2. Academic Validation
  3. LRRC8A as a central mediator promotes colon cancer metastasis by regulating PIP5K1B/PIP2 pathway

LRRC8A as a central mediator promotes colon cancer metastasis by regulating PIP5K1B/PIP2 pathway

  • Biochim Biophys Acta Mol Basis Dis. 2024 Feb 11;1870(4):167066. doi: 10.1016/j.bbadis.2024.167066.
Haifeng Zhang 1,  Rong Liu 2,  Zhenghui Jing 2,  Chunying Li 3,  Wentao Fan 4,  Houli Li 5,  Hongbing Li 6,  Jie Ren 6,  Shiyu Cui 2,  Wenbao Zhao 2,  Lei Yu 7,  Yuhui Bai 8,  Shujing Liu 8,  Chunlu Fang 8,  Wenqi Yang 8,  Yuan Wei 8,  Liangming Li 9,  Shuang Peng 10
Affiliations

Affiliations

  • 1 Department of Pathology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China. Electronic address: zhf19841011@xjtu.edu.cn.
  • 2 Department of Pathology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
  • 3 School of Nursing, Li Shui University, Lishui, Zhejiang 323020, China.
  • 4 Guangzhou Huayin Medical Laboratory Center. Ltd, Guangzhou, Guangdong 510663, China.
  • 5 Department of Pharmacy, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
  • 6 Department of Internal Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
  • 7 Department of Pathophysiology, School of Medicine, Jinan University, Guangzhou, Guangdong 510632, China.
  • 8 Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou, Guangdong 510500, China.
  • 9 Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou, Guangdong 510500, China; School of Sport and Health Sciences, Guangzhou Sport University, Guangzhou, Guangdong 510500, China.
  • 10 Key Laboratory of Sports Technique, Tactics and Physical Function of General Administration of Sport of China, Scientific Research Center, Guangzhou Sport University, Guangzhou, Guangdong 510500, China; School of Sport and Health Sciences, Guangzhou Sport University, Guangzhou, Guangdong 510500, China. Electronic address: pengshuang@gzsport.edu.cn.
PMID: 38350542 DOI: 10.1016/j.bbadis.2024.167066
Abstract

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.

Keywords

Colon cancer; LRRC8A; Metastasis; NF-κB2; PIP2.

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