调解人
转移
结直肠癌
信号转导
MAPK/ERK通路
下调和上调
癌症研究
医学
内科学
癌症
生物
细胞生物学
生物化学
基因
作者
Haifeng Zhang,Rong Liu,Zhenghui Jing,Chunying Li,Wentao Fan,Houli Li,Hongbing Li,Jie Ren,Shiyu Cui,Wenbao Zhao,Lei Yu,Yuhui Bai,Shujing Liu,Chunlu Fang,Wei Yang,Yuan Wei,Liangming Li,Shuang Peng
标识
DOI:10.1016/j.bbadis.2024.167066
摘要
Colorectal cancer (CRC) has been the third most common malignancy and the second cause of cancer-related mortality. As the core of volume-sensitive chloride currents, leucine-rich repeat-containing 8A (LRRC8A) contributes to tumor progression but is not consistent, especially for whom the roles in colon carcinoma metastasis were not fully elucidated. Herein, LRRC8A proteins were found highly expressed in hematogenous metastasis from human colorectal cancer samples. The oxaliplatin-resistant HCT116 cells highly expressed LRRC8A, which was related to impaired proliferation and enhanced migration. The over-expressed LRRC8A slowed proliferation and increased migration ex vivo and in vivo. The elevated LRRC8A upregulated the focal adhesion, MAPK, AMPK, and chemokine signaling pathways via phosphorylation and dephosphorylation. Inhibition of LRRC8A impeded the TNF-α signaling cascade and TNF-α-induced migration. LRRC8A binding to PIP5K1B regulated the PIP2 formation, providing a platform for LRRC8A to mediate cell signaling transduction. Importantly, LRRC8A self-regulated its transcription via NF-κB1 and NF-κB2 pathways and the upregulation of NIK/NF-κB2/LRRC8A transcriptional axis was unfavorable for colon cancer patients. Collectively, our findings reveal that LRRC8A is a central mediator in mediating multiple signaling pathways to promote metastasis and targeting LRRC8A proteins could become a potential clinical biomarker-driven treatment strategy for colon cancer patients.
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