The antihyperlipidemic drug potassium piperonate impairs the migration and tumorigenesis of breast cancer cells via the upregulation of miR-31.
The antihyperlipidemic drug potassium piperonate impairs the migration and tumorigenesis of breast cancer cells via the upregulation of miR-31.
复制标题
DOI：
10.3389/fonc.2022.828160
复制
发表时间：
2022
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
乳腺癌是女性癌症死亡的第二大原因，肿瘤转移是死亡的首要原因。由于多种调控分子和信号通路的参与，转移瘤的发生发展还需进一步研究。microRNA（miRNAs）是一类广泛表达的小分子非编码RNA，在多种疾病的诊断和治疗中发挥着重要作用，也是肿瘤转移控制的候选基因。本研究旨在探讨胡椒酸钾（potassium piperonate，GBK）通过靶向miR-31抑制乳腺癌细胞侵袭和转移的机制。乳腺癌细胞，无论是与GBK处理或不处理，评估迁移和侵袭能力，使用伤口愈合和transwell测定。使用RT-qPCR鉴定并验证GBK靶向miRNA。Western blotting用于验证miR-31靶向基因表达水平的变化。进行甲基化特异性PCR以检测GBK对lncRNA L0 C554202宿主基因甲基化水平的影响。GBK和化疗药物顺铂（DDP）对乳腺癌细胞的协同作用通过体外细胞增殖、集落形成和RT-qPCR测定以及体内肿瘤异种移植模型进行了验证。 我们发现miR-31是GBK的主要靶点。GBK处理通过下调DNA甲基转移酶影响CpG位点的表观遗传修饰。因此，在乳腺癌细胞中，lncRNA LOC 554202的CpG相关甲基化水平显著降低，进而上调miR-31及其宿主基因LOC 554202。我们还观察到GBK治疗后miR-31靶向基因的显著抑制，包括RHOA，WAVE 3和SATB 2，其功能与癌细胞侵袭，迁移和增殖密切相关。此外，我们发现GBK和DDP的组合在体外和体内对抑制乳腺癌细胞增殖具有协同作用，特别是在三阴性乳腺癌（TNBC）中。本研究探讨了GBK抑制乳腺癌迁移和侵袭的靶点及其相关机制，为GBK作为辅助药物用于临床治疗提供理论支持。
Breast cancer is the second cause of cancer death in women, and tumor metastasis is the primary cause of mortality. Due to the involvement of many regulatory molecules and signaling pathways, the occurrence and development of metastases needs to be further studied. MicroRNAs (miRNAs) are ubiquitously expressed small non-coding RNAs that have been shown to play an important role in the diagnosis and treatment of many diseases, as well as representing an attractive candidate for metastasis control. In this study, we investigated the mechanism of potassium piperonate (GBK) in impairing breast cancer cell invasion and metastasis by targeting miR-31. Breast cancer cells, either treated with GBK or left untreated, were assessed for migration and invasion capacities using wound healing and transwell assays. GBK-targeted miRNAs were identified and verified using RT-qPCR. Western blotting was used to validate the changes in expression levels of miR-31-targeted genes. Methylation specific PCR was performed to detect the effect of GBK on the methylation levels of the lncRNA LOC554202 host gene. The synergistic effect of GBK and the chemotherapy drug cisplatin (DDP) on breast cancer cells was verified using cell proliferation, colony formation, and RT-qPCR assays in vitro, and the tumor xenograft model in vivo. We found that miR-31 was the main target of GBK. GBK treatment affected the epigenetic modification at CpG sites by downregulating DNA methyltransferases. Thus, the CpG-associated methylation levels of lncRNA LOC554202 decreased significantly, and in turn upregulated both miR-31 and its host gene LOC554202 in breast cancer cells. We also observed the significant inhibition of miR-31-targeted genes following GBK treatment, including RHOA, WAVE3, and SATB2, with functions closely related to cancer cell invasion, migration, and proliferation. Furthermore, we revealed that the combination of GBK and DDP had a synergistic effect on inhibiting the proliferation of breast cancer cells in vitro and in vivo, especially in triple negative breast cancer (TNBC). This study investigated the target of GBK in the inhibition of breast cancer migration and invasion, and the underlying mechanisms involved, providing theoretical support for the development of GBK as an auxiliary drug for clinical treatment.
登录
查看更多内容
影响因子：
4.9
作者：
Mizoguchi F;Murakami Y;Saito T;Miyasaka N;Kohsaka H
通讯作者：
Kohsaka H
影响因子：
3.7
作者：
Huang S;Chen Y;Wu W;Ouyang N;Chen J;Li H;Liu X;Su F;Lin L;Yao Y
通讯作者：
Yao Y
影响因子：
3.7
作者：
Hu J;Guo H;Li H;Liu Y;Liu J;Chen L;Zhang J;Zhang N
通讯作者：
Zhang N
影响因子：
37.3
作者：
Augoff K;McCue B;Plow EF;Sossey-Alaoui K
通讯作者：
Sossey-Alaoui K
影响因子：
4.8
作者：
Chang, Kuo-Wei;Kao, Shou-Yen;Lin, Shu-Chun
通讯作者：
Lin, Shu-Chun