Exosomal miR-21 regulates the TETs/PTENp1/PTEN pathway to promote hepatocellular carcinoma growth
Authors: Xue-Wei Yang
Liang-Qi Cao
Yu-Bin Chen
Xiao-Feng Jiang
Da-Wei Zhang
Ping Xue
Journal: Molecular cancer (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Exosome; Hepatocellular carcinoma; PTEN; PTENp1; TET
Affiliations: Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Guangzhou Medical University, 250# Changgang East Road, Haizhu District, Guangzhou, 510260, People's Republic of China. ., Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Guangzhou Medical University, 250# Changgang East Road, Haizhu District, Guangzhou, 510260, People's Republic of China.

Abstract:  Background: As an important means of communication, exosomes play an important role in the development of hepatocellular carcinoma (HCC). Methods: Bioinformatics analysis, dual-luciferase reporter assays, methylation-specific quantitative PCR, and ChIP-PCR analysis were used to gain insight into the underlying mechanism of miR-21 in HCC. Results: The detection of miRNAs in exosomes of HCC showed that miR-21 expression in exosomes was positively correlated with the expression level of miR-21 in cells and negatively correlated with the expression of its target genes PTEN, PTENp1 and TETs. HCC cell-derived exosomes could increase miR-21 and p-Akt expression in HCC cells and downregulate the expression of PTEN, PTENp1 and TETs. MiR-21 inhibitors or PTENp1 overexpression vectors could weaken the effect of the abovementioned exosomes and simultaneously weaken their role in promoting cell proliferation and migration and inhibiting apoptosis. Further studies showed that miR-21 not only directly regulated the expression of PTEN, PTENp1 and TETs but also increased the methylation level of the PTENp1 promoter by regulating the expression of TETs, thereby inhibiting the expression of PTENp1 and further downregulating the expression of PTEN. Conclusions: Exosomal miR-21 can regulate the expression of the tumor suppressor genes PTEN and PTENp1 in various ways and affect the growth of HCC cells. 

Retracted: No

PubPeer comments:
 Figure 3D and 7D. * Blue boxes: The Exo-S+PTENp1-O panel in Figure 3D appears to share an overlap with the miR-21 I+TET1 siRNA panel in Figure 7D. * Green boxes: The miR-21 I+TET1 siRNA panel in Figure 7D appears to share an overlap with the TET1-O+PTENp1 siRNA panel.  , 
 Also, the tumors on the nude mice in Figure 8A appear to be very big. Could the authors please clarify that the sizes were in accordance to animal ethics rules?  Close up photo of two mice:  , 
 An update with a contribution from a person on Twitter on an additional region of similarity: * Red boxes: The Control panel in Figure 7D appears to share an overlap with the TET1-O+PTENp1 siRNA panel.  , 
 I m so sorry to be failure to reply immidiately, it has been exceptionally busy working at the front line in our hospital to fight against COVID-19. Thanks a lot for your kindly help to improve the quality of the paper. We will check the problems and give reasonable explanations as soon as possible. , 
 Thanks a lot for your kindly help to improve the quality of the paper. Actually, in this study, the animal care and use followed the ethical guidelines of the Chinese Council on Animal Care and were reviewed and approved by the Institutional Animal Care and Use Committee. For the nude mice showed in Figure 8A, the group of SUN-449+Exo is a very important control group for comparison, so we could not execute the mice before the end time point. The two animal shown in this image are just representative ones for this group. Althoug the tumors look like big, it is still at around 10% of the body weight. So, it is in accordance to animal ethics rules. After careful check, we confirm that there is a question about the image of transwell invasion in the Figure 7 in the article. The images of the cells were captured from the same picture. We carelessly confused the images mistake of u201cControlu201d, u201cmiR-21 I+TET1 siRNAu201d and u201cTET1-O+PTENp1 siRNAu201d groups in the process of arranging diagrams. We have carried out repeated experiments to verify the above results. Therefore, for the scientific rigor, we want to replace these wrong images in the Figure 7 to make it clear. we have contacted the journal for correction. The correct picture will be published in the latest issue of the journal. We apologize for the mistake and any inconvenience or misunderstanding that these errors may have caused, guaranteeing the image editing does not affect the integrity of the research and conclusions of the published paper. , 
 Thanks a lot for your kindly help to improve the quality of the paper. Actually, in this study, the animal care and use followed the ethical guidelines of the Chinese Council on Animal Care and were reviewed and approved by the Institutional Animal Care and Use Committee. For the nude mice showed in Figure 8A, the group of SUN-449+Exo is a very important control group for comparison, so we could not execute the mice before the end time point. The two animal shown in this image are just representative ones for this group. Althoug the tumors look like big, it is still at around 10% of the body weight. So, it is in accordance to animal ethics rules. After careful check, we confirm that there is a question about the image of transwell invasion in the Figure 7 in the article. The images of the cells were captured from the same picture. We carelessly confused the images mistake of u201cControlu201d, u201cmiR-21 I+TET1 siRNAu201d and u201cTET1-O+PTENp1 siRNAu201d groups in the process of arranging diagrams. We have carried out repeated experiments to verify the above results. Therefore, for the scientific rigor, we want to replace these wrong images in the Figure 7 to make it clear. we have contacted the journal for correction. The correct picture will be published in the latest issue of the journal. We apologize for the mistake and any inconvenience or misunderstanding that these errors may have caused, guaranteeing the image editing does not affect the integrity of the research and conclusions of the published paper. ,