
Weiwei Chen
Shuang Miao
Journal: EBioMedicine (2018)
Discipline: CLINICAL MEDICINE
Keywords: ABCG2; Cisplatin resistant; EMT; ERCC1; MicroRNA-495
Affiliations: Cancer research institute, Binzhou Medical University Hospital, Binzhou 256603, PR China. Electronic address: ., Department of Pain Management, Binzhou Medical University Hospital, Binzhou 256603, PR China., Cancer research institute, Binzhou Medical University Hospital, Binzhou 256603, PR China.

Abstract:  Cisplatin (DDP) resistance has become the leading cause of mortality in non-small cell lung cancer (NSCLC). miRNA dysregulation significantly contributes to tumor progression. In this study, we found that miR-495 was significantly downregulated in lung cancer tissue specimens. This study aimed to elucidate the functions, direct target genes, and molecular mechanisms of miR-495 in lung cancer. miR-495 downregulated its substrate UBE2C through direct interaction with UBE2C 3'- untranslated region. UBE2C is a proto-oncogene activated in lung cancer; however, its role in chemotherapeutic resistance is unclear. Herein, UBE2C expression levels were higher in DDP-resistant NSCLC cells; this was associated with the proliferation, invasion, and DDP resistance in induced cisplatin-resistant NSCLC cells. Furthermore, epithelial-mesenchymal transitions (EMT) contributed to DDP resistance. Moreover, UBE2C knockdown downregulated vimentin. In contrast, E-cadherin was upregulated. Importantly, miR-495 and UBE2C were associated with cisplatin resistance. We attempted to evaluate their effects on cell proliferation and cisplatin resistance. We also performed EMT, cell migration, and invasion assays in DDP-resistant NSCLC cells overexpressing miR-495 and under-expressing UBE2C. Furthermore, in silico assays coupled with western blotting and luciferase assays revealed that UBE2C directly binds to the 5'-UTR of the drug-resistance genes ABCG2 and ERCC1. Furthermore, miR-495 downregulated ABCG2 and ERCC1 via regulation of UBE2C. Together, the present results indicate that the miR495-UBE2C-ABCG2/ERCC1 axis reverses DDP resistance via downregulation of anti-drug genes and reducing EMT in DDP-resistant NSCLC cells. 

Retracted: Yes

PubPeer comments:
 Another paper with image concerns by this group. Highlighted here is Figure 1A. Common background features for the miR-495 and GAPDH bands suggest that the two images are misaligned. Immediately below I have flipped the GAPDH band horizontally and shifted it one lane to the left, at which point the common background features (marked with yellow boxes) appear to better align. I have other concerns with this image, but if the authors are able to post here the original uncropped scans of the gels, those concerns may be alleviated. *** Flipped GAPDH and contrast enhanced for comparison.  *** Original  , 
 Dear Actinopolyspora Biskrensis, thank you very much for reminding us the mistake. We have checked our original data of images and found that this error. We will submit the right image to the journal to make a correction. Fortunately, this correction does not affect the results, discussions and conclusions of this paper. We apologize for such an inadvertent error and thank you again for the comments. , 
 #2 Thank you for your reply. I am pleased that you were able to find the original data. Could you please post the original uncropped scan here so other readers can see? , 
 Dear Actinopolyspora Biskrensis, Sorry for the late reply. Thank you very much for your comments on our research. It will be helpful for our future work. Now let us explain it. When we were preparing the results in Fig 1A, the bands of GAPDH were unintentionally mixed up with the monitoring and control system band. In addition, we carelessly mistook for the order of the samples leading to reverse the monitoring and control system band and then aligned with the band of miR-495. The corrected version of Fig 1A is included below. This unintentional error also has no bearing on the work s scientific conclusions in any way. The authors apologize to the readership for any inconvenience caused. We have contacted the editorial office of EBioMedicine for correction and the corrected data will be published soon. Sincerely, JW Guo  , 
 An additional concern: Figure 1E appears to have some repetition in the Tubulin band. See cyan colored boxes (also noted by arrows). Both original and false color shown below. There may be other repetitions throughout this figure. ***  , 
 There seem to be duplicate images in Figure 1 that overlap with Figure 1 of another article of the same author that is published in the same journal in the same issue https: pubpeer.com publications B7B7BAA24DEDB2643B70ADECA5DCC9  , 
 There are more duplicates images There seem to be duplicate images in Figure 1 and 2 that overlap with Figure 1 of another article of the same author that is published in the same journal in the same issue https: pubpeer.com publications B7B7BAA24DEDB2643B70ADECA5DCC9  , 
 FIG4K duplication  FIG5N duplication  FIG6A multiple artifacts in high resolution view  FIG6I circular artifacts and duplication  FIG7G duplicated picture  , 
 Thanks for the comments. For the Fig 1J, 2E and 7J, we have checked our original data of images and found that the errors for Fig 1J. After our investigation, we draw the following conclusions: the graduated student conducted multiple samples together for transwell assay and mistakenly mixed up the data for Fig 1J, 2E and 7J. When organizing the results, the Fig 1J (miR-495 inhibitor and control group) was unintentionally duplicated from Fig 2E (DDP treatment in the control group) and 7J (PBS treatment in the miR-495+control group). We show the corrected the Fig 1J as following. For Fig 4K and 5N, we have carefully checked our original data of images and found that the errors. The possible reason is that during organizing the results, the image of miR-495 inhibitors+siUBE2C group was unintentionally duplicated from the control group in Fig 4K in addition the image of DDP treatment was unintentionally duplicated from the control treatment in the A549 DDP cell group in Fig 5N, in which the multiple samples were conducted together for transwell assay. We show the corrected the Fig 4K and 5N as following. For the Fig 7I and 8G, we have carefully checked our original data of images and found that the errors. When organizing the results, the image of the DDP treatment was unintentionally duplicated from the control treatment in the miR-495+siUBE2C group in Fig 7I. The IHC image of UBE2C was unintentionally duplicated into the image of ERCC1 in Fig 8G. We show the corrected the Fig 7I and 8G as following. In a conclusion, the unintentional error has no bearing on the work s scientific conclusions. we have contacted the editorial office of EBioMedicine for correction.  , 
 Could the authors please upload a high resolution image of the corrected Figure 7I? Thank you. , 
 There are more duplicated images between this publication and doi: 10.1016 j.ebiom.2018.10.04. Perhaps, the  error-prone graduate student needs some coaching. The colony forming assays between Figure S3 and Figure 6 of another article of the same author that is published in the same journal of the same issue are identical https: pubpeer.com publications B7B7BAA24DEDB2643B70ADECA5DCC9  , 
 The colony forming assays in figure 4j, in turn, seem to be borrowed from another paper. https: pubpeer.com publications 77517B8E35CDC292739BE7D1033984  , 
 This article has been retracted at the request of the Authors. After publication of our EBioMedicine article [1], several concerns were raised with respect to the veracity of the data. Evidence of image duplication was found within figures relating to the transwell assays, scratch assays, immunohistochemistry images, and clone formation assays. The corresponding author Jiwei Guo and all co-authors would like to withdraw this article to maintain the integrity of the scientific record. The authors sincerely apologise to the editors and journal readership for these oversights and inconvenience that this may have caused. ,