2. Academic Validation
  3. eIF3i facilitates NELFCD translation to promote metastasis via regulating EMT and invadopodia

eIF3i facilitates NELFCD translation to promote metastasis via regulating EMT and invadopodia

  • Br J Cancer. 2025 Nov 28. doi: 10.1038/s41416-025-03269-x.
Qing Huang # 1,  Juan Zhao 2 3,  Yang Zhang 1,  Ying Zhou 1,  Xuyang Yang 1,  Xiaoting Chen 4,  Mingtian Wei 1,  Junhong Han 5 6,  Yaguang Zhang # 7
Affiliations

Affiliations

  • 1 Laboratory of Gastrointestinal Tumor Epigenetics and Genomics, State Key Laboratory of Biotherapy and Cancer Center, and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, PR China.
  • 2 Department of Clinical Laboratory, Sichuan Provincial People's Hospital, Sichuan Academy of Medical Sciences, Chengdu, PR China.
  • 3 Chongzhou People's Hospital, Chengdu, PR China.
  • 4 Animal Experimental Center, West China Hospital, Sichuan University, Chengdu, PR China.
  • 5 Laboratory of Gastrointestinal Tumor Epigenetics and Genomics, State Key Laboratory of Biotherapy and Cancer Center, and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, PR China. [email protected].
  • 6 Tianfu Jincheng Laboratory, Frontiers Medical Center, Chengdu, PR China. [email protected].
  • 7 Laboratory of Gastrointestinal Tumor Epigenetics and Genomics, State Key Laboratory of Biotherapy and Cancer Center, and Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, PR China. [email protected].
  • # Contributed equally.
PMID: 41315067 DOI: 10.1038/s41416-025-03269-x
Abstract

Background: Translational reprogramming enables Cancer cells to drive tumour progression and metastasis. eIF3i is a core component of the translational regulatory machinery, but the underlying mechanisms through which it promotes tumour metastasis remain unclear.

Methods: Proteomic analysis identified eIF3i-regulated targets. Functional validation utilised in vitro and in vivo models, including migration/invasion assays, polysome profiling, RNA-binding assays (RIP and RNA pull-down), and mouse metastatic models. Clinical relevance was assessed in CRC patients with liver metastases.

Results: eIF3i was significantly overexpressed in metastatic CRC. Its knockdown inhibited cell migration, invasion, epithelial-mesenchymal transition (EMT), invadopodia formation in vitro, and lung metastasis in vivo. NELFCD was identified as a key downstream target, whose translation is directly promoted by eIF3i binding to its mRNA, independent of transcription. NELFCD knockdown phenocopied the anti-metastatic effects of eIF3i depletion. Crucially, the pro-metastatic capacity of eIF3i overexpression was abolished by concurrent NELFCD knockdown. eIF3i and NELFCD protein levels showed a significant positive correlation in clinical CRC metastases.

Conclusions: The eIF3i-NELFCD axis drives CRC metastasis by directly upregulating NELFCD translation, thereby facilitating EMT and invadopodia formation. This pathway represents a promising therapeutic target for inhibiting metastatic progression in CRC.

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