MicroRNA let-7c Inhibits Cell Proliferation and Induces Cell Cycle Arrest by Targeting CDC25A in Human Hepatocellular Carcinoma
Authors: Lingjiao Wu
Xiuming Zhu
Zhijian Yang
Qiangfeng Wang
Fusheng Wu
Jian Yao
Han Jiang
Journal: PLoS ONE (2015)
Discipline: Multidisciplinary
Keywords: let-7c; hepatocellular carcinoma; CDC25A; cell cycle regulator; tumor growth
Affiliations: Department of Surgical Oncology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China; Department of Oncology, Zhejiang Provincial People's Hospital, Hangzhou, China., State key Laboratory for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China., Department of Surgical Oncology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China., Origin Biosciences Inc, Nanjing, China.

Abstract:  Down-regulation of the microRNA let-7c plays an important role in the pathogenesis of human hepatocellular carcinoma (HCC). The aim of the present study was to determine whether the cell cycle regulator CDC25A is involved in the antitumor effect of let-7c in HCC. The expression levels of let-7c in HCC cell lines were examined by quantitative real-time PCR, and a let-7c agomir was transfected into HCC cells to overexpress let-7c. The effects of let-7c on HCC proliferation, apoptosis and cell cycle were analyzed. The in vivo tumor-inhibitory efficacy of let-7c was evaluated in a xenograft mouse model of HCC. Luciferase reporter assays and western blotting were conducted to identify the targets of let-7c and to determine the effects of let-7c on CDC25A, CyclinD1, CDK6, pRb and E2F2 expression. The results showed that the expression levels of let-7c were significantly decreased in HCC cell lines. Overexpression of let-7c repressed cell growth, induced cell apoptosis, led to G1 cell cycle arrest in vitro, and suppressed tumor growth in a HepG2 xenograft model in vivo. The luciferase reporter assay showed that CDC25A was a direct target of let-7c, and that let-7c inhibited the expression of CDC25A protein by directly targeting its 3' UTR. Restoration of CDC25A induced a let-7c-mediated G1-to-S phase transition. Western blot analysis demonstrated that overexpression of let-7c decreased CyclinD1, CDK6, pRb and E2F2 protein levels. In conclusion, this study indicates that let-7c suppresses HCC progression, possibly by directly targeting the cell cycle regulator CDC25A and indirectly affecting its downstream target molecules. Let-7c may therefore be an effective therapeutic target for HCC. 

Retracted: No

PubPeer comments:
 Figure 3C: An image of a tumor has been duplicated and manipulated. Figure 4D: An image of a tumor has been duplicated and manipulated. ![file] , 
 Any developement in this case? , 
 Thanks for the kind reminding. According to your comment, we found out the original images, in Fig 3C control group, we missed the tumor 4 unintentionally (see Fig3C). For Fig 4D, combined multiple images, we misused the same image twice. Still, we misused the pictures and this is all of our fault. We deeply apologize for this matter. I have contacted the Corresponding Author of this paper Dr. Wu, and we have been get in touch with the journal to correct this mistake. Thanks for pointing out this problem.![file] , 
 Still no action taken. I can add that the Western immunoblots look suspicious (diffuse bands, strange background) and the presented tumors in Figure 3 do not correspond to the graph showing the tumor size. The variation in tumor size for the treated group is much larger than showed in the graph. ![file] , 
 #4 Thanks for the kind reminding. We first saw and know your comment in July 2021. Based on your comments, I quickly contacted the magazine and the corresponding author of the article. We have also made relevant explanations to your questions. At the request of the magazine, we promptly sent the original data of the article to the publication ethics team, and gave a point by point explanation to the questions raised by the magazine in July 29, 2021. After another review by the publication ethics team, they approved it. The screenshot below is our contact with the magazine. ![file] , 
 #4 In addition, in response to the two questions you raised in particular. First, the Western immunoblots images, we have sent the original images to the publication ethics team of the journal, review again and they finally approved it. Second, regarding the tumor images in Figure 3: we found out the original images (see Fig 1), in Fig 3C control group, we missed the tumor 4 unintentionally and misused tumor 6 twice (see Fig 1). Still, we misused the picture and this is all of our fault. We deeply apologize for this matter. We have corrected Fig 3C (see Update Fig 3C). After we checked the data carefully, the data is correct. Thanks again for pointing out this problem. Fig 1 ![file] Update Fig 3C ![file] Finally, I am very sorry that my mistake has caused trouble to the editorial department and readers. Thanks again to the editorial department for helping me find the errors in the article and giving me the opportunity to correct them. This experience will also guide me to be more serious and rigorous when editing pictures in the future. ,