Epigenetic silencing of miR-130a ameliorates hemangioma by targeting tissue factor pathway inhibitor¬†2 through FAK/PI3K/Rac1/mdm2 signaling
Authors: Guang-Qi Xu
Zhen Meng
Feng Xue
Ren-Rong Liu
Ran Huo
Fa-Gang Wang
Feng Gao
Jian Zhang
Jian-Hai Bi
Journal: International Journal of Oncology (2017)
Discipline: CLINICAL MEDICINE
Keywords: Hemangiomas; microRNA-130a; TFPI2; cell growth; apoptosis
Affiliations: Department of Aesthetic, Plastic and Burn Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shangdong 250021, P.R. China.

Abstract:  Hemangiomas are the most common vascular tumors that occur frequently in prematures and females. microRNA (miR)-130a is associated with the growth and invasion in many tumors, and its role in hemangiomas has not been addressed so far. The present study revealed that miR‚Ä?30a was overexpressed in infantile hemangioma tissues compared with matched tumor-adjacent tissues. The inhibitor of miR-130a restrained cell growth and induced cell apoptosis in vitro. miR‚Ä?30a inhibitor also induced a cell cycle arrest at G2/M phase. Further studies revealed that tissue factor pathway inhibitor 2 (TFPI2) was a novel miR-130a target, due to miR-130a bound directly to its 3'-untranslated region and miR-130a inhibitor enhanced the expression of TFPI2. Contrary to the effects of miR-130a inhibitor, TFPI2 siRNA strongly promoted cell growth and colony formation, whereas TFPI2 overexpression contributed to the suppressing effect of miR-130a inhibitor in cell viability. Furthermore, miR-130a inhibitor reduced the activation of focal adhesion kinase (FAK)/phosphoinositide 3-kinase (PI3K)/Rac1/anti-mouse double minute (mdm2) pathway proteins, inhibited the expression and nuclear translocation of mdm2. Moreover, FAK overexpression prevented miR-130a inhibitor-induced cell cycle arrest and decrease of cell viability. In vivo experiments, miR-130a inhibition effectively suppressed the tumor growth, restrained angiogenesis by decreasing the expression of angiogenesis markers and the percentage of CD31+ and CD34+. Taken together, our research indicated that miR-130a functions as an oncogene by targeting TFPI2, miR-130a inhibition reduced the growth and angiogenesis of hemangioma by inactivating the FAK/PI3K/Rac1/mdm2 pathway. Thus, miR-130a may serve as a potential therapeutic strategy for the treatment of hemangioma. 

Retracted: Yes

PubPeer comments:
 Fig 6A.  miR-130a-inhibiton or control XPTS-1 cells (106 ) were injected subcutaneously into nude mice (n=5). At 25 days after implantation, the mice were sacrificed and the tumors were recovered.  One of [a series of  travelling tumors ] , arranged on the same creased fabric sheet with the same ruler, appearing in at least a dozen papers from different authors. For instance, Fig 6A from [Wang et al (2017)] :  , 
 Fig 2G.  Cell apoptosis was measured by flow cytometry .  Blue and green boxes mark the similarity to corresponding plots in Fig 5D of [Zhang et al (2017a)] . Other manifestations are linked in that thread.  Light brown and light purple boxes are to facilitate comparison with plots in Fig 2E of [Zhang et al (2017b)] .  Flow cytometry was performed to determine the percentages of apoptosis in SW1990 and PANC-1 cells .  , 
 At right, Fig 4D.  A statistically significant inverse correlation between miR-130a and TFPI2 mRNA levels in hemangioma specimens . At left, Fig 4D from [Nie et al (2017)] .  The correlation between relative expression of miRNA-138 and H19 in 21 samples .  The scatterplots as well as the correlations appear to be identical, despite the different subjects and the lack of overlap between authors. Inquiring minds would like to know how this happened. , 
 Retracted [October 2020] . ------------------------------------ Following the publication of this paper, it was drawn to the authors attention by an interested reader that some tumours featured in Fig. 6A of the above paper were strikingly similar to those featured in Fig. 8A of an article appearing in the same journal [Fan Fu2011Y, Deng R, Yi H, Sun Hu2011P, Zeng Y, He Gu2011C and Su Y: The inhibitory effect of MEG3 miRu2011214 AIFM2 axis on the growth of Tu2011cell lymphoblastic lymphoma. Int J Oncol 51: 316u2011326, 2017]. Furthermore, flow cytometric images featured in Fig. 2G of the above paper were strikingly similar to data featured in the following article [Zhang Hu2011j, Wei Qu2011f, Wang Su2011j, Zhang Hu2011j, Zhang Xu2011y, Geng Q, Cui Yu2011h and Wang Xu2011h: LncRNA HOTAIR alleviates rheumatoid arthritis by targeting miRu2011138 and inactivating NFu2011u03baB pathway. Int Immunopharmacol 50: 283u2011290, 2017]. The Editor asked the authors for an explanation to account for the appearance of strikingly similar data in their paper independently, and they responded to request that the paper be retracted from International Journal of Oncology. All the authors agreed that the article should be retracted. The Editor apologizes to the readership for any inconvenience caused. ,