Lactic acid induced microRNA-744 enhances motility of SiHa cervical cancer cells through targeting ARHGAP5
Lactic acid induced microRNA-744 enhances motility of SiHa cervical cancer cells through targeting ARHGAP5
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乳酸诱导的 microRNA-744 通过靶向 ARHGAP5 增强 SiHa 宫颈癌细胞的运动能力
DOI：
10.1016/j.cbi.2018.10.027
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发表时间：
2019-01-25
影响因子：
5.1
通讯作者：
Jin, Liping
中科院分区：
文献类型：
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作者：
Li, Chao;Jia, Linyan;Jin, Liping
高危型人乳头状瘤病毒（HPV）感染和整合是导致宫颈癌的主要原因，其中E6和E7癌基因在宫颈癌组织中的表达和保留，可能通过影响细胞的迁移和侵袭，以及肿瘤的转移，使细胞永生化。然而，介导该过程的潜在机制，如肿瘤微环境中宫颈癌细胞的运动性，尚未得到很好的理解。在此，我们研究了一个可能的因素-细胞外乳酸，糖酵解肿瘤细胞中的最终化学物质，对HPV 16阳性SiHa细胞的运动性。结果表明，乳酸通过刺激miR-744的表达增强细胞的迁移和侵袭行为。证实ARHGAP 5是miR-744的靶点，并且沉默ARHGAP 5表现出与通过抑制miR-744观察到的一样的对细胞迁移和侵袭的抑制作用。此外，乳酸下调E6和E7蛋白水平，miR-744或ARHGAP 5的过表达也可降低E6和E7水平。总体而言，我们的研究结果表明，miR-774/ARHGAP 5轴可能在触发乳酸诱导的SiHa细胞迁移和侵袭中发挥重要作用，而不管由于E6和E7表达的部分抑制而导致的效应减弱。
High-risk (hr) human papillomaviruses (HPV) infection and integration has caused the majority of cervical cancer, of which E6 and E7 oncogenes are invariably retained and expressed to immortalize cells probably via affecting cell migration and invasion, and tumor metastasis. However, the underlying mechanism that mediates the procedure such as motility of cervical cancer cells within the tumor microenvironment is not well understood. Herein, we examined one possible factor-extracellular lactic acid, an end up chemical in glycolytic tumor cells, on the motility in HPV16 positive SiHa cells. The results showed that lactic acid enhanced cell migration and invasion behavior via stimulating the expression of miR-744. ARHGAP5 was confirmed to be a target of miR-744, and silencing ARHGAP5 exhibited an inhibiting effect on cell migration and invasion as that observed by suppressing miR-744. In addition, lactic acid down-regulated E6 and E7 protein levels, and overexpression of either miR-744 or ARHGAP5 could also reduce E6 and E7 levels. Overall, our findings suggest that the miR-774/ARHGAP5 axis may provide a vital role in triggering lactic acid-induced migration and invasion in SiHa cells, regardless of the diminished effect due to the partial inhibition of E6 and E7 expression.