Suppression of Tumorigenicity 5 Ameliorates Tumor Characteristics of Invasive Breast Cancer Cells via ERK/JNK Pathway.
Suppression of Tumorigenicity 5 Ameliorates Tumor Characteristics of Invasive Breast Cancer Cells via ERK/JNK Pathway.
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DOI：
10.3389/fonc.2021.621500
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发表时间：
2021
影响因子：
4.7
通讯作者：
Chen S
中科院分区：
文献类型：
--
作者：
Cheng J;Li M;Tzeng CM;Gou X;Chen S
抑瘤基因ST 5（Suppression of tumorigenicity 5）是HeLa细胞中的一个抑癌基因。然而，它在乳腺癌进展中的作用仍然模糊。在线数据库分析由Oncomine和Breast Cancer Gene-Expression Miner v4.4（bc-GenExMiner v4.4）确定。采用MTT法、创伤愈合模型、Transwell法和流式细胞术检测肿瘤生物学行为。甲基化特异性PCR（MSP）检测基因启动子甲基化。与癌旁组织或非浸润性乳腺癌相比，在乳腺癌标本中观察到低水平的ST 5，特别是在复发性、浸润性乳腺癌病例中。与具有低侵袭能力的MCF-7细胞相比，在具有高侵袭能力的MDA-MB-231和SKBR 3细胞系中也证实了ST 5的下调。ST 5与乳腺癌的病理分期呈负相关。ST 5下调可促进MDA-MB-231细胞的增殖、细胞周期和迁移，而ST 5上调则可抑制MDA-MB-231细胞的增殖、细胞周期和迁移。此外，ST 5敲低抑制MDA-MB-231细胞的凋亡，而ST 5过表达促进MDA-MB-231细胞的凋亡。然而，ST 5修饰，无论是上调还是下调，对MCF-7细胞的肿瘤行为没有显著影响。从机制上讲，ST 5蛋白消融激活，而ST 5上调抑制磷酸化ERK 1/2和JNK的活性，随后抑制c-Myc的表达。PD 98059介导的ERK 1/2抑制消除了ST 5缺失对ERK 1/2/JNK/c-Myc信号传导轴的刺激作用，以及ST 5缺失介导的细胞过度增殖和迁移。值得注意的是，浸润性乳腺癌细胞中的ST 5减少应该与ST 5启动子区域的超甲基化有关。我们的研究结果提示ST 5可能通过调控ERK/JNK信号通路在浸润性乳腺癌中发挥抑癌基因的作用，为乳腺癌的治疗提供了新的思路。
Suppression of tumorigenicity 5 (ST5) has been considered as a tumor suppressor gene in HeLa tumor cells. However, its role in the progression of breast cancer remains vague. Online database analysis was determined by Oncomine and Breast Cancer Gene-Expression Miner v4.4 (bc-GenExMiner v4.4). Tumor biology behaviors were measured by MTT assay, wound healing model, Transwell and Flow cytometry assays. Methylation-specific PCR (MSP) was employed to detect promoter methylation. Low level of ST5 was observed in breast cancer specimens, particularly in recurrent, invasive breast cancer cases compared to para-carcinoma tissue or non-invasive breast cancer. The downregulation of ST5 was also proved in MDA-MB-231 and SKBR3 cell lines with a high invasive capability as compared to MCF-7 cell with a low invasive capability. ST5 was negatively associated with pathological stages of breast cancer. ST5-downregulation promoted, while ST5-upregulation inhibited the progression of cell proliferation, cell cycle and migration of MDA-MB-231 cells. Additionally, ST5 knockdown inhibited, whereas ST5 overexpression promoted apoptosis of MDA-MB-231 cells. However, ST5 modification, either upregulation or downregulation, had no significant impact on tumor behaviors of MCF-7 cells. Mechanistically, ST5 protein ablation activated, while ST5-upregulation repressed the activities of phosphorylated ERK1/2 and JNK, and subsequently the expression of c-Myc. PD98059-mediated ERK1/2 inhibition abolished the stimulatory effects of ST5-depletion on ERK1/2/JNK/c-Myc signaling axis, and ST5 depletion-mediated cell over-proliferation and migration. Of note, ST5 reduction in invasive breast cancer cells should implicate in the hypermethylation of ST5 promoter region. Our findings suggest that ST5 potentially acts as a tumor suppressor gene in invasive breast cancer through regulating ERK/JNK signaling pathway and provide a novel insight for breast cancer treatment.
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