High-metastatic cancer cells derived exosomal miR92a-3p promotes epithelial-mesenchymal transition and metastasis of low-metastatic cancer cells by regulating PTEN/Akt pathway in hepatocellular carcinoma
Authors: Jian Wu
Yunhao Chen
Rongliang Tong
Xiaode Feng
Qiyang Cheng
Jingbang Wu
Xianlei Cai
Junru Chen
Hua Liu
Wenxuan Wu
Yuejie Lu
Beng Yang
Zhen Lv
Hanxi Yu
Kejiong Liang
Jiating Hu
Changbiao Li
Shusen Zheng
Journal: Oncogene (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Exosomes; Hepatocellular carcinoma; Metastasis; miR-92a-3p; Epithelial-mesenchymal transition
Affiliations: Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China., Department of gynecology and obstetrics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China., Department of orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China., Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China. .

Abstract:  Exosomes play an important role in intercellular communication and metastatic progression of hepatocellular carcinoma (HCC). However, cellular communication between heterogeneous HCC cells with different metastatic potentials and the resultant cancer progression are not fully understood in HCC. Here, HCC cells with high-metastatic capacity (97hm and Huhm) were constructed by continually exerting selective pressure on primary HCC cells (MHCC-97H and Huh7). Through performing exosomal miRNA sequencing in HCC cells with different metastatic potentials (MHCC-97H and 97hm), many significantly different miRNA candidates were found. Among these miRNAs, miR-92a-3p was the most abundant miRNA in the exosomes of highly metastatic HCC cells. Exosomal miR92a-3p was also found enriched in the plasma of HCC patient-derived xenograft mice (PDX) model with high-metastatic potential. Exosomal miR-92a-3p promotes epithelial-mesenchymal transition (EMT) in recipient cancer cells via targeting PTEN and regulating its downstream Akt/Snail signaling. Furthermore, through mRNA sequencing in HCC cells with different metastatic potentials and predicting potential transcription factors of miR92a-3p, upregulated transcript factors E2F1 and c-Myc were found in high-metastatic HCC cells promote the expression of cellular and exosomal miR-92a-3p in HCC by directly binding the promoter of its host gene, miR17HG. Clinical data showed that a high plasma exosomal miR92a-3p level was correlated with shortened overall survival and disease-free survival, indicating poor prognosis in HCC patients. In conclusion, hepatoma-derived exosomal miR92a-3p plays a critical role in the EMT progression and promoting metastasis by inhibiting PTEN and activating Akt/Snail signaling. Exosomal miR92a-3p is a potential predictive biomarker for HCC metastasis, and this may provoke the development of novel therapeutic and preventing strategies against metastasis of HCC. 

Retracted: No

PubPeer comments:
 Figure 5e: Duplication of data. Figure 6c: Duplication of data. ![file] , 
 Hi, Indigofera, we think we have answered these questions in our previous communications. Firstly, for duplication of datauff08The bands of AKT in figure 5e AND GAPDH in Fig 6cuff09, the reason for this mistake is that there are so many immunoblot pictures in our manuscript, we misplaced the WB pictures accidentally and unconsciously when we uploaded our results. The primary pictures of AKT immunoblot in figure 5e and GAPDH immunoblot in figure 6c are attached. Figure 5e: We performed this Akt immunoblot on 03 28 2019, and the Akt immunoblot band of 97h and Huh7 cells was pointed out by red frame and blue frame. Figure 6c: we performed this GAPDH immunoblot on 05 11 2020, and the GAPDH immunoblot band of Huh7 and 97h cells was pointed out by red frame and blue frame. What s more, we performed this GAPDH immunoblot replication assay in the meanwhile. Secondly, as for the different band shapes of p-Akt and Akt in Figure 6c, we performed these two immunoblots in two separate gels rather than use striping buffer and incubate primary antibodies in the same gel. This is why the band shape is different. We apologize for our mistakes and appreciate your comment. ![file] ![file] ,