KRAS/PI3K axis driven GTF3C6 expression and promotes LUAD via FAK pathway

  • J Adv Res. 2024 Apr 27:S2090-1232(24)00171-1. doi: 10.1016/j.jare.2024.04.028.
Xingzhao Ji  1 ,  Mingqiang Liu  2 ,  Tianyi Zhang  3 ,  Weiying Zhang  4 ,  Fuyuan Xue  3 ,  Qiang Wan  5 ,  Yi Liu  6
Affiliations
  • 1. Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Infections Respiratory Disease, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China.
  • 2. Key Laboratory of Cell Metabolism in Medical and Health of Shandong Provincial Health Commission, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Department of Pharmacy, Pingdu People's Hospital, Qingdao, Shandong 266799, China.
  • 3. Key Laboratory of Cell Metabolism in Medical and Health of Shandong Provincial Health Commission, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
  • 4. Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.
  • 5. Key Laboratory of Cell Metabolism in Medical and Health of Shandong Provincial Health Commission, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China. Electronic address: [email protected].
  • 6. Department of Pulmonary and Critical Care Medicine, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China; Shandong Key Laboratory of Infections Respiratory Disease, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China. Electronic address: [email protected].
PMID: 38685529 DOI: 10.1016/j.jare.2024.04.028
Abstract

Introduction: Effective targeting drugs for KRAS mutation-mediated Lung Adenocarcinoma (LUAD) are currently are limited.

Objectives: Investigating and intervening in the downstream key target genes of KRAS is crucial for clinically managing KRAS mutant-driven LUAD. GTF3C6, a newly identified member of the general transcription factor III (GTF3) family, plays a role in the transcription of RNA polymerase III (pol III)-dependent genes. However, its involvement in Cancer remains unexplored.

Methods: This study examined the expression, roles, and potential molecular mechanisms of GTF3C6 in LUAD tissues, LSL-KrasG12D/+;LSL-p53-/- LUAD mouse models, and LUAD patients-derived Organoid using Western blot, qRT-PCR, immunofluorescence, immunohistochemistry, and gene manipulation assays.

Results: We present the first evidence that GTF3C6 is highly expressed in LUAD tissues, LSL-KrasG12D/+;LSL-p53-/- LUAD mouse models, and LUAD organoids, correlating with poor clinical prognosis. Furthermore, GTF3C6 was found to promote anchorage-independent proliferation, migration, and invasion of LUAD cells. Mechanistically, KRAS mutation drives GTF3C6 expression through the PI3K pathway, and GTF3C6 knockdown reverses the malignant phenotype of KRAS mutation-driven LUAD cells. Additionally, the FAK pathway emerged as a crucial downstream signaling pathway through which GTF3C6 mediates the malignant phenotype of LUAD. Finally, GTF3C6 knockdown suppresses LUAD Organoid formation and inhibits tumor growth in vivo.

Conclusion: Our findings demonstrate that GTF3C6, driven by KRAS mutation, promotes LUAD development by regulating FAK phosphorylation, suggesting its potential as a biomarker and therapeutic target in KRAS mutant-driven LUAD.

Keywords
FAK; GTF3C6; KRAS; LUAD.
Products