Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 40402, Taiwan.
Center for Molecular Medicine, China Medical University Hospital, Taichung 40447, Taiwan.
Int J Mol Sci. 2022 May 19;23(10):5679. doi: 10.3390/ijms23105679.
Invasion is the most prominent lethal feature of malignant cancer. However, how cell proliferation, another important feature of tumor development, is integrated with tumor invasion and the subsequent cell dissemination from primary tumors is not well understood. Proliferating cell nuclear antigen (PCNA) is essential for DNA replication in cancer cells. Loss of phosphorylation at tyrosine 211 (Y211) in PCNA (pY211-PCNA) mitigates PCNA function in proliferation, triggers replication fork arrest/collapse, which in turn sets off an anti-tumor inflammatory response, and suppresses distant metastasis. Here, we show that pY211-PCNA is important in stromal activation in tumor tissues. Loss of the phosphorylation resulted in reduced expression of mesenchymal proteins as well as tumor progenitor markers, and of the ability of invasion. Spontaneous mammary tumors that developed in mice lacking Y211 phosphorylation contained fewer tumor-initiating cells compared to tumors in wild-type mice. Our study demonstrates a novel function of PCNA as an essential factor for maintaining cancer stemness through Y211 phosphorylation.
侵袭是恶性肿瘤最显著的致命特征。然而，细胞增殖（肿瘤发展的另一个重要特征）如何与肿瘤侵袭以及随后的肿瘤细胞从原发性肿瘤中扩散相整合，目前还不是很清楚。增殖细胞核抗原（PCNA）是癌细胞中 DNA 复制所必需的。PCNA 中酪氨酸 211 位点（Y211）的磷酸化缺失（pY211-PCNA）减轻了 PCNA 在增殖中的功能，引发复制叉停滞/崩溃，从而引发抗肿瘤炎症反应，并抑制远处转移。在这里，我们表明 pY211-PCNA 在肿瘤组织中的基质激活中很重要。磷酸化缺失导致间充质蛋白以及肿瘤祖细胞标记物的表达减少，侵袭能力也降低。与野生型小鼠相比，缺乏 Y211 磷酸化的小鼠自发形成的乳腺肿瘤中，肿瘤起始细胞的数量减少。我们的研究表明，PCNA 通过 Y211 磷酸化作为维持癌症干细胞的必需因素发挥了新的功能。
