PRAS40 hyperexpression promotes hepatocarcinogenesis
Authors: Hongyong Fu
Ting Zhang
Yingjie Wu
Lingling Jin
Lianying Guo
Haifeng Luo
Lei Song
Lin Huang
Tonghui Ma
He Zhang
Jie Wu
Shuyun Zhao
Gena Huang
Tianhua Zhang
Zhaolai Qi
Journal: EBioMedicine (2020)
Discipline: CLINICAL MEDICINE
Keywords: Carcinogenesis; Cell signaling; Hepatocellular carcinoma; Microrna; Molecular oncology.
Affiliations: Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, 9 South Lvshun Road, Dalian, Liaoning 116044, PR China., The Second Affiliated Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, Liaoning 116023, PR China., Hepatobiliary Surgical Department, the First Affiliated Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, Liaoning 116011, PR China., Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, 9 South Lvshun Road, Dalian, Liaoning 116044, PR China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, 9 South Lvshun Road, Dalian, Liaoning 116044, PR China., Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, 9 South Lvshun Road, Dalian, Liaoning 116044, PR China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, 9 South Lvshun Road, Dalian, Liaoning 116044, PR China; Division of Endocrinology, Diabetes and Bone Disease, Department of Medicine, Icahn Mount Sinai School of Medicine, New York 10029, United States., Department of Pathophysiology, College of Basic Medical Sciences, Dalian Medical University, 9 South Lvshun Road, Dalian, Liaoning 116044, PR China; Liaoning Provence Key Lab of Genome Engineered Animal Models, Dalian Medical University, 9 South Lvshun Road, Dalian, Liaoning 116044, PR China. Electronic address: .

Abstract:  Background: Hepatocellular carcinoma (HCC) is one of the most common cancers, whereas the molecular mechanism remains largely unknown. PRAS40 (encoded by AKT1S1) phosphorylation was increased in human melanoma, prostate cancer and lung cancer specimens, which was considered as the results of Akt activation. However the mechanism in detail and its role in HCC stay elusive. Methods: PRAS40 expression and phosphorylation were analyzed in HCC specimens, and the survival rates of patients were investigated. Functional analyses of PRAS40 in HCC were performed in vivo and in vitro. The miR-124-3p binding sites in PRAS40 were investigated using luciferase assay. MiR-124-3p expression in HCC specimens was examined by In Situ hybridization, and the correlation to PRAS40 level was evaluated. Findings: The phosphorylation, protein and mRNA levels of PRAS40 were increased significantly in HCC specimens from our cohorts and TCGA database, which was positively correlated to the poor prognosis of HCC patients. Compared to Akt1s1+/+ mice, hepatocarcinogenesis was suppressed in Akt1s1-/- mice, and the activation of Akt was impaired. PRAS40 depletion resulted in the inhibition of HCC cellular proliferation. Tumor suppressor miR-124-3p was found to downregulate PRAS40 expression by targeting its 3'UTR. MiR-124-3p levels were inversely correlated to PRAS40 protein and phosphorylation levels in HCC specimens. The proliferation inhibition by miR-124-3p mimics was partially reversed by exogenous PRAS40 introduction in HCC cells. Interpretation: PRAS40 hyperexpression induced by loss of miR-124-3p contributes to PRAS40 hyperphosphorylation and hepatocarcinogenesis. These results could be expected to offer novel clues for understanding hepatocarcinogenesis and developing approaches. 

Retracted: No

PubPeer comments:
 u03b2-actin photo in Figure 7 was deliberately applied to Figure 5.![file] The lanes of u03b2-actin are actually 8, which is different from the 7 lanes of the target proteins.![file] These two photos are actually the same one. ![file] , 
 I agree with these findings. In summary, adding the Figure numbers here for clarity: * The middle b-actin panel in Figure 5D appears to look similar to four lanes in the the mirrored b-actin panel in Figure 7A * Figure 4D: the b-actin panel on the right end of the photo has 8 lanes, while the other panels have only 7 lanes * Figure 7E: two panels appear to share an overlap. The overlap is a bit larger than depicted in #1, so here is a new version showing the overlapping areas in aqua blue. Some cells are colored a bit differently suggesting that the plane of view or lighting angle might be slightly different between the two photos, but most of the cells appear to be at the same relative distance from each other. ![file] ,