miR-200c inhibits TGF-β-induced-EMT to restore trastuzumab sensitivity by targeting ZEB1 and ZEB2 in gastric cancer
Authors: Riyang Zhao
Xinliang Zhou
Lianmei Zhao
Jing Zuo
Jing Han
Meixiang Sang
Baoen Shan
Zhisong Fan
Xian-De Liu
Yudong Wang
Yalei Lv
Xinyi Men
Journal: Cancer gene therapy (2018)
Discipline: CLINICAL MEDICINE
Keywords: Gastric cancer; Trastuzumab resistance; HER2; Epithelial-mesenchymal transition; E-cadherin
Affiliations: Department of Oncology, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People's Republic of China., Department of Pediatrics, the Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People's Republic of China., Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People's Republic of China., Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Research Center, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People's Republic of China. ., Tumor Research Institute, the Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050011, People's Republic of China. .

Abstract:  Gastric cancer is the fifth most common malignancy in the world, with Eastern Asia as one of areas with the highest incidence rates. Trastuzumab, a HER2-targeting antibody, combined with chemotherapy has been successfully employed for the gastric cancer patients with HER2 overexpression/amplification. However, trastuzumab resistance is a major problem in clinical practice. Here we observed that the trastuzumab-resistant gastric cancer cell line NCI-N87/TR expressed high levels of epithelial-mesenchymal transition factors and demonstrated increased migration and invasion capability compared with NCI-N87 cells. Downregulated E-cadherin and increased N-cadherin, TGF-β, ZEB1, ZEB2, TWIST1, and Snail were detected in NCI-N87/TR cells. We also found that miR-200c was downregulated in NCI-N87/TR cells compared with parental cells NCI-87 by qRT-PCR. Treatment with TGF-β downregulated the expression of miR-200c and upregulated ZEB2, and significantly decreased the trastuzumab sensitivity of NCI-N87 cells. miR-200c restored trastuzumab sensitivity and inhibited migration and invasion through suppressing ZEB1 and ZEB2. In summary, TGF-β/ZEB2 axis plays an encouraging role in trastuzumab resistance of gastric cancer, while miR-200c overexpression downregulates ZEB1/ZEB2 and resensitizes drugs resistance. Our findings might provide a potential therapeutic strategy for trastuzumab resistance of gastric cancer. 

Retracted: No

PubPeer comments:
 This paper figures on the list of  The best of Cancer Gene Therapy 2018-2019 . It also contains many cases where data have been duplicated and presented as something else. Figure 2A and Figure 4D: one micrograph has been duplicated and presented as somethings else. Figure 2C and Figure 4C: one micrograph has been duplicated and presented as somethings else. Figure 3B and Figure 4J: the two beta-actin bands are more similar than you would expect. , 
 Here is the illustration: ![file] ![file] , 
 Since this article recently was corrected, I cross checked with other papers from the same research group. There seems to be some re-use of data going on: Western immunoblotting data in Figure 1B have been taken from two other papers from 2015, manipulated and presented as something else. ![file] , 
 No response, but more serious problems detected in this article: Many of the PCR primers listed in Table S1 are incorrect. Using NCBI nucleotide blast with filter for Humans retrieves no similarities for many primers. However, some distant species are detected. Interestingly, European badger is again highly represented, which seem to be popular in papermill papers from China. ![file] , 
 Just an update. This additonal duplications was not mentioned earlier. The published correction does not cover several concerns mentioned earlier (reuse of data from other publications and PCR primer sequences). ![file] ,