Guangnan Huang, Lei Gao, Shu Fang, Likun Xu, Xiaowei Zhao
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引用次数: 0
Abstract
Background: Epithelial–mesenchymal transition and cancer cell stemness (CSC) are critical processes that driving the invasion and lethality of lung adenocarcinoma (LUAD). The chromatin remodeler ARID4B has been implicated in other cancers; however, its specific role and underlying mechanism in LUAD progression remain unclear.
Aims: To elucidate the function of ARID4B in LUAD.
Study design: This study integrated bioinformatics analysis, in vitro cellular functional assays, and in vivo orthotopic lung cancer models to investigate the oncogenic role of ARID4B.
Methods: ARID4B expression and its correlation with patient prognosis were analyzed using public databases. ARID4B was silenced using two independent short hairpin RNAs in A549 and H1650 LUAD cell lines, and subsequent changes in invasion, migration, and stemness markers were assessed. Tumor metastasis was evaluated using orthotopic and tail-vein injection mouse models. The regulatory mechanism by which ARID4B controls GPRC5C expression was investigated using dual-luciferase reporter and chromatin immunoprecipitation assays.
Results: ARID4B was significantly upregulated in LUAD and was associated with poor patient prognosis. Silencing ARID4B in LUAD cells significantly reduced their invasion and migration capabilities (adj. p < 0.01). Furthermore, ARID4B knockdown resulted in downregulation of SNAIL, upregulation of E-cadherin, and impairment of stem-like characteristics, as demonstrated by decreased CSC marker expression and reduced sphere-forming ability (adj. p < 0.05). In the orthotopic model, ARID4B deficiency markedly inhibited tumor metastasis (adj. p < 0.001). Mechanistically, ARID4B transcriptionally activated GPRC5C (adj. p < 0.01). Furthermore, ARID4B knockdown increased histone H1 occupancy at the GPRC5C promoter (adj. p < 0.01), indicating that ARID4B facilitates an open chromatin state. Rescue experiments further confirmed that GPRC5C is required for ARID4B-mediated maintenance of tumor invasiveness and cancer stemness.
Conclusion: ARID4B promotes LUAD malignancy by transcriptionally activating GPRC5C, thereby driving EMT and cancer stemness.
期刊介绍：
The Balkan Medical Journal (Balkan Med J) is a peer-reviewed open-access international journal that publishes interesting clinical and experimental research conducted in all fields of medicine, interesting case reports and clinical images, invited reviews, editorials, letters, comments and letters to the Editor including reports on publication and research ethics. The journal is the official scientific publication of the Trakya University Faculty of Medicine, Edirne, Turkey and is printed six times a year, in January, March, May, July, September and November. The language of the journal is English.
The journal is based on independent and unbiased double-blinded peer-reviewed principles. Only unpublished papers that are not under review for publication elsewhere can be submitted. Balkan Medical Journal does not accept multiple submission and duplicate submission even though the previous one was published in a different language. The authors are responsible for the scientific content of the material to be published. The Balkan Medical Journal reserves the right to request any research materials on which the paper is based.
The Balkan Medical Journal encourages and enables academicians, researchers, specialists and primary care physicians of Balkan countries to publish their valuable research in all branches of medicine. The primary aim of the journal is to publish original articles with high scientific and ethical quality and serve as a good example of medical publications in the Balkans as well as in the World.
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