Liu Yinfeng, Hao Jun, Yuan Guanli, Wei Mengyu, Bu Yuhui, Jin Tingting, Ma Li
Department of Breast Disease Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, 050000, People's Republic of China.
Department of Breast Surgery, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, 066000, People's Republic of China.
Int J Gen Med. 2021 Oct 22;14:7077-7087. doi: 10.2147/IJGM.S328184. eCollection 2021.
Circadian clock genes play a crucial role in physiological and pathological processes, and their aberrant expressions were involved in various human cancers. The objective of this study was to investigate the expression level of Period circadian regulator 1 (PER1), an important circadian clock gene, and its biological roles in the development and progression of breast cancer.
The expression level of PER1 in breast cancer samples was analyzed using the Oncomine database, and the correlation between PER1 expression and clinicopathologic parameters was assessed by bc-GenExMiner v4.5. In addition, Kaplan-Meier plotter database was used to determine the prognostic significance of PER1 expression for breast cancer patients. The expressions of PER1 in breast cancer tissues and cells were validated by Western blot. The loss-or-gain assay of PER1 was conducted to investigate the effects of its expression on cell proliferation, migration and invasion of breast cancer. The relationship between PER1 expression and epigenetic modifications was further explored by Western blot.
The results of the bioinformatics analysis revealed that the expression level of PER1 was markedly reduced in breast cancer tissues (P<0.001), and patients with high expression of PER1 had a better overall survival (HR:0.78, 95% CI:0.63-0.97, P=0.026) and recurrence-free survival (HR:0.83, 95% CI:0.75-0.93, P=0.001) than those with low expression. The assay of gene loss-or-gain indicated that downregulation of PER1 expression markedly promoted cell proliferation, migration and invasion (P<0.05), whereas these malignant phenotypes of breast cancer cells were inhibited by PER1 overexpression (P<0.05). Further studies showed that trichostatin A (TSA), a histone deacetylase inhibitor, induced the expression of PER1 protein in breast cancer cells (P<0.05).
PER1 functions as a tumor suppressor in the development and progression of breast cancer, and its expression silencing might be regulated by epigenetic modifications.
生物钟基因在生理和病理过程中起关键作用，其异常表达与多种人类癌症有关。本研究的目的是探讨重要生物钟基因周期昼夜调节因子1（PER1）的表达水平及其在乳腺癌发生发展中的生物学作用。
使用Oncomine数据库分析乳腺癌样本中PER1的表达水平，并通过bc-GenExMiner v4.5评估PER1表达与临床病理参数之间的相关性。此外，使用Kaplan-Meier plotter数据库确定PER1表达对乳腺癌患者的预后意义。通过蛋白质免疫印迹法验证PER1在乳腺癌组织和细胞中的表达。进行PER1的缺失或过表达实验，以研究其表达对乳腺癌细胞增殖、迁移和侵袭的影响。通过蛋白质免疫印迹法进一步探讨PER1表达与表观遗传修饰之间的关系。
生物信息学分析结果显示，乳腺癌组织中PER1的表达水平明显降低（P<0.001），PER1高表达的患者总生存期（HR：0.78，95%CI：0.63-0.97，P=0.026）和无复发生存期（HR：0.83，95%CI：0.75-0.93，P=0.001）均优于低表达患者。基因缺失或过表达实验表明，PER1表达下调显著促进细胞增殖、迁移和侵袭（P<0.05），而PER1过表达则抑制乳腺癌细胞的这些恶性表型（P<0.05）。进一步研究表明，组蛋白去乙酰化酶抑制剂曲古抑菌素A（TSA）可诱导乳腺癌细胞中PER1蛋白的表达（P<0.05）。
PER1在乳腺癌的发生发展中起肿瘤抑制作用，其表达沉默可能受表观遗传修饰调控。
