Circadian Rhythm Gene PER3 Negatively Regulates Stemness of Prostate Cancer Stem Cells via WNT/β-Catenin Signaling in Tumor Microenvironment.
Circadian Rhythm Gene PER3 Negatively Regulates Stemness of Prostate Cancer Stem Cells via WNT/β-Catenin Signaling in Tumor Microenvironment.
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DOI：
10.3389/fcell.2021.656981
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发表时间：
2021
影响因子：
5.5
通讯作者：
Chen X
中科院分区：
文献类型：
--
作者：
Li Q;Xia D;Wang Z;Liu B;Zhang J;Peng P;Tang Q;Dong J;Guo J;Kuang D;Chen W;Mao J;Li Q;Chen X
前列腺癌（PCa）细胞是异质性的，包含多种在肿瘤微环境中具有表型和功能差异的癌细胞，其中前列腺癌干细胞（PCSC）在PCa发展中起着至关重要的作用。我们早期的研究表明，ALDHhiCD 44+（DP）PCa细胞和相应的ALDHloCD 44-（DN）PCa细胞分别表现为PCSC和非PCSC，但调节PCSC干细胞性的潜在机制尚未完全了解。为了解决这个问题，我们在本研究中对DP（与DN）细胞进行了RNA测序和生物信息学分析。我们发现，PER 3（周期昼夜节律调节器3），一个昼夜节律基因，在DP细胞中显著下调。在DP细胞中过表达PER 3显著抑制了它们的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PER 3显著促进其集落形成和肿瘤起始能力。临床上，PER 3在人前列腺癌样本中下调，并且PER 3表达水平与PCa患者的预后高度相关。从机制上讲，我们观察到低水平的PER 3刺激BMAL 1的表达，导致β-连环蛋白的磷酸化和WNT/β-连环蛋白途径的激活。总之，我们的结果表明，PER 3通过肿瘤微环境中的WNT/β-连环蛋白信号传导负调节PCSC的干性，提供了治疗PCa患者的新策略。
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 ALDHhiCD44+ (DP) PCa cells and the corresponding ALDHloCD44– (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.
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影响因子：
11.2
作者：
Shafi AA;Knudsen KE
通讯作者：
Knudsen KE
影响因子：
50.3
作者：
Domingo-Domenech J;Vidal SJ;Rodriguez-Bravo V;Castillo-Martin M;Quinn SA;Rodriguez-Barrueco R;Bonal DM;Charytonowicz E;Gladoun N;de la Iglesia-Vicente J;Petrylak DP;Benson MC;Silva JM;Cordon-Cardo C
通讯作者：
Cordon-Cardo C
影响因子：
21.3
作者：
Vermeulen, Louis;Melo, Felipe De Sousa E.;Medema, Jan Paul
通讯作者：
Medema, Jan Paul
影响因子：
11.2
作者：
Collins, AT;Berry, PA;Maitland, NJ
通讯作者：
Maitland, NJ
影响因子：
2.9
作者：
Sancar, Aziz;Lindsey-Boltz, Laura A.;Gaddameedhi, Shobhan;Selby, Christopher P.;Ye, Rui;Chiou, Yi-Ying;Kemp, Michael G.;Hu, Jinchuan;Lee, Jin Hyup;Ozturk, Nuri
通讯作者：
Ozturk, Nuri