CSN6 Promotes the Migration and Invasion of Cervical Cancer Cells by Inhibiting Autophagic Degradation of Cathepsin L
Authors: Cheng Chen
Miao-Miao Sang
Wen-Tao Zhu
Zun Mao
Dong-Sheng Pei
Yu-Sen Gong
Journal: International Journal of Biological Sciences (2019)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: CSN6; CTSL; autophagy; cervical cancer; metastasis.
Affiliations: Laboratory of Clinical and Experimental Pathology, Xuzhou Medical University, Xuzhou 221004, Jiangsu, China., Department of Rehabilitation, The Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China.

Abstract:  CSN6 is one subunit of the highly conserved constitutive photomorphogenesis 9 (COP9) signalosome (CSN), which is overexpressed in many types of cancers, and has received great attention as a regulator of the degradation of cancer-related proteins, suggesting its importance in oncogenic activity. CSN6 has been shown to be overexpressed in cervical cancer (CC) and associated with CC development. CC remains to be one of the most aggressive cancers affecting women. Cathepsin L (CTSL), significantly associated with the autophagy, plays a critical role in degradation of extracellular matrix for metastasis. However, the detailed biological functions of CSN6 on CTSL in CC metastasis have not been well clarified. Our data has shown that CSN6 and CTSL are positively correlated. The overexpression of CSN6 and CTSL might be a strong indicator for CC enhanced aggressiveness. CSN6 could suppress the degradation of CTSL, then facilitated the migration and invasion of CC cells. Interestingly, our results indicated that autophagy is essential for decreasing CTSL, while CSN6 could inhibit the autophagy ability of CC cells. In addition, blocking of the mammalian target of rapamycin (mTOR) pathway reversed CSN6-mediated autophagy inhibition. We further demonstrated that CSN6 positively regulated CTSL expression through an autophagy-lysosomal system. Taken together, we concluded that CSN6 might promote the migration and invasion of cervical cancer cells by inhibiting autophagic degradation of CTSL and serve as a potential gene therapy target for the treatment of CC metastasis. 

Retracted: No

PubPeer comments:
 Figure 2 3 4 9: * Some panels appear to show an overlap. And that is an understatement. Boxes of the same color drawn by an image forensics program. Could the authors please check what might have gone wrong here?  This work was supported by the National Natural Science Foundation of China (No. 81572349, 81872080), Jiangsu Provincial Medical Talent (ZDRCA 2016055), the Science and Technology Department of Jiangsu Province (BK20181148, BK20161157) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).  , 
 Dear Elisabeth M Bik We really appreciate your careful reviewing of our article, which will be helpful for us to improve the quality of the study. The first author, Zun Mao, graduated and left our university, who mainly concentrated on the experiments of this research. I have contacted with her to proof the data and provide further explanation. , 
 Dear Prof. Elisabeth M Bik Thanks for your attention to this article and we deeply apologize that this careless mistake was not identified before publication. As the first author of this manuscript, I have proofed the original data to identify the source of these errors and analyzed it very carefully. We performed multiple parallel experiments in the migration and invasion assay 3 years ago. In order to ensure the same size of the image after scaling down, we put many images of later experiments on software related to early experiments for processing at the same time. We found that indeed some panels look similar with others. Due to the high similarity of the experiments themselves, part of them were could not be updated and saved in time after scaling down. Some original photos in early experiments might be covered by later photos. The error was generated when the Figure was assembled. We failed to identify this error during manuscript preparation. Thanks for catching this error and we deeply apologize that this careless mistake was not identified before publication. However, this mistake does not affect the conclusions of this report. We sincerely apologize for this mistake due to similarities between some panels. Attached are the corrected figures. For further clarity, we can repeat this part of our research and we will show you the updated result if necessary. At last, thanks for your attention and great comments for our work. Best wishes Zun Mao        , 
 #3 Thank you for responding. It will be interesting to see how the journal reacts to this new data. , 
 #3 Thank you for providing explanation and corrections. However, I do not accept your assertion that  this mistake does not affect the conclusions of this report . Just take a look of the two versions of your Fig 2H and Fig 3C. Please compare those panels questioned by Dr. Bik (#1) and the corresponding ones in you new version. We can see EVERY single one of these 17 images is so different now from then, some 53% of your images. If half of your images are likely highly unreliable, how can the study findings not be affected? In addition, repeating experiment or not is totally your call; however, a repeated set of experiments is a totally different set of data. For a new set of data, I d say please submit as a new manuscript, rather than piggybacking on the very wrong current published paper.  , 
 Thank you Dr Mao, for replacing the image panels in half of these images with new ones. However, I completely agree with Tulipa in Comment #5 that these replacements do not restore the faith in this data or in the remainder of the images. How can you say that these 17 mistakes do  not affect the conclusions of this report ? At best, it appears to show a lack of proper labeling of the photos obtained in your experiments. While one mistake could be attributed to an honest error, 17 of these mislabelings show a complete lack of keeping track of which photo belonged to which experiment. And that also casts great concerns about the labeling accuracy of the other data presented in your paper. Especially in the case of similar-looking photos, one should be extra careful in labeling them. That does not appear to have happened here. In fact, there is an additional duplication that I just noticed, and that is still present in the new set of figures. In Figure 2H, the SiHa siCSN6 migration and invasion panels still appear to overlap. I have marked that here in red:  At this point, I have lost all faith in the reliability of your paper, and I am deeply concerned about how casually you replaced these images with other data. ,