GP73 promotes epithelial–mesenchymal transition and invasion partly by activating TGF-β1/Smad2 signaling in hepatocellular carcinoma
Authors: Hua Zhang
Huarong Zhao
Ruili Zhang
Zhifang Yang
Qiang Liu
Rui Mao
Tuerxun Ailijiang
Yongxing Bao
Chunli Jia
Zhipeng Li
Ying Yang
Sha Ya
Journal: Carcinogenesis (2018)
Discipline: CLINICAL MEDICINE
Keywords: transforming growth factor-β1; TGF-β1 signaling pathways; cell metastasis; epithelial-mesenchymal transition; EMT
Affiliations: Department of Cancer Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China., Department of Urology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, China.

Abstract:  The transforming growth factor-β1 (TGF-β1) signaling pathways contribute to cell metastasis and epithelial-mesenchymal transition (EMT). Golgi protein 73 (GP73), a type II transmembrane protein in the Golgi apparatus, was initially regarded as a potential biomarker for the diagnosis of hepatocellular carcinoma (HCC). Recently, it was reported that GP73 acts as a key oncogene by promoting HCC growth and metastasis. However, the role of GP73 in metastasis, especially when involving signaling pathways, is uncertain. Here, we report that GP73, which is upregulated in HCC tissues and cell lines, is associated with tumor size, tumor node metastasis stage, distant metastasis and vascular invasion. The ectopic overexpression of GP73 increased HCC cell invasion, EMT and metastasis both in vitro and in vivo. Conversely, GP73 knockdown inhibited invasion and EMT. Moreover, GP73 enhanced p-Smad2 and p-Smad3 levels by mediating TGF-β1, thus leading to the promotion of EMT and invasion in HCC cells. In contrast, we used SB431542 (SB) to repress p-Smad2 and p-Smad3 expression, which resulted in a reversion of EMT. Furthermore, when the TGF-β1/Smad pathway was blocked, upregulation of GP73 still caused an enhanced EMT and invasion, and downregulation of GP73 resulted in a decreased in EMT and invasion. In clinical HCC samples, GP73 positively correlated with TGF-β1/Smad2, which was upregulated in HCC. Taken together, our findings highlight the important role of GP73 in regulating EMT and metastasis in HCC partly by targeting TGF-β1/Smad2 signaling, suggesting that GP73 may represent a novel potential therapeutic target and prognostic marker for the treatment and diagnosis of HCC. 

Retracted: No

PubPeer comments:
 Figure 2A and Figure 3A: Several panels look remarkably similar to panels in Figure 4A of Ying Yang et al., Oncology Reports 37: 1182-1188, 2017, DOI: 10.3892 or.2017.5351, https: pubpeer.com publications B16D89FE99477155F01FBD827FA496 ![file] ![file]  This work was supported by grants from the National Natural Science Foundation of China (81560388), the Natural Science Foundation of Xinjiang Uygur Autonomous Region (2015211C079), The Postgraduate Innovation research Foundation of Xinjiang Uygur Autonomous Region (XJGRI2017082). , 
 Figure 2B and 4C: Some panels representing different cell lines and conditions appear to look similar (wine-red and mustard boxes). ![file] , 
 Figure 1B and 4B: Some bands appear to look similar, as marked with orange and blue arrows. Could the authors please provide original blots to take away any concerns? ![file] , 
 Figure 5: ![file] , 
 #1 Dear Elisabeth M Bikuff1a Thank you for your interest of our study and pointing out this mistake . GP73 and epithelial to mesenchymal transformation related protein expressions were detected by Western blot. After checking the original data, we found that GP73, E-cadherin, Vimentin, u03b2-actin and other indicators were all detected, but the panels were reused. The paper of Oncology Reports in 2017 was the result of the pre-experiment, and the data of Carcinogenesis was re-verification of Western blot in 2018. We have been aware of the error and are now applying for the correction with the editor office of carcinogensis. This error will not affect the final conclusion. We apologize for the inconvenience. Best regards, YingYang. , 
 #2 #4 Dear Elisabeth M Bikuff0c We appreciate your interest in our work and bringing the issue to our attention. In Figure 2B and Figure 4C, Transewell assay was done to explore the role of GP73 in invasion in HCC cells. We immediately checked our original data and found that we put the same pictures for shGP73 group and shCon group in SK-Hep-1 cells in Figure 2B for Con-TGF-u03b21 group and Con+TGF-u03b21 group by mistake in Figure 4C.In addition, Figures 5C, the panel for the u2018sh-Con groupu2019 with TGFu03b21+SB treatment was incorrectly chosen. The reason was that Transwell pictures in SK-Hep-1 group were not named clearly at that time, so there was error in the image typesetting. We sincerely apologize for our mistakes and any inconvenience caused to readers. Now, we have contacted with the editor office of carcinogensis to make correction. Again many thanks for your comments. YingYang. , 
 #3 Dear Elisabeth M Bikuff0c Thank you for your interest of our study and pointing the mistakes out. In Figure 1B and Figure 4B, GP73 and Vimentin protein expressions were detected by Western blot. After checking our original data, we found that we put the same picture for Vimentin protein strip and GP73 protein strip by carelessly. we mistakenly reused the panel of Vimentin expression in the process of displaying the pictures. We apologize for our inadvertent error and any inconvenience caused to readers. Now, we have contacted with the editor office of carcinogensis to make correction. Again many thanks for your comments. Best regards, YingYang. , 
 Dear Dr. Yang, I very much appreciate your reply and checking all the figures. So, if I understand correctly, you confirmed that: * Several Western Blots had been incorrectly reused to represent other proteins of cell lines than in another paper from your lab * Four Transwell panels had been incorrectly reused to represent different experiment * Four lanes in a Western blot were inadvertently reshuffled and made to represent a different protein. With all these inadvertent errors you confirmed, can you please let us know how the remainder of the data in this paper can be trusted? At this point, would it not be better to retract the paper? , 
 Dear Elisabeth M Bikuff1a We appreciate your interest in our work and bringing the issue to our attention. We have found the original experimental data at that time and sent them to the editorial Office of the magazine. Our experimental results are of important research significance, and the experimental results of the article are correct, which have been verified by other researchers, and we are very confirm that these errors did not affect the conclusions reported in the study. We apologize for our errors and any inconvenience caused. In addition, we have realize that we must deal with scientific papers with more careful and rigorous attitude from now on. We sincerely hope the editors allow us to make a Corrigendum, for the experiment of this article took us more than 2 year to complete and this paper is of great importance to us. Again many thanks for your comments. YingYang. ,