The small GTP-binding Ras-like protein DIRAS2 promotes cell proliferation in oral leukoplakia via the RAF/MEK/MAPK pathway

IF 2.7 4区生物学 Q1 ANATOMY & MORPHOLOGY

Tissue & cell Pub Date : 2025-07-05 DOI:10.1016/j.tice.2025.103037

Jing Li , Zitong Tian , Wenjing Li , Min Wang , Xiaofei Tang , Min Zhang

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引用次数: 0

Abstract

Background

The small GTP-binding Ras-like protein DIRAS2 may function as tumor suppressors in some tumors. However, a precise relation of DIRAS2 to precancerous lesions and their progression into cancer remains uncharted. Methods. DIRAS2 expression was detected in human oral leukoplakia (OLK) tissues and normal epithelial tissues. Using the Crispr/Cas9 and Cre-LoxP technology, homozygous knockout DIRAS2^flox/flox mice were produced, and crossed to K14-Cre mice in which the Cre recombinase specifically expressed in the epithelium. Epithelium specific DIRAS2 conditional knockout mice were generated. 4NQO-induced mouse model of DIRAS2 conditional knockout mice and control mice was used to explore the impact of epithelium specific deletion of DIRAS2 on the progression of tongue precancerous lesions and underlining mechanism was investigated. Results and Conclusion. The expression of DIRAS2 was abnormally higher in human OLK tissues than that in normal mucosa tissues. DIRAS2 conditional knockout in epithelium could inhibit the progression of tongue precancerous lesions in mice induced by 4NQO within the period analyzed. Besides, cell proliferation was decreased and the MAPK signaling cascade proteins were down-regulated expressed in both DIRAS2 knockdown human dysplastic oral keratinocyte cells and the tongue precancerous tissues of DIRAS2 conditional-knockout mice compared with the control, respectively. In summary, DIRAS2 may promote cell proliferation of OLK via the RAF/MEK/MAPK pathway.

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小的gtp结合ras样蛋白DIRAS2通过RAF/MEK/MAPK途径促进口腔白斑细胞增殖

小的gtp结合ras样蛋白DIRAS2可能在某些肿瘤中起肿瘤抑制作用。然而，DIRAS2与癌前病变及其发展为癌症的确切关系尚不清楚。方法。在人口腔白斑（OLK）组织和正常上皮组织中检测到DIRAS2的表达。利用Crispr/Cas9和Cre- loxp技术，制备了纯合敲除的DIRAS2flox/flox小鼠，并与Cre重组酶在上皮中特异性表达的K14-Cre小鼠杂交。产生上皮特异性DIRAS2条件敲除小鼠。采用4nqo诱导的小鼠模型和对照小鼠，探讨上皮特异性缺失DIRAS2对舌癌前病变进展的影响，并探讨其机制。结果与结论。人OLK组织中DIRAS2的表达异常高于正常粘膜组织。在分析期内，上皮细胞条件敲除DIRAS2可抑制4NQO诱导的小鼠舌癌前病变的进展。此外，与对照组相比，敲除DIRAS2的人口腔角化细胞增生异常细胞和条件敲除DIRAS2的小鼠舌癌前组织中，细胞增殖减少，MAPK信号级联蛋白表达下调。综上所述，DIRAS2可能通过RAF/MEK/MAPK通路促进OLK细胞增殖。

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来源期刊

Tissue & cell 医学-解剖学与形态学

CiteScore

3.90

自引率

0.00%

发文量

234

期刊介绍： Tissue and Cell is devoted to original research on the organization of cells, subcellular and extracellular components at all levels, including the grouping and interrelations of cells in tissues and organs. The journal encourages submission of ultrastructural studies that provide novel insights into structure, function and physiology of cells and tissues, in health and disease. Bioengineering and stem cells studies focused on the description of morphological and/or histological data are also welcomed. Studies investigating the effect of compounds and/or substances on structure of cells and tissues are generally outside the scope of this journal. For consideration, studies should contain a clear rationale on the use of (a) given substance(s), have a compelling morphological and structural focus and present novel incremental findings from previous literature.