Department of Molecular Microbiology, Research Institute for Microbial Diseases, Osaka University, 3-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo, 135-8550, Japan.
Nat Commun. 2017 Dec 12;8(1):2050. doi: 10.1038/s41467-017-02281-x.
p16 and p21 act as tumour suppressors through induction of cellular senescence. However, senescence-independent roles of these CDK inhibitors are not well understood. Here, we report an unexpected function of p16 and p21, namely, tumour promotion through chemotaxis. In monocytic myeloid-derived suppressor cells (Mo-MDSCs), p16 and p21 are highly expressed and stimulate CX3CR1 chemokine receptor expression by preventing CDK-mediated phosphorylation and inactivation of SMAD3. Thus, deletion of p16 and p21 reduces CX3CR1 expression, thereby inhibiting Mo-MDSC accumulation in tumours expressing CX3CL1 and suppressing the tumour progression in mice. Notably, blockade of the CX3CL1/CX3CR1 axis suppresses tumour growth, whereas inactivation of CDKs elicits the opposite effect. These findings reveal an unexpected function of p16 and p21 and indicate that regulation of Mo-MDSCs chemotaxis is a valuable potential strategy for control of tumour development.
p16 和 p21 通过诱导细胞衰老发挥肿瘤抑制作用。然而，这些 CDK 抑制剂的衰老非依赖性作用尚不清楚。在这里，我们报告了 p16 和 p21 的一个意想不到的功能，即通过趋化作用促进肿瘤。在单核细胞髓样来源的抑制细胞（Mo-MDSCs）中，p16 和 p21 高表达，并通过防止 CDK 介导的 SMAD3 磷酸化和失活来刺激 CX3CR1 趋化因子受体表达。因此，p16 和 p21 的缺失会降低 CX3CR1 的表达，从而抑制表达 CX3CL1 的肿瘤中 Mo-MDSC 的积累，并抑制小鼠的肿瘤进展。值得注意的是，阻断 CX3CL1/CX3CR1 轴可抑制肿瘤生长，而 CDK 的失活则产生相反的效果。这些发现揭示了 p16 和 p21 的一个意想不到的功能，并表明调节 Mo-MDSC 的趋化作用是控制肿瘤发展的一个有价值的潜在策略。
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