Shikonin inhibits migration and invasion of triple-negative breast cancer cells by suppressing epithelial-mesenchymal transition via miR-17-5p/PTEN/Akt pathway.
Shikonin inhibits migration and invasion of triple-negative breast cancer cells by suppressing epithelial-mesenchymal transition via miR-17-5p/PTEN/Akt pathway.
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Shikonin 通过 miR-17-5p/PTEN/Akt 通路抑制上皮间质转化，从而抑制三阴性乳腺癌细胞的迁移和侵袭。
DOI：
10.7150/jca.47553
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发表时间：
2021
影响因子：
3.9
通讯作者：
Pan J
中科院分区：
文献类型：
--
作者：
Bao C;Liu T;Qian L;Xiao C;Zhou X;Ai H;Wang J;Fan W;Pan J
背景：三阴性乳腺癌（TNBC）是一种高转移性的乳腺癌，严重威胁着全球女性的健康。上皮间质转化（EMT）被认为是转移过程中的关键事件。因此，EMT的药物靶向治疗可能是提高TNBC疗效的一个很有前途的策略。本研究旨在探讨紫草素对TNBC细胞EMT及转移的影响及其机制。方法：采用transwell侵袭和创伤愈合实验检测MDA-MB-231和BT549细胞的侵袭和迁移能力。通过qRT-PCR检测miR-17 - 5p表达。利用不同的生物信息学算法从四个数据库（TargetScan、miRanda、PITA和picTar）预测miR-17 - 5p靶向基因，并通过京都基因和基因组百科全书（KEGG）途径富集分析进一步筛选。基于癌症基因组图谱（TCGA）数据库，确定预测基因的差异表达及其与miR-17 - 5p的相关性。通过荧光素酶报告基因分析10号染色体上缺失的磷酸酶和张力蛋白同源物（PTEN）与miR-17 - 5p之间的相互作用。构建PTEN过表达载体和小干扰RNA（siRNA），研究PTEN在肿瘤转移和EMT调控中的作用。Western blot检测EMT标志物蛋白激酶B（Akt）和磷酸化Akt（p-Akt）的表达。结果如下：紫草素可抑制MDA-MB-231和BT549细胞的迁移和侵袭能力，并可引起MDA-MB-231细胞EMT标志物的改变。紫草素抑制乳腺癌中上调的miR-17 - 5p的表达。通过荧光素酶报告基因分析发现，PTEN的3'-非翻译区（3'-UTR）是miR-17 - 5p的直接结合靶标。PTEN在TNBC细胞的转移和EMT中起抑制作用。Akt和p-Akt（Ser473）参与紫草素抑制癌细胞迁移、侵袭和EMT的过程。结论：紫草素通过miR-17 - 5p/PTEN/Akt途径抑制EMT，从而抑制TNBC细胞的迁移和侵袭。这表明紫草素是一种有前途的治疗剂，以抵消转移的TNBC患者。
Background: Triple-negative breast cancer (TNBC) is a great threat to global women's health due to its high metastatic potential. Epithelial-to-mesenchymal transition (EMT) is considered as a key event in the process of metastasis. So the pharmacological targeting of EMT might be a promising strategy in improving the therapeutic efficacy of TNBC. Here, we investigated the effect of shikonin exerting on EMT and consequently the metastasis of TNBC cells and its underlying mechanism. Methods: The invasive and migratory capacities of MDA-MB-231 and BT549 cells were tested using transwell invasion and wound healing assay. MiR-17-5p expression was examined by qRT-PCR. MiR-17-5p targeted genes were predicted with different bioinformatic algorithms from four databases (TargetScan, miRanda, PITA and picTar) and further screened by Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. The differential expressions of predicted genes and their correlations with miR-17-5p were identified in breast cancer patients based on The Cancer Genome Atlas (TCGA) database. The interaction between phosphatase and tensin homolog deleted on chromosome ten (PTEN) and miR-17-5p was analyzed by luciferase reporter assay. The overexpression vector and small interfering RNA were constructed to investigate the role PTEN played in metastasis and EMT regulation. The expressions of EMT markers, protein kinase B (Akt) and phospho-Akt (p-Akt) were evaluated by western blot. Results: Shikonin suppressed the migration and invasion of MDA-MB-231 and BT549 cells and meanwhile the corresponding alterations of EMT biomarkers were observed in shikonin treated MDA-MB-231 cells. Shikonin inhibited the expression of miR-17-5p, which was upregulated in breast cancer. The 3'-untranslated region (3'-UTR) of PTEN was found to be direct binding target of miR-17-5p by luciferase reporter assays. PTEN functioned as a suppressor both in the metastasis and EMT of TNBC cells. Moreover, Akt and p-Akt (Ser473) were involved in the process of inhibition in cancer cell migration, invasion and EMT by shikonin. Conclusions: Shikonin inhibits migration and invasion of TNBC cells by suppressing EMT via miR-17-5p/PTEN/Akt pathway. This suggests shikonin as a promising therapeutic agent to counteract metastasis in the TNBC patients.
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影响因子：
5.6
作者：
Pattarayan, Dhamotharan;Sivanantham, Ayyanar;Rajasekaran, Subbiah
通讯作者：
Rajasekaran, Subbiah
影响因子：
4.2
作者：
Jang, Soon Young;Lee, Jae Koan;Kim, Jong-Ho
通讯作者：
Kim, Jong-Ho
影响因子：
4.6
作者：
Lin KH;Huang MY;Cheng WC;Wang SC;Fang SH;Tu HP;Su CC;Hung YL;Liu PL;Chen CS;Wang YT;Li CY
通讯作者：
Li CY
影响因子：
4.6
作者：
Liao PL;Lin CH;Li CH;Tsai CH;Ho JD;Chiou GC;Kang JJ;Cheng YW
通讯作者：
Cheng YW
miR-655 通过靶向三阴性乳腺癌中的 Prrx1 抑制上皮间质转化。
影响因子：
5.3
作者：
Lv ZD;Kong B;Liu XP;Jin LY;Dong Q;Li FN;Wang HB
通讯作者：
Wang HB