<p>MicroRNA-939 Directly Targets <em>HDGF</em> to Inhibit the Aggressiveness of Prostate Cancer via Deactivation of the WNT/β-Catenin Pathway</p>
Authors: Wentao Huang
Hao Zhang
Yunhua Mao
Zi Jin
Jie Situ
Ke Li
Journal: OncoTargets and Therapy (2020)
Discipline: CLINICAL MEDICINE
Keywords: WNT/β-catenin signaling; hepatoma-derived growth factor; microRNA-939; prostate cancer.
Affiliations: Department of Urology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China., Department of Hepatological Surgery, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, People's Republic of China.

Abstract:  Purpose: MicroRNA-939 (miR-939) has crucial roles in several types of human cancer. However, the expression profile and precise functions of miR-939 in prostate cancer (PCa) are still unclear. This study aimed to determine miR-939 expression in PCa and explore its roles in PCa tumorigenesis. Methods: miR-939 expression was determined in PCa tissues and cell lines using reverse transcription-quantitative polymerase chain reaction. Cell Counting Kit-8, colony formation, and flow cytometric assays were used to determine the role of miR-939 in PCa cell proliferation and apoptosis in vitro, whereas a tumor xenograft model was generated to evaluate the effect of miR-939 on tumor growth in vivo. Transwell assays were performed to investigate whether miR-939 affects the migration and invasiveness of PCa cells. Results: miR-939 was found to be downregulated in PCa tissues and cell lines, and this downregulation was significantly correlated with tumor stage and lymphatic metastasis. Patients with PCa exhibiting low miR-939 expression had shorter overall survival than those exhibiting high miR-939 expression. Exogenous miR-939 expression suppressed PCa cell proliferation, colony formation, migration, and invasion in vitro; enhanced apoptosis in vitro; and decreased tumor growth in vivo. Investigation of the underlying molecular mechanisms revealed hepatoma-derived growth factor (HDGF) as a direct target gene of miR-939 in PCa. HDGF was found to be significantly upregulated in PCa tissues, and its expression was inversely correlated with miR-939 expression. HDGF silencing and miR-939 upregulation showed similar effects in PCa. Restored HDGF expression counteracted the tumor-suppressive activity of miR-939 overexpression in PCa cells. Furthermore, ectopic miR-939 expression inhibited the WNT/β-catenin pathway activation in PCa both in vitro and in vivo by downregulating HDGF. Conclusion: miR-939 functions as a tumor suppressor during PCa tumorigenesis by directly targeting HDGF and deactivating the WNT/β-catenin pathway, suggesting the miR-939/HDGF/WNT/β-catenin pathway as an effective target for PCa therapy. 

Retracted: Yes

PubPeer comments:
 *[above]* Fig 8A.  DU145 cells transfected with either agomir-939 or agomir-NC were subcutaneously inoculated into nude mice. Images of the tumor xenografts at the end of the experiment are shown . *[below]* Fig 6A from [Chen et al (2019)] .  Representative images of subcutaneous tumor xenografts from groups agomir-432 and agomir-NC . ![file] The tumors appear to be identical, though slightly rotated. At right, contrast adjusted for easier comparison of the markings and scratches on the rulers. They seem to be the same ruler, although there is no obvious connection between the research teams or their institutions. How did this happen? , 
 Retracted [5 October 2021] . ---------------------------- The Editor and Publisher of OncoTargets and Therapy wish to retract the published article. Concerns were raised over alleged image duplication in Figure 8A with similar images from unrelated articles, specifically: - Figure 8A appears to have been duplicated with a similar image in Figure 6A from Chen et al, 2019 . The authors did not respond to our queries and the Editor determined the findings of the study were no longer valid and advised for the article to be retracted. 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. , 
 Fig 8A was not the only concern with this paper: the WBs, flow-cytometry, Transwell-assay images, and colony-formation images all conform to the [styles used by a prolific papermill] . ![file] , 
 - *[left]* Fig 2c. - *[right]* Fig 4b from  NEAT1 miR-23a-3p KLF3: a novel regulatory axis in melanoma cancer progression ([Ding et al 2019] ). ![file] , 
 - *[left]* Fig 2c again. - *[right]* Fig 4C from  MicroRNA-652 suppresses malignant phenotypes in glioblastoma multiforme via FOXK1-mediated AKT mTOR signaling pathway ([Yang et al 2019] ). ![file] Both papers are retracted, but it is still worth documenting the extent of image recycling within this papermill s oeuvre. , 
 - *[left]* Fig 6c. - *[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 from  microRNA-944 inhibits the malignancy of hepatocellular carcinoma by directly targeting IGF-1R and deactivating the PI3K Akt signaling pathway ([Lv et al 2019] ). ![file] , 
 - *[left]* Fig 6E from  Long noncoding RNA VPS9D1-AS1 augments the malignant phenotype of non-small cell lung cancer by sponging microRNA-532-3p and thereby enhancing HMGA2 expression ([Han et al 2020] ). - *[right]* Fig 5d from  TRG-AS1 is a potent driver of oncogenicity of tongue squamous cell carcinoma through microRNA-543 Yes-associated protein 1 axis regulation ([He et al 2020] ). ![file] - Fig 6E F. ![file] Fig 2C from  MicroRNA-675 directly targets MAPK1 to suppress the oncogenicity of papillary thyroid cancer and is sponged by long non-coding RNA RMRP ([Wang et al 2019] ). ![file] , 
 - Fig 3D from  LncRNA NOP14-AS1 Promotes Tongue Squamous Cell Carcinoma Progression by Targeting MicroRNA-665 HMGB3 Axis ([Li et al 2021] ); - Fig 4D from  Long noncoding RNA VPS9D1-AS1 augments the malignant phenotype of non-small cell lung cancer by sponging microRNA-532-3p and thereby enhancing HMGA2 expression ([Han et al 2020] ); - **Fig 6E** again. ![file] ,