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

Xingzhao Ji; Mingqiang Liu; Tianyi Zhang; Weiying Zhang; Fuyuan Xue; Qiang Wan; Yi Liu

doi:10.1016/j.jare.2024.04.028

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. Online ahead of print.

Authors

Xingzhao Ji¹, Mingqiang Liu², Tianyi Zhang³, Weiying Zhang⁴, Fuyuan Xue³, Qiang Wan⁵, Yi Liu⁶

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: wanqiang@sdu.edu.cn.
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: liuyishanyi@email.sdu.edu.cn.

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-Kras^G12D/+;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-Kras^G12D/+;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.