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CCL23 通过 CCR1/AKT/ESR1 反馈回路抑制肝癌进展。

CCL23 suppresses liver cancer progression through the CCR1/AKT/ESR1 feedback loop.

机构信息

Key Laboratory of Xinjiang Endemic and Ethnic Diseases/The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China.

NHC Key Laboratory of Prevention and Treatment of Central Asia High Incidence Diseases, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, China.

出版信息

Cancer Sci. 2021 Aug;112(8):3099-3110. doi: 10.1111/cas.14995. Epub 2021 Jun 19.

DOI:10.1111/cas.14995
PMID:34050704
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8353945/
Abstract

With the ability to activate certain signaling pathways, chemokines and their receptors may facilitate tumor progression at key steps, including proliferation, immunomodulation, and metastasis. Nevertheless, their prognostic value and regulatory mechanism warrant thorough studies in liver cancer. Here, by screening the expression profiles of all known chemokines in independent liver cancer cohorts, we found that CCL23 was frequently downregulated at mRNA and protein levels in liver cancer. Decreased CCL23 correlated with shortened patient survival, enrichment of signatures related to cancer stem cell property, and metastatic potential. In addition to serving as a tumor suppressor through recruiting CD8 T cell infiltration in liver cancer, CCL23 could repress cancer cell proliferation, stemness, and mobility. Mechanistically, the expression of CCL23 was transcriptionally regulated by ESR1. On the other hand, CCL23 could suppress the activation of AKT signaling and thus promote the expression of ESR1, forming a feedback loop in liver cancer cells. Collectively, these findings reveal that loss of CCL23 drives liver cancer progression by coordinating immune evasion and metastasis initiation. Targeting the ESR1/CCL23/CCR1/AKT regulatory axis could be an effective therapeutic strategy.

摘要

通过激活特定的信号通路，趋化因子及其受体可能在关键步骤中促进肿瘤的进展，包括增殖、免疫调节和转移。然而，它们的预后价值和调节机制需要在肝癌中进行深入研究。在这里，我们通过对独立的肝癌队列中所有已知趋化因子的表达谱进行筛选，发现趋化因子 CCL23 在肝癌中的 mRNA 和蛋白水平经常下调。CCL23 的减少与患者生存时间缩短、与癌症干细胞特性相关的特征富集以及转移潜能相关。除了通过招募 CD8 T 细胞浸润在肝癌中作为肿瘤抑制因子外，CCL23 还可以抑制癌细胞的增殖、干性和迁移能力。在机制上，CCL23 的表达受 ESR1 的转录调控。另一方面，CCL23 可以抑制 AKT 信号的激活，从而促进 ESR1 的表达，在肝癌细胞中形成一个反馈回路。总之，这些发现表明，CCL23 的缺失通过协调免疫逃逸和转移起始来驱动肝癌的进展。靶向 ESR1/CCL23/CCR1/AKT 调节轴可能是一种有效的治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37ee/8353945/1b8a60aa4600/CAS-112-3099-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37ee/8353945/6047ac403bb6/CAS-112-3099-g006.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37ee/8353945/bfb3f1413651/CAS-112-3099-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37ee/8353945/567a5867b40b/CAS-112-3099-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37ee/8353945/ce9a5604cfc0/CAS-112-3099-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37ee/8353945/1b8a60aa4600/CAS-112-3099-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37ee/8353945/6047ac403bb6/CAS-112-3099-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37ee/8353945/0ebe4c050d85/CAS-112-3099-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37ee/8353945/bfb3f1413651/CAS-112-3099-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37ee/8353945/567a5867b40b/CAS-112-3099-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37ee/8353945/ce9a5604cfc0/CAS-112-3099-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/37ee/8353945/1b8a60aa4600/CAS-112-3099-g002.jpg

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