Li Qilin, Xia Ding, Wang Zhihua, Liu Bo, Zhang Jing, Peng Ping, Tang Qiujun, Dong Jie, Guo Juan, Kuang Dong, Chen Weimin, Mao Jing, Li Qiuhui, Chen Xin
Department of Stomatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Front Cell Dev Biol. 2021 Mar 18;9:656981. doi: 10.3389/fcell.2021.656981. eCollection 2021.
Prostate cancer (PCa) cells are heterogeneous, containing a variety of cancer cells with phenotypical and functional discrepancies in the tumor microenvironment, where prostate cancer stem cells (PCSCs) play a vital role in PCa development. Our earlier studies have shown that ALDHCD44 (DP) PCa cells and the corresponding ALDHCD44 (DN) PCa cells manifest as PCSCs and non-PCSCs, respectively, but the underlying mechanisms regulating stemness of the PCSCs are not completely understood. To tackle this issue, we have performed RNA-Sequencing and bioinformatic analysis in DP (versus DN) cells in this study. We discovered that, PER3 (period circadian regulator 3), a circadian rhythm gene, is significantly downregulated in DP cells. Overexpression of PER3 in DP cells significantly suppressed their sphere- and colony-forming abilities as well as tumorigenicity in immunodeficient hosts. In contrast, knockdown of PER3 in DN cells dramatically promoted their colony-forming and tumor-initiating capacities. Clinically, PER3 is downregulated in human prostate cancer specimens and PER3 expression levels are highly correlated with the prognosis of the PCa patient. Mechanistically, we observed that low levels of PER3 stimulates the expression of BMAL1, leading to the phosphorylation of β-catenin and the activation of the WNT/β-catenin pathway. Together, our results indicate that PER3 negatively regulates stemness of PCSCs via WNT/β-catenin signaling in the tumor microenvironment, providing a novel strategy to treat PCa patients.
前列腺癌细胞具有异质性，在肿瘤微环境中包含多种表型和功能存在差异的癌细胞，其中前列腺癌干细胞（PCSCs）在前列腺癌发展中起着至关重要的作用。我们早期的研究表明，ALDHCD44（DP）前列腺癌细胞和相应的ALDHCD44（DN）前列腺癌细胞分别表现为前列腺癌干细胞和非前列腺癌干细胞，但调节前列腺癌干细胞干性的潜在机制尚未完全明确。为了解决这个问题，我们在本研究中对DP（与DN相比）细胞进行了RNA测序和生物信息学分析。我们发现，昼夜节律基因PER3（period circadian regulator 3）在DP细胞中显著下调。在DP细胞中过表达PER3可显著抑制其成球和集落形成能力以及在免疫缺陷宿主中的致瘤性。相反，在DN细胞中敲低PER3可显著促进其集落形成和肿瘤起始能力。临床上，PER3在人类前列腺癌标本中下调，且PER3表达水平与前列腺癌患者的预后高度相关。从机制上讲，我们观察到低水平的PER3刺激BMAL1的表达，导致β-连环蛋白磷酸化和WNT/β-连环蛋白通路激活。总之，我们的结果表明，PER3通过肿瘤微环境中的WNT/β-连环蛋白信号通路负向调节前列腺癌干细胞的干性，为治疗前列腺癌患者提供了一种新策略。
