Suppression of Tumorigenicity 5 Ameliorates Tumor Characteristics of Invasive Breast Cancer Cells via ERK/JNK Pathway
- Front Oncol. 2021 Jul 28;11:621500. doi: 10.3389/fonc.2021.621500.
- 1. Shaanxi Key Laboratory of Brain Disorders and School of Basic Medical Science, Xi'an Medical University, Xi'an, China.
- 2. Translational Medicine Research Center (TMRC), School of Pharmaceutical Science, Xiamen University, Xiamen, China.
- 3. Department of Otolaryngology-Head and Neck Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, China.
- 4. Xiamen Key Laboratory of Otolaryngology Head and Neck Surgery, Xiamen, China.
- 5. Institute of Basic and Translational Medicine, Xi'an Medical University, Xi'an, China.
- 6. Academician Workstation of Chen Zhi-nan, Xi'an Medical University, Xi'an, China.
Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.