Sun Chao, Zeng Boning, Zhou Jilong, Li Nan, Li Mingwei, Zhu Chaowei, Xie Shouxia, Wang Yifei, Wang Shaoxiang, Wang Xiao
Department of Pharmacy, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, China.
Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, China.
Cancer Sci. 2025 Jan;116(1):233-247. doi: 10.1111/cas.16351. Epub 2024 Oct 15.
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.
可变剪接（AS）是转录后调控中的一种关键机制，与多种癌症进程有关。据报道，溶质载体（SLC）转运蛋白的几种剪接变体在肿瘤发生和肿瘤发展中起关键作用。然而，目前缺乏对结肠腺癌（COAD）中SLC可变剪接图谱的深入分析。在此，我们分析了来自癌症基因组图谱的数据，鉴定出243个SLC基因中的1215个可变剪接事件，其中包括COAD中涉及62个SLC基因的109个差异表达可变剪接（DEAS）事件。差异剪接的SLC在生物过程中富集，包括跨膜转运蛋白活性、转运蛋白活性、铁死亡和胆碱代谢。在COAD患者中，肿瘤组织中线粒体载体SLC25A16较长异构体的表达高于相邻正常组织，这与生物信息学分析结果一致。对与生存相关的DEAS的蛋白质编码序列和跨膜螺旋进行了预测，结果显示剪接位点的改变会改变其跨膜蛋白的数量和结构。我们基于筛选出的6个SLC-AS（SLC7A6_RI_37208（SLC7A6-RI）、SLC11A2_AP_21724、SLC2A8_ES_87631、SLC35B1_AA_42317、SLC39A11_AD_43204和SLC7A8_AP_26712）构建了一个预后风险模型。敲低SLC7A6-RI异构体的内含子区域可增强结肠癌细胞的增殖。在体内，敲低SLC7A6-RI异构体的内含子区域可促进结肠癌肿瘤生长。机制上，si-SLC7A6-RI异构体通过激活PI3K-Akt-mTOR信号通路并促进细胞增殖发挥致癌作用，蛋白质印迹法检测关键调节因子磷酸化雷帕霉素靶蛋白（p-mTOR）和细胞增殖标志物增殖细胞核抗原（PCNA）表达增加可证明这一点。我们的研究阐明了COAD中的SLC可变剪接，突出了其作为预后和治疗靶点的潜力，并强调了SLC7A6-RI对结肠癌进展的抑制作用。
