ETV4 promotes the growth, metastasis, glycolysis, and oxaliplatin resistance of colorectal cancer by transcription activation-mediated SLC38A5 upregulation

IF 2.9 4区医学 Q2 PATHOLOGY

Pathology, research and practice Pub Date : 2025-05-21 DOI:10.1016/j.prp.2025.156033

Yujun Huang , Jinyong He , Nan Chen , Xiuting Du , Junhui Peng

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引用次数: 0

Abstract

Background

Colorectal cancer (CRC) is one of the most common malignancies worldwide with a poor prognosis. Previous studies have indicated that solute carrier family 38 member 5 (SLC38A5), an amino acid transporter, plays an important role in some solid tumors. However, the role and mechanism of SLC38A5 in the progression of CRC are poorly deﬁned.

Methods

In this research, TIMER, UALCAN, and GEPIA databases were applied to analyze the expression of SLC38A5 in CRC. SLC38A5 and E26 transformation-specific variant 4 (ETV4) mRNA levels were determined using real-time quantitative polymerase chain reaction (RT-qPCR) assay. SLC38A5, ETV4, HK-2, and LDHA protein levels were measured using western blot. Cell proliferation, migration, invasion, and Oxaliplatin (L-OHP) resistance were examined using Cell Counting Kit-8 (CCK-8) assay and Transwell assay. Glucose consumption, lactate production, and ATP levels were assessed using relevant kits. Binding between ETV4 and SLC38A5 promoter was predicted by JASPAR and validated using Chromatin immunoprecipitation (ChIP) and dual-luciferase reporter assays. The biological role of ETV4 on CRC tumor growth was examined by the xenograft tumor model in vivo.

Results

ETV4 and SLC38A5 were highly expressed in CRC tissues and cells. Moreover, SLC38A5 deficiency could hinder CRC cell proliferation, migration, invasion, glycolysis, and improved L-OHP sensitivity in vitro. Mechanistically, ETV4 was a transcription factor of SLC38A5 and activated the transcriptional activity of SLC38A5 via binding to its promoter region. ETV4 silencing knockdown repressed tumor growth in vivo.

Conclusion

SLC38A5 transcriptionally mediated by ETV4 expedites CRC cell growth, metastasis, glycolysis, L-OHP resistance, which provides a promising therapeutic target for CRC treatment.

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ETV4通过转录激活介导的SLC38A5上调，促进结直肠癌的生长、转移、糖酵解和奥沙利铂耐药

结直肠癌（CRC）是世界范围内最常见的恶性肿瘤之一，预后较差。已有研究表明，溶质载体家族38成员5 （SLC38A5）是一种氨基酸转运蛋白，在某些实体肿瘤中起重要作用。然而，SLC38A5在结直肠癌进展中的作用和机制尚不明确。方法本研究采用TIMER、UALCAN和GEPIA数据库分析SLC38A5在结直肠癌中的表达。采用实时定量聚合酶链反应（RT-qPCR）检测SLC38A5和E26转化特异性变异4 (ETV4) mRNA水平。western blot检测SLC38A5、ETV4、HK-2、LDHA蛋白水平。采用细胞计数试剂盒-8 （CCK-8）法和Transwell法检测细胞增殖、迁移、侵袭和奥沙利铂（L-OHP）耐药性。使用相关试剂盒评估葡萄糖消耗、乳酸生成和ATP水平。通过JASPAR预测ETV4与SLC38A5启动子的结合，并通过染色质免疫沉淀（ChIP）和双荧光素酶报告基因检测进行验证。通过体内异种移植肿瘤模型检测ETV4对结直肠癌肿瘤生长的生物学作用。结果setv4和SLC38A5在结直肠癌组织和细胞中高表达。此外，SLC38A5缺乏可能会阻碍结直肠癌细胞的增殖、迁移、侵袭、糖酵解，并提高L-OHP的体外敏感性。从机制上讲，ETV4是SLC38A5的转录因子，通过结合SLC38A5的启动子区激活SLC38A5的转录活性。在体内，ETV4沉默敲低抑制肿瘤生长。结论ETV4转录介导的slc38a5可促进结直肠癌细胞的生长、转移、糖酵解和L-OHP耐药，为结直肠癌治疗提供了一个有前景的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pathology, research and practice 医学-病理学

CiteScore

5.00

自引率

3.60%

发文量

405

审稿时长

24 days

期刊介绍： Pathology, Research and Practice provides accessible coverage of the most recent developments across the entire field of pathology: Reviews focus on recent progress in pathology, while Comments look at interesting current problems and at hypotheses for future developments in pathology. Original Papers present novel findings on all aspects of general, anatomic and molecular pathology. Rapid Communications inform readers on preliminary findings that may be relevant for further studies and need to be communicated quickly. Teaching Cases look at new aspects or special diagnostic problems of diseases and at case reports relevant for the pathologist''s practice.