对 SLC 基因替代剪接的分析发现,SLC7A6 RI 异构体是结直肠癌的治疗靶点。

IF 5.7 2区 医学 Q1 Medicine
Cancer Science Pub Date : 2024-10-15 DOI:10.1111/cas.16351
Chao Sun, Boning Zeng, Jilong Zhou, Nan Li, Mingwei Li, Chaowei Zhu, Shouxia Xie, Yifei Wang, Shaoxiang Wang, Xiao Wang
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引用次数: 0

摘要

替代剪接(AS)是转录后调控的一种重要机制,与多种癌症过程有关。据报道,溶质载体(SLC)转运体的几种剪接变体在肿瘤发生和发展中起着关键作用。然而,目前还缺乏对结肠腺癌(COAD)中 SLC 的 AS 图谱的深入分析。在此,我们分析了癌症基因组图谱中的数据,发现了243个SLC基因中的1215个AS事件,其中包括涉及COAD中62个SLC基因的109个差异表达AS(DEAS)事件。差异剪接的SLC富集在生物过程中,包括跨膜转运体活性、转运体活性、铁变态反应和胆碱代谢。与邻近的正常组织相比,COAD 患者的肿瘤组织中线粒体载体 SLC25A16 同工酶的表达较长,这与生物信息学分析结果一致。我们预测了与存活相关的 DEAS 的蛋白编码序列和跨膜螺旋,发现剪接位点的变化改变了其跨膜蛋白的数量和结构。我们根据筛选出的6-SLC-AS(SLC7A6_RI_37208 (SLC7A6-RI)、SLC11A2_AP_21724、SLC2A8_ES_87631、SLC35B1_AA_42317、SLC39A11_AD_43204和SLC7A8_AP_26712)建立了一个预后风险模型。敲除 SLC7A6-RI 同工型的内含子区会增强结肠癌细胞的增殖。在体内,敲除 SLC7A6-RI 同工酶的内含子区会增强结肠癌的肿瘤生长。从机理上讲,si-SLC7A6-RI同工酶通过激活PI3K-Akt-mTOR信号通路和促进细胞增殖来发挥致癌作用,这一点可以通过关键调节因子磷酸化哺乳动物雷帕霉素靶标(p-mTOR)和细胞增殖标志物增殖细胞核抗原(PCNA)的表达增加得到证实。我们的研究阐明了SLC-AS在COAD中的作用,突出了其作为预后和治疗靶点的潜力,并强调了SLC7A6-RI在结肠癌进展过程中的抑制作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Analysis of SLC genes alternative splicing identifies the SLC7A6 RI isoform as a therapeutic target for colorectal cancer.

Alternative splicing (AS), a crucial mechanism in post-transcriptional regulation, has been implicated in diverse cancer processes. Several splicing variants of solute carrier (SLC) transporters reportedly play pivotal roles in tumorigenesis and tumor development. However, an in-depth analysis of AS landscapes of SLCs in colon adenocarcinoma (COAD) is lacking. Herein, we analyzed data from The Cancer Genome Atlas and identified 1215 AS events across 243 SLC genes, including 109 differentially expressed AS (DEAS) events involving 62 SLC genes in COAD. Differentially spliced SLCs were enriched in biological processes, including transmembrane transporter activity, transporter activity, ferroptosis, and choline metabolism. In patients with COAD, tumor tissues exhibited higher expression of longer mitochondrial carrier SLC25A16 isoforms than adjacent normal tissues, consistent with bioinformatics analysis. Protein-coding sequences and transmembrane helices of survival-related DEAS were predicted, revealing that shifts in splicing sites altered the number and structure of their transmembrane proteins. We developed a prognostic risk model based on the screened 6-SLC-AS (SLC7A6_RI_37208 (SLC7A6-RI), SLC11A2_AP_21724, SLC2A8_ES_87631, SLC35B1_AA_42317, SLC39A11_AD_43204, and SLC7A8_AP_26712). Knockdown of the intronic region of SLC7A6-RI isoform enhanced colon cancer cell proliferation. In vivo, knockdown of the intronic region of SLC7A6-RI isoform enhanced tumor growth in colon cancer. Mechanistically, si-SLC7A6-RI isoform exerted oncogenic effects by activating the PI3K-Akt-mTOR signaling pathway and promoting cell proliferation, evidenced by increased expression of key regulators Phosphorylated Mammalian Target of Rapamycin (p-mTOR) and a cell proliferation marker Proliferating Cell Nuclear Antigen (PCNA) using western blotting. Our study elucidated SLC-AS in COAD, highlighting its potential as a prognostic and therapeutic target and emphasizing the suppressive influence of SLC7A6-RI in colon cancer progression.

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来源期刊
Cancer Science
Cancer Science ONCOLOGY-
CiteScore
9.90
自引率
3.50%
发文量
406
审稿时长
17 weeks
期刊介绍: Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.
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