Abstract
BackgroundThe aberrant expression of E3 ubiquitin ligase Pellino-1 (PELI1) contributes to several human cancer development and progression. However, its expression patterns and functional importance in papillary thyroid cancer (PTC) remains unknown.MethodsPELI1 expression profiles in PTC tissues were obtained and analyzed through the starBase v3.0 analysis. Real-time PCR, Immunohistochemical assays (IHC) and Western blot were used to investigate the mRNA and protein levels of PELI1 in PTC. The effects of PELI1 on PTC cell progression were evaluated through CCK-8, colony formation, Transwell, and Wound healing assay in vitro, and a PTC xenograft mouse model in vivo. The downstream target signal of PELI1 in PTC was analyzed by using Kyoto encyclopedia of genes and genomes (KEGG), and bioinformatics tools were used to identify potential miRNAs targeting PELI1. Human umbilical cord mesenchymal stem cells were modified by miR-30c-5p and the miR-30c-5p containing extracellular vesicles were collected (miR-30c-5p-EVs) by ultra-high-speed centrifugation method. Then, the effects of miR-30c-5p-EVs on PELI1 expression and PTC progression were evaluated both in vitro and in vivo.ResultsBoth mRNA and protein expression of PELI1 were widely increased in PTC tissues, and overexpression of PELI1 was positively correlated with bigger tumor size and lymph node metastases. PELI1 promoted PTC cell proliferation and migration in vitro. While, PELI1 silencing significantly suppressed PTC growth in vivo accompanied with reduced expression of Ki-67 and matrix metallopeptidase 2 (MMP-2). Mechanistically, PI3K-AKT pathway was identified as the downstream target of PELI1, and mediated the functional influence of PELI1 in PTC cells. Moreover, we found that the expression of miR-30c-5p was inversely correlated with PELI1 in PTC samples and further confirmed that miR-30c-5p was a tumor-suppressive miRNA that directly targeted PELI1 to inhibit PTC cell proliferation and migration. Furthermore, we showed that miR-30c-5p-EVs could effectively downregulate PELI1 expression and suppress the PTC cell growth in vitro and in vivo.ConclusionThis study not only supported the first evidence that miR-30c-5p loss-induced PELI1 accumulation facilitated cell proliferation and migration by activating the PI3K-AKT pathway in PTC but also provided novel insights into PTC therapy based on miR-carrying-hUCMSC-EVs.
Highlights
The aberrant expression of E3 ubiquitin ligase Pellino-1 (PELI1) contributes to several human cancer development and progression
We found that the PELI1 expression was significantly increased in thyroid cancer (THCA) specimens compared with normal tissues (Fig. 1A)
Consistent with the mRNA levels, the PELI1 protein levels were higher in papillary thyroid cancer (PTC) tissues than in adjacent non-tumor tissues, and PELI1 was predominantly localized in the nucleus and cytoplasm of PTC cells based on Immunohistochemical assays (IHC) (Fig. 1G)
Summary
The aberrant expression of E3 ubiquitin ligase Pellino-1 (PELI1) contributes to several human cancer development and progression. E3 ubiquitin ligases are a class of critical enzymes that can catalyse the transfer of ubiquitin to the substrate, and their genetic alteration, abnormal expression, or dysfunction account for the occurrence and progression of human cancers [3]. They are emerging as attractive therapeutic targets for cancer therapy [4]. PELI1 could regulate the metabolic actions of mTORC1 to suppress antitumor T cell responses in melanoma [10] These reports identified PELI1 was an oncogene. The expression patterns and functional importance of PELI1 in PTC are not known
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