<p>microRNA-944 inhibits the malignancy of hepatocellular carcinoma by directly targeting IGF-1R and deactivating the PI3K/Akt signaling pathway</p>
Authors: Xiaodong Wang
Tonghui Ma
Lili Lv
Journal: Cancer Management and Research (2019)
Discipline: CLINICAL MEDICINE
Keywords: PI3K/Akt pathway; epithelial-mesenchymal transition; hepatocellular carcinoma; insulin-like growth factor 1 receptor; microRNA-944.
Affiliations: Department of Oncology and Hematology, The Second Hospital of Jilin University, Changchun, Jilin 130000, People's Republic of China., Department of Digestive Endoscopy, The Second Hospital of Jilin University, Changchun, Jilin 130000, People's Republic of China., Jilin Provincial Key Laboratory on Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun, Jilin 130000, People's Republic of China.

Abstract:  Purpose: Recent studies have identified microRNA-944 (miR-944) as a cancer-related miRNA, but its expression and precise functions in hepatocellular carcinoma (HCC) remain unknown. Patients and methods: miR-944 expression in HCC tissues and cell lines were detected by RT-qPCR. A series of functional assays were utilized to examine the influence of miR-944 on the malignant phenotypes of HCC cells in vitro and in vivo. More importantly, the associated mechanisms underlying the activity of miR-944 in HCC cells were investigated using bioinformatics, luciferase reporter assays, RT-qPCR, and western blot analysis. Results: In this study, we report for the first time, a significant downregulation of miR-944 in HCC tissues and cell lines and the correlation between its downregulation and malignant clinical parameters, including Edmondson-Steiner grade, TNM stage, and venous infiltration. Low miR-944 expression predicted poorer overall survival rate and disease-free survival rate in patients with HCC. Functionally, exogenous miR-944 expression attenuated cell proliferation, clone formation, metastasis, and epithelial-mesenchymal transition and increased apoptosis in HCC, whereas miR-944 knockdown produced the opposite results. In addition, ectopic miR-944 expression hindered HCC tumor growth in vivo. Mechanistically, insulin-like growth factor 1 receptor (IGF-1R) was demonstrated to be the direct target gene of miR-944 in HCC cells. Furthermore, the expression level of miR-944 was inversely correlated with IGF-1R expression in HCC tissues. Rescue experiments showed that IGF-1R was at least partially responsible for the effects of miR-944 on the malignant phenotypes of HCC cells. In addition, the PI3K/Akt pathway was notably deactivated, both in vitro and in vivo, upon miR-944 upregulation. Conclusion: This study provides the first evidence that miR-944 directly targets IGF-1R and inhibits the aggressiveness of HCC, in vitro and in vivo, by decreasing PI3K/Akt signaling. Hence, targeting miR-944 may open a new avenue for the treatment of patients with HCC. 

