Upregulation of long noncoding RNA ZEB1-AS1 promotes tumor metastasis and predicts poor prognosis in hepatocellular carcinoma
Authors: T Li
H Chen
Q Zhan
Y Shi
H Li
D Cheng
B Shen
C Shen
X Deng
C Peng
Z Zhu
J Xie
Z Wu
Journal: Oncogene (2016)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Hepatocellular carcinoma; lncRNAs; ZEB1-AS1; tumor progression; DNA methylation
Affiliations: Department of Hepato-Bilio-Pancreatic Surgery, Shanghai Institute of Digestive Surgery, Rui Jin Hospital affiliated with Shanghai Jiaotong University, Shanghai, People's Republic of China.

Abstract:  Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related mortality worldwide. Despite progress in diagnostics and treatment of HCC, its prognosis remains poor. Emerging studies showed that long noncoding RNAs (lncRNAs) have crucial regulatory roles in cancer biology. In the current study, differentially expressed lncRNAs between HCC and paired non-tumor tissues were identified using microarrays. The effects of a specific differentially expressed lncRNA (termed ZEB1-AS1) on tumor progression were investigated in vitro and in vivo. We found that ZEB1-AS1 is frequently upregulated in HCC samples, especially in metastatic tumor tissues. DNA methylation analysis shows a tumor-specific ZEB1-AS1 promoter hypomethylation. Aberrant methylation is tightly correlated with overexpression of ZEB1-AS1 in HCC. Patients with ZEB1-AS1 hypomethylation or with high ZEB1-AS1 expression have poor recurrence-free survival. Functionally, ZEB1-AS1 promotes tumor growth and metastasis, acts as an oncogene in HCC. The ZEB1-AS1 gene is located in physical contiguity with ZEB1 and positively regulates the ZEB1 expression. ZEB1 inhibition partially abrogates ZEB1-AS1-induced epithelial to mesenchymal transition (EMT) and cancer metastasis. Our results provide novel insights into the function of lncRNA-driven hepatocarcinogenesis, highlight the important role of ZEB1-AS1 and ZEB1 in HCC progression, and indicate that ZEB1-AS1 may be served as a valuable prognostic biomarker for HCC. 

Retracted: No

PubPeer comments:
 Figure 3b: a part of a micrograph (Huh7 cells) are surprisingly similar a part of another micrograph (SMMC7721 cells). Figure 5e: two areas in one micrograph (control) have been duplicated and presented in the same micrograph. This article has been cited at least 214 times and figures as  The best of Oncogene 2016-2017 . ![file] , 
 Fig 5a. ![file] , 
 Figure 4D appears to have some repetitive parts. I did not try to mark them all. ![file] , 
 Figure 6G: * Teal boxes: two panels appear to have the same group of cells, but then differ in all the other cells. ![file] , 
 According to Editor-in-Chief Justin Stebbing and senior publishing manager Lucinda Haines they are investigating. In March 14 they  reached out to the authors to clarify the points raised and a response has now been received which is being considered by the editors and our research integrity team. An expression of concern has not yet been published. , 
 More than two weeks after they received the response from the authors. Still no action. One more citation (total 218). , 
 In addition to the above mentioned issues, looking at the figures, it seems that a large amount of data is based on the SMMC-7721 (RRID:CVCL_0534) cell line. This cell line is since 2015 on the ICLAC list of contaminated cell lines. Shown to be a HeLa derivative (PubMed=26116706; PubMed=28807831). Originally thought to originate from a hepatocellular carcinoma. Additionally, the authors write in the Methods section that the cell lines used were purchased from the ATCC, though this is very curious, as the SMMC-7221 cell line was established by Chinese researchers and is NOT distributed by the ATCC. https: web.expasy.org cellosaurus CVCL_0534 , 
 Fig 4F ![file] , 
 still 4F An additional pair, maybe more... ![file] , 
 ![file] A third pair still in 4F I try to make them together Maybe more.... , 
 Three weeks since the editorial office got a response from the authors. Additional problematic issues reported. Still no action from the publisher. , 
 In March 14 they  reached out to the authors to clarify the points raised and a response has now been received which is being considered by the editors and our research integrity team. Almost six weeks has passed, still no action. You can still buy this totally falsified article for $32. , 
 #12 Thank you very much for your attention and comments. We have conducted a relevant investigation on our experiments and submitted the results to the editorial department. We will keep in touch with the editors. Thanks a lot. , 
 Eight weeks have passed since the Oncogene editorial office received a response from the authors. Still no action. , 
 Nine weeks have passed since the Oncogene editorial office received a response from the authors. Now 222 citations. , 
 #15 Thank you for your sustained attention. Maybe due to the limitations of internet in China, we failed to reply you here before. We are so sorry for this. We have been communicating with the magazine after getting the inquiry email from the magazine,and we hope to provide more detailed raw data of the repeated experiments at that time. Due to the Shanghai s COVID-19 lockdown policy, we need time to deal with it. Anyway, we sincerely apologize for our article. We will let you know if it goes progress. Thanks a lot. , 
 There are no excuses for the obvious falsification of data we have identified in several figures. It make no sense to provide new data when the original data were falsified. , 
 Thirteen weeks since the Oncogene editorial office received a report from the authors of the fabricated paper. Still no action. Now 223 citations. , 
 Retraction, 30 September 2022: https: www.nature.com articles s41388-022-02480-x.pdf  The Editor-in-Chief has retracted this article. After publication, concerns were raised regarding potential repetitive elements in the following figures: * Fig. 3B between the ZEB1-AS1 Huh7 and SMMC7721 images; * Fig. 4D within various images; * Fig. 4F between the SMMC7721 Control and ZEB1-AS1 images; * Fig. 5A within the ZEB1-AS1 image; * Fig. 5E within the Control image; * Fig. 6G between the siZEB1-AS1 Huh7 and SMMC7721 images. The authors were unable to provide the original images used for the figures to address these concerns. Additionally, the study used the SMMC-7721 and L02 cell lines, which are known to be contaminated with HeLa. The Editor-in-Chief therefore no longer has confidence in the presented data. T. Li, C. Shen, D. Cheng, Z. Wu, X. Deng, H. Chen, C. Peng, H. Li, Q. Zhan and Z. Zhu have not responded to any correspondence from the editor or publisher about this retraction notice. The Publisher has not been able to obtain a current email address for J Xie, Y Shi and B Shen. ,