Analysis of SLC genes alternative splicing identifies the SLC7A6 RI isoform as a therapeutic target for colorectal cancer

Abstract 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.