Novel crosstalk between KLF4 and ZEB1 regulates gemcitabine resistance in pancreatic ductal adenocarcinoma
Authors: Guozhe Xian
Zhenhai Zhang
Yuan Chen
Xinxing Wang
Zhiyi Wang
Xianping Cui
Chengkun Qin
Yanliang Lin
Journal: International Journal of Oncology (2017)
Discipline: CLINICAL MEDICINE
Keywords: Pancreatic ductal adenocarcinoma; KLF4; gemcitabine resistance; miR-200b; miR-183
Affiliations: Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China., Department of Paediatrics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China., Department of Center Laboratory, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China.

Abstract:  Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with broad resistance to chemotherapeutic drugs. Krüppel-like factor 4 (KLF4) is a candidate tumor suppressor in PDAC. However, the precise role of KLF4 in gemcitabine resistance of PDAC remains largely unclear. In this study, we demonstrated that gemcitabine inhibited KLF4 expression. Moreover, gemcitabine also reduced the levels of miR‑200b and miR‑183, but promoted ZEB1 expression in PDAC cells. KLF4 knockdown blocked the expression of miR‑200b and miR‑183, and inversely, KLF4 overexpression promoted the expression of miR‑200b and miR‑183, suggesting that KLF4 positively regulated the expression of miR‑200b and miR‑183. Moreover, KLF4 knockdown enhanced ZEB1 expression and gemcitabine resistance while KLF4 overexpression induced the opposite effect. ChIP assays verified that KLF4 positively regulated the expression of miR‑200b and miR‑183 by directly binding to their promoters. Then, miR‑200b and miR‑183 directly inhibited ZEB1 expression by targeting its 3'UTR region. ZEB1 knockdown attenuated gemcitabine resistance in PDAC cells. KLF4 overexpression promoted gemcitabine sensitivity of PDAC in vivo by negatively regulating ZEB1 expression. Our results revealed that novel crosstalk between KLF4 and ZEB1 regulated gemcitabine resistance in PDAC. 

Retracted: No

PubPeer comments:
 Figure 1A. * Some parts of these panels appear to show repetitive features as marked with boxes of the same color. ![file] , 
 Thank You for your comments. Due to the change of the email address of the corresponding author, we did not see the email in time, we are very sorry. We have checked the raw data and uploaded the raw images. We have compared the images and found many differences at the indicated locations. Your comment is valuable and very helpful for the future studies. ![file] ![file] , 
 Dear Dr. Xian, The raw data - straight from the FACS machine - should consists of discrete black dots against a white background. The images you show above in #2 do not appear to show the raw data. They contain many square blocks in shades of grey, not discrete dots. Maybe the analysis was run on a compressed image? Could you please show us the original, raw, straight-from-the-machine plot, please? Either way, my concern was not about differences between the plots, but about the repetitive patterns in certain parts of the plot, which I actually still see in your analysis of the compressed plots. Example: ![file] , 
 Dr.Bik, we apologize to trouble you. We will provide another set of experimental data to the magazine for modification. Thank you for your comments! , 
 Dear Dr. Xian, I am afraid that redoing the experiment is not going to take away my concerns about the images I flagged above. Do you not have the original data to share here? Sharing the original, uncompressed images would take away any concerns we might have, assuming these do not have the duplicated areas. , 
 December 2020 correction: https: www.spandidos-publications.com 10.3892 ijo.2020.5157  Subsequently to the publication of the above article, an interested reader drew to the attention of the Editorial Office that, in Fig. 1C on p. 1242, the flow cytometric images contained what appeared to be regular and repeating groups of cells. The office consequently asked the authors to provide the raw data for these images, as they would have been generated from the printouts, and the authors were able to demonstrate that these apparent anomalies were not contained in the original data. It is possible that the anomalous appearance of the data in this Figure may have resulted either from low resolution of the images, or the Figure itself may have been compressed. We are reprinting Fig. 1C opposite, highlighting the data of interest in greater detail. We trust that this satisfies the concerns of the reader in this instance, and thank them for their enquiry to the Editorial Office. The authors also requested that, after having provided the raw data of the original image in order to clarify the concerns of the reader, they may republish Fig. 1 featuring alternative data for Fig. 1C. The revised version of Fig. 1 is consequently shown on the next page. In this figure, flow cytometric analysis demonstrated that treatment with 10 u00b5M gemcitabine induced the death of 66.5% of the BxPCu20113 cells, 29.54% of the Pancu20111 cells, and 34.52% of the MIApacau20112 cells (Fig. 1C). The authors confirm that these data support the main conclusions presented in their paper, and are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a Corrigendum. They also apologise to the readership for any inconvenience caused. [the original article was published in International Journal of Oncology 51: 1239u20111248, 2017; DOI: 10.3892 ijo.2017.4099]. ,