Interplay between cancer cells and M2 macrophages is necessary for miR-550a-3-5p down-regulation-mediated HPV-positive OSCC progression
Authors: Jian Jiang
Ke Wang
Ya-Ling Tang
Xiang-Hua Yu
Xin-Wei Qiao
Jia-Shun Wu
Jing-Biao Wu
Ya-Jie Tang
Mei-Chang Huang
Wei-Long Zhang
Ming-Xin Cao
Xin-Hua Liang
Journal: Journal of Experimental & Clinical Cancer Research (2020)
Discipline: CLINICAL MEDICINE
Keywords: EMT; Human papillomavirus; Microenvironment; OSCC; microRNA.
Affiliations: State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, 610041, Sichuan, China., State Key Laboratory of Microbial Technology, Shandong University, Qingdao, 266237, Shandong, China., Department of Head and Neck Surgery, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610041, Sichuan, China., State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, No.14, Sec.3, Renminnan Road, Chengdu, 610041, Sichuan, China. .

Abstract:  Background: Human papillomavirus (HPV)-positive oral squamous cell carcinoma (OSCC) is increasing worldwide with typically higher grade and stage, while better prognosis. microRNAs (miRNAs) has been shown to play a critical role in cancer, however, their role in HPV-positive OSCC progression remains unclear. Methods: miRNA microarray was performed to identify differentially expressed miRNAs. qRT-PCR and FISH were performed to determine the relative expression of miR-550a-3-5p. CCK-8, Flow cytometry, Wound healing, Cell invasion assays and xenograft experiments were conducted to analyze the biological roles of miR-550a-3-5p. Tumor-associated macrophages (TAMs) generation, co-culturing of cancer cells with TAMs, Western blot, Dual-luciferase reporter gene assay, Immunohistochemistry and animal studies were performed to explore the mechanisms underlying the functions of miR-550a-3-5p. Results: We identified 19 miRNAs differentially expressed in HPV-positive OSCC specimens and miR-550a-3-5p was down-regulated. The low expression of miR-550a-3-5p correlated with higher tumor size and nodal metastasis of HPV-positive OSCC patients. Then, we found that miR-550a-3-5p suppressed the migration, invasion and EMT of HPV-positive OSCC cells dependent on decreasing M2 macrophages polarization. Moreover, miR-550a-3-5p, down-regulated by E6 oncoprotein, inhibited M2 macrophages polarization by YAP/CCL2 signaling, which in turn abrogating EMT program in HPV-positive OSCC cells. In addition, in both xenografts and clinical HPV-positive OSCC samples, miR-550a-3-5p levels were inversely associated with YAP, CCL2 expressions and the number of M2 macrophages. Conclusions: E6/miR-550a-3-5p/YAP/CCL2 signaling induces M2 macrophages polarization to enhance EMT and progression, revealing a novel crosstalk between cancer cells and immune cells in HPV-positive OSCC microenvironment. 

Retracted: Yes

PubPeer comments:
 Figure 2. Several panels look very similar to each other. Boxes of the same color focus attention to panels that look similar. Reported to the journal in August 2014. ![file] , 
 I think this is a mistake from our end (figure 2A). However, several other figures have control image for comparison with the treated. Two panels in Figure 2D, also looks same. However, there is no effect on interpretation of the results as there are two more concentrations of the molecule used in the same panel. We are sorry for this mistake. , 
 Any updates for this paper? Is there a correction in the pipeline? , 
 #3 I think no need to make any correction as many doses are taken in the study which is sufficient to support the conclusions. , 
 Thank you Dr. Tomar, but it appears that at least three errors were made in the assembly of the figures. How would you be able to argue that the three visible errors in the figures still support the conclusions? You seem to be pretty nonchalant about this, but what other, non-visible errors might there be in this paper? ,