Retracted: Yes

PubPeer comments:
 Figs 2D, 6D.  The percentage of apoptotic Hep3B cells increased after transfection with miR-944 mimics, whereas the apoptosis rate was suppressed in miR-944 inhibitor-transfected Huh7 cells ;  apoptosis of the aforementioned cells were determined using the ... cell apoptosis assays . ![file] Several panels have already appeared in other papers from unrelated teams of researchers. Pink and blue rectangles: see Figs 2G,H and 4G,H from [Ji, Zhang Li (2017)] . ![file] Here in context. ![file] --------------------------------------- Violet rectangle marks a panel that appears twice in Figs 2D,5D,6D of [Zhao, Xu Zhang (2017)] , once in Figs 2D,5D,6D of [Kang et al (2017)] , and again in Figs 2D,5D of [Hu, Jin Wang (2018)] : ![file] Grey-marked panel also appears in Zhao, Xu Zhang (2017); and in Figs 2D,5D,6D of [Zhao et al (2018)] . ![file] Khaki-marked panel also appears in Kang et al (2017) and twice in Figs 2D, 5D, 6E of [Wang et al (2019)] . ![file] , 
 Fig 2D, 6D again. ![] Yellow-boxed panel matches a panel in [Cheng et al (2020)] . It is not a perfect match, with the 2019 version containing many points absent from the 2020 version, as if they had been plotted from the same raw data file, differently filtered or gated. ![] , 
 Figs 2D,6D again. ![file] Red box marks a panel shared with Figs 2C,4C, 6B of [Li, Li Sun (2019)] . ![] ![] --------------------------------------------------------------- Orange box marks a panel shared with Figs 2C, 4C, 5C of [Zhou Li (2019)] . ![] ![] , 
 *[left]* Fig 9A.  Representative images of tumor xenografts from nude mice inoculated with Hep3B cells that were transfected with miR-944 mimics or miR-NC . *[right]* Fig 7B from [Jia et al (2019)] .  Representative images of tumor xenografts derived from nude mice implanted with agomir-NC- or agomir-605-transfected U251 cells . ![file] I have concerns. , 
 Retracted [16 June 2021] . -------------------------------- The Editor and Publisher of Cancer Management and Research wish to retract the published article. Concerns were raised that the flow cytometry data presented in Figure 2 and Figure 6 was previously published in other articles by other research groups. Specifically: - Figure 2D panel miR-944 mimics appears to be duplicated with Figure 2D panel miR-411 mimics from Zhao et al, 2018 . - Figure 6D panel Hep3B 1 appears to be duplicated with Figure 5F panel miR-543 mimics+pcDNA3.1-ADAM9 from Ji et al, 2017 . - Figure 6D panel Hep3b 2 appears to be duplicated with Figure 5F panel miR-543 mimics from Ji et al, 2017 . The authors were unable to provide a satisfactory explanation for the alleged data duplication and the decision was made to retract the article. The authors wish to apologise for this error. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as u201cRetractedu201d. , 
 - *[left]* Fig 6c from  Circular RNA ITCH suppressed prostate cancer progression by increasing HOXB13 expression via spongy miR-17-5p ([Wang et al 2019] ). - *[right]* **Fig 6c**. ![file] , 
 - *[left]* Fig 3A B. - *[right]* Fig 2D E from  Long Noncoding RNA FOXD2-AS1 Promotes the Malignancy of Cervical Cancer by Sponging MicroRNA-760 and Upregulating Hepatoma-Derived Growth Factor ([Dou et al 2020] ). ![file] Two panels overlap. , 
 #6 ![] Another sighting! Fig 8e from  LncRNA LINC00261 overexpression suppresses the growth and metastasis of lung cancer via regulating miR-1269a FOXO1 axis ([Guo et al 2020] ). ![file] , 
 - *[left]* Fig 7A. - *[right]* Fig 6D from  Long Non-Coding RNA ASB16-AS1 Functions as a miR-760 Sponge to Facilitate the Malignant Phenotype of Osteosarcoma by Increasing HDGF Expression ([Yin et al 2020] ). ![file] Both papers are retracted, but it is still worth documenting the level of image reuse in the oeuvre of this papermill. , 
 - *[left]* Fig 6c from  MicroRNA-939 Directly Targets em HDGF em to Inhibit the Aggressiveness of Prostate Cancer via Deactivation of the WNT u03b2-Catenin Pathway ([Situ et al 2020] ) **[retracted]**. - *[upper right]* Fig 1E from  LncRNA HOTTIP leads to osteoarthritis progression via regulating miR-663a Fynrelated kinase axis ([He et al 2021] ). - *[lower right]* **Fig 6C** again. ![file] , 
 Fig 3A B again: ![] Blue circle marks an overlap with Fig 4C D from  Long Noncoding RNA FOXD2-AS1 Promotes the Malignancy of Cervical Cancer by Sponging MicroRNA-760 and Upregulating Hepatoma-Derived Growth Factor ([Dou et al 2020] ). ![] ,