Exosome-mediated transfer of circRNA563 promoting hepatocellular carcinoma by targeting the microRNA148a-3p/metal-regulatory transcription factor-1 pathway.
Exosome-mediated transfer of circRNA563 promoting hepatocellular carcinoma by targeting the microRNA148a-3p/metal-regulatory transcription factor-1 pathway.
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外泌体介导的circRNA 563转移通过靶向microRNA 148 a-3 p/金属调节转录因子-1途径促进肝细胞癌
DOI：
10.3748/wjg.v29.i46.6060
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发表时间：
2023-12-14
影响因子：
4.3
通讯作者：
Yang Z
中科院分区：
文献类型：
--
作者：
Lyu ZZ;Li M;Yang MY;Han MH;Yang Z
间充质干细胞（Mesenchymal stem cells，MSCs）通过含有非编码RNA（non-coding RNA，ncRNA）的exosomes发挥抗肿瘤作用，在肿瘤生物学中发挥重要作用。我们的初步研究确定了ncRNA hsa_circ_0000563（circ 563）和circ 563相关的miR-148 a-3 p在外来体中的相互作用，因为miR-148 a-3 p及其靶向金属调节转录因子-1（MTF-1）与肝细胞癌（HCC）进展有关。明确circ 563在肝癌中的临床意义、功能意义和作用机制。比较来源于MSC和HCC细胞的外泌体中miR-148 a-3 p和MTF-1的表达水平，并评估它们对HCC细胞的影响。使用双荧光素酶报告基因分析，miR-148 a-3 p被鉴定为circ 563的相关microRNA，其在HCC调控中的作用在体外和体内进行了评估。circ 563基因沉默可抑制肝癌细胞的增殖和侵袭，并诱导细胞凋亡。在circ 563过表达后，HCC细胞与MSC来源的外泌体共培养促进细胞增殖和转移，并引起miR-148 a-3 p和MTF-1表达的变化。miR-148 a-3 p过表达或MTF-1缺失可部分抑制circ 563的促肿瘤作用。在裸鼠中进行的异种移植实验证实，富含circ 563的外泌体通过上调MTF-1的表达促进肿瘤生长。在HCC组织中，circ 563表达与miR-148 a-3 p表达呈负相关，但与MTF-1水平呈正相关。MSC可能通过外泌体circ 563/miR-148 a-3 p/MTF-1途径表现出抗HCC活性，而外泌体可以通过竞争性结合miR-148 a-3 p以激活MTF-1来传递circ 563以促进致癌行为。
Mesenchymal stem cells (MSCs) exert anti-oncogenic effects via exosomes containing non-coding RNA (ncRNA), which play important roles in tumor biology. Our preliminary study identified the interaction of the ncRNA hsa_circ_0000563 (circ563) and the circ563-associated miR-148a-3p in exosomes, as miR-148a-3p and its target metal-regulatory transcription factor-1 (MTF-1) are implicated in hepatocellular carcinoma (HCC) progression. To identify the clinical significance, functional implications, and mechanisms of circ563 in HCC. The expression levels of miR-148a-3p and MTF-1 in exosomes derived from MSC and HCC cells were compared, and their effects on HCC cells were assessed. Using a dual-luciferase reporter assay, miR-148a-3p was identified as an associated microRNA of circ563, whose role in HCC regulation was assessed in vitro and in vivo. The silencing of circ563 blocked the HCC cell proliferation and invasion and induced apoptosis. Co-culturing of HCC cells with MSC-derived exosomes following circ563 overexpression promoted cell proliferation and metastasis and elicited changes in miR-148a-3p and MTF-1 expression. The tumor-promoting effects of circ563 were partially suppressed by miR-148a-3p overexpression or MTF-1 depletion. Xenograft experiments performed in nude mice confirmed that circ563-enriched exosomes facilitated tumor growth by upregulating the expression of MTF-1. In HCC tissues, circ563 expression was negatively correlated with miR-148a-3p expression but positively correlated with MTF-1 levels. MSCs may exhibit anti-HCC activity through the exosomal circ563/miR-148a-3p/MTF-1 pathway, while exosomes can transmit circ563 to promote oncogenic behavior by competitively binding to miR-148a-3p to activate MTF-1.
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