期刊
CANCER LETTERS
卷 450, 期 -, 页码 1-13出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2019.02.022
关键词
PD-L1; Colorectal cancer (CRC); Cancer stem cells (CSCs); HMGA1
类别
资金
- National Natural Science Foundation of China [81602598]
- Science and Technology Planning Project of Guangdong Province of China [2017A020215009]
- Fundamental Research Funds for the Central Universities [2017MS125]
- Guangzhou Science, Technology and Innovation Commission [201805010003, 201804010062]
PD-L1 is critical for tumor cell escape from immune surveillance by inhibiting T cell function via the PD-1 receptor. Accumulating evidence demonstrates that anti-PD-L1 monoclonal antibodies might potently enhance antitumor effects in various tumors, but the effect of PD-Li on colorectal cancer stem cells (CSCs) remains unclear. We observed high PD-Ll expression in CD133(+)CD44(+) colorectal CSCs and CSC-enriched tumorspheres. Altering PD-Ll expression promoted colorectal CSC self-renewal by increasing the expression of stemness genes, the CD133(+)CD44(+) cell population sizes and the ability to form tumorspheres. Additionally, PD-L1 expression was markedly increased in chemoresistant colorectal cancer (CRC) cells in vitro and in vivo. More importantly, PD-Li enhanced CRC cell tumorigenicity in nude mice; the inoculation of 1 x 10(4) cells resulted in high tumor formation efficiency. Mechanistically, PD-L1 directly interacted with HMGA1, and HMGA1 upregulation by PD-L1 activated HMGA1-dependent pathways, including the PI3K/Akt and MEK/ERK pathways, and promoted CSC expansion. HMGA1 downregulation rescued the PD-L1-induced phenotypes, highlighting the role of HMGA1 in PD-L1-mediated colorectal CSC self-renewal. Moreover, PD-L1 expression was correlated with the expression of CSC markers and HMGA1 in clinical CRC specimens. Thus, PD-L1 could crucially contribute to the maintenance of CSC self-renewal by activating HMGA1-dependent signaling pathways.
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