The knockdown of MALAT1 inhibits the proliferation, invasion and migration of hemangioma endothelial cells by regulating MiR-206 / VEGFA axis
Introduction
Infantile hemangioma (IH) is a common benign endothelial cell tumor among infants and young children, with an incidence of approximately 4%–10% [1]. IH is sometimes accompanied by some potential complications such as permanent disfiguration, ulcers, scarring, bleeding, visual impairment, airway obstruction and congestive heart failure, and death under certain severe circumstances [2]. The progression of IH can be divided into proliferation phase, involuting phase, and involuted phase [3]. In proliferation phase, hemangioma rapidly proliferates and significantly increases tumor volume, and local lesion will develop into internal body [4]. Compared with local lesions, deep lesions are at a higher risk of developing ulcer and functional damages, thus, active intervention at early clinical stage is required in order to promote the spontaneous regressive process of IH and reduce hemangioma proliferation and invasion to surrounding tissues [5,6]. At present, the mechanism of IH development is still unclear, however, some studies showed that excessive proliferation of vascular endothelial cells and rapid vascular growth are distinct characteristics of hemangioma histopathology [[7], [8], [9]], thus, exploring the relevant mechanism of IH angiogenesis is possibly a potential therapeutic target for treating IH.
As a class of non-coding transcripts with a length greater than 200 bases, long non-coding RNAs (LncRNAs) are involved in a variety of life processes, including angiogenesis [10]. Studies have confirmed that LncRNAs play important regulatory roles in physiological angiogenesis and pathological angiogenesis [11,12]. LncRNA JHDM1D-AS1 has been shown to promote pancreatic cancer tumor growth by regulating angiogenesis in response to nutrient starvation [13]. LncRNA SNHG7 inhibits angiogenesis of high glucose-induced human retinal endothelial cells through regulating miR-543/SIRT1 axis [14]. LncRNA MALAT1 has been demonstrated to promote proliferation, angiogenesis, and immunosuppressive properties of mesenchymal stem cells by inducing VEGF and IDO [15]. Cremer S et al. found that Malat1−/− mice enhances displayed enhanced adhesion to atherosclerotic arteries in vivo due to the accumulation of hematopoietic cells [16]. Additionally, lncRNA MALAT1 plays a critical role in the regulation of tumor angiogenesis in many diseases [17,18]. One recent report indicates that nine differentially expressed lncRNAs including MALAT1 have been identified in IH, and silencing of MALAT1 promotes apoptosis and cell cycle arrest in human umbilical vein endothelial cells [19]. It is also reported that MALAT1 promotes the progression of IH through regulating miR-424 [20]. Taken these together, we infer that MALAT1 may play a crucial role in IH, eventhough, the function and molecular mechanisms of MALAT1 in IH remain largely unknown. Besides, as the hemangioma endothelial cells account the majority of IH, thus, we decided to focus on the effect of MALAT1on behaviors of hemangioma endothelial cells during IH.
Studies have shown that miRNAs and lncRNAs can not only directly interact with each other, but also indirectly affect the occurrence and development of tumors via other molecules [21]. Vascular endothelial growth factor A (VEGFA) is a vascular permeability factor that induces angiogenesis [22]. Current studies confirmed that VEGFA signaling pathway is an important target for inhibiting tumor angiogenesis [23]. In the present study, Targetscan7.2 predicted that VEGFA could directly target miR-206. Therefore, we further explored the effects of MALAT1 and miR-206 on targeting VEGFA in HemECs. We found that MALAT1 silencing significantly up-regulated the expression of miR-206, while overexpressed miR-206 inhibited the expression of VEGFA. Moreover, knocking down MALAT1 inhibited the growth of IH through regulating miR-206/VEGFA axis.
Section snippets
Clinical specimens
Normal skin tissues and IH tissue in regression phase and proliferative phase samples were obtained from IH patients (n = 30) who attended Yichang Yiling Hospital for treatment from May 2018 to April 2019. The samples were collected from 14 male patients and 16 female patients, who aged from 3 to 15 months old, with a mean age of 6.811 months. The tissue samples were maintained in liquid nitrogen and stored at −80 °C. Parents or guardians of the subjects signed the informed consent, and this
MALAT1 expression in IH tissues and HemEC
The expression of MALAT1 was obviously higher in IH tissues of involuting phase and proliferation phase than in normal tissues (PÂ <Â 0.001, Fig. 1A). In order to further explore the effect of MALAT1 on IH, HemECs from the lesion tissue was isolated and cultured, and we found that the positive rate of CD31-FITC was 94.27% in the cells obtained by CD31 immunomagnetic bead positive separation (PÂ <Â 0.001, Fig. 1B). Those purified CD31+ cells were considered to be HemECs, which have been also
Discussion
MALAT1 may have different regulatory roles in cells of different tissues or in different developmental stages of the same organism. Michalik et al. reported that silencing MALAT1 increased endothelial cell migration, which is different from the results of the present study [27]. Liu et al. found that knockdown of MALAT1 reduced endothelial cell migration and tube formation in vitro [18]. In the present study, we found that the expression level of MALAT1 in IH tissues in the involuting phase and
Conclusion
To conclude, the current study is the first to report the mechanism of the crosstalk among MALAT1, miR-206 and VEGFA in IH. In IH tissues, MALAT1 and VEGFA are high-expressed, while miR-206 is low-expressed. MALAT1 directly targets miR-206 to inhibit its expression, and VEGFA is the target gene for miR-206. Silencing of MALAT1 inhibits proliferation, migration, invasion and vasoformation of HemECs through regulating miR-206/VEGFA axis. Thus, MALAT1 could be potentially used as a therapeutic
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
CRediT authorship contribution statement
Shengqiang Wang: Conceptualization, Resources, Visualization, Writing - original draft, Writing - review & editing. Liang Ren: Conceptualization, Resources, Visualization, Writing - original draft, Writing - review & editing. Guanguo Shen: Data curation. Mingyun Liu: Formal analysis, Supervision. Jun Luo: Investigation, Methodology, Validation.
Declaration of competing interest
The authors declare no conflicts of interest.
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These authors contributed equally to this work.