2. Academic Validation
  3. Nuclear PD-L1 promotes cell cycle progression of BRAF-mutated colorectal cancer by inhibiting THRAP3

Nuclear PD-L1 promotes cell cycle progression of BRAF-mutated colorectal cancer by inhibiting THRAP3

  • Cancer Lett. 2022 Feb 28;527:127-139. doi: 10.1016/j.canlet.2021.12.017.
Rui Ma 1,  Yunpeng Liu 1,  Xiaofang Che 2,  Ce Li 1,  Ti Wen 1,  Kezuo Hou 1,  Xiujuan Qu 3
Affiliations

Affiliations

  • 1 Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, China Liaoning Province Clinical Research Center for Cancer, Shenyang, 110001, China; Liaoning Province Clinical Research Center for Cancer, Shenyang, 110001, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, Shenyang, 110001, China.
  • 2 Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, China Liaoning Province Clinical Research Center for Cancer, Shenyang, 110001, China; Liaoning Province Clinical Research Center for Cancer, Shenyang, 110001, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, Shenyang, 110001, China. Electronic address: [email protected].
  • 3 Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, 110001, China; Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, The First Hospital of China Medical University, China Liaoning Province Clinical Research Center for Cancer, Shenyang, 110001, China; Liaoning Province Clinical Research Center for Cancer, Shenyang, 110001, China; Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors (China Medical University), Ministry of Education, Shenyang, 110001, China. Electronic address: [email protected].
PMID: 34923044 DOI: 10.1016/j.canlet.2021.12.017
Abstract

Colorectal cancers (CRCs) with the BRaf V600E mutation exhibit upregulation of programmed death ligand 1 (PD-L1) but fail to respond to immunotherapy targeting programmed cell death protein 1 (PD-1)/PD-L1. Recent studies have explored the intracellular functions of PD-L1. Here, we demonstrate that PD-L1 was highly expressed in both the cytoplasm and nucleus of BRAF-mutated CRC tumor cells and tissues. Nuclear PD-L1 (nPD-L1) promoted the growth of tumor cells both in vitro and in vivo. Mechanistic investigations revealed that PD-L1 translocation into the nucleus was facilitated by the binding of p-ERK. Further, nPD-L1 upregulated the expression of cell cycle regulator BUB1 via interactions with thyroid hormone receptor-associated protein 3 (THRAP3), thereby accelerating cell cycle progression and promoting cell proliferation. Moreover, BRaf V600E-mutated CRC cells exhibited upregulation of PD-L1 expression via the transcription factor LEF-1. These findings reveal a novel role of nPD-L1, which promotes cell cycle progression in an immune-independent manner in BRaf V600E-mutated CRC. Our study provides novel insight into the mechanisms underlying BRaf V600E-mutated CRC progression.

Keywords

Colorectal cancer; Nuclear PD-L1; THRAP3; Tumor proliferation; p-ERK.

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