Department of Colorectal Surgery, Cancer Hospital Affiliated to Shanxi Medical University, Shanxi Province Cancer Hospital, Shanxi Hospital Affiliated to Cancer Hospital, Chinese Academy of Medical Sciences, Taiyuan, China.
Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Capital Medical University, No.10 Xitoutiao, You An Men Wai, Beijing, 100069, China.
J Exp Clin Cancer Res. 2024 Jul 27;43(1):208. doi: 10.1186/s13046-024-03114-8.
Colorectal cancer (CRC) metachronous liver metastasis is a significant clinical challenge, largely attributable to the late detection and the intricate molecular mechanisms that remain poorly understood. This study aims to elucidate the role of Solute Carrier Family 14 Member 1 (SLC14A1) in the pathogenesis and progression of CRC metachronous liver metastasis.
We conducted a comprehensive analysis of CRC patient data from The Cancer Genome Atlas and GSE40967 databases, focusing on the differential expression of genes associated with non-metachronous liver metastasis and metachronous liver metastasis. Functional assays, both in vitro and in vivo, were performed to assess the biological impact of SLC14A1 modulation in CRC cells. Gene set enrichment analysis, molecular assays and immunohistochemical analyses on clinical specimens were employed to unravel the underlying mechanisms through which SLC14A1 exerts its effects.
SLC14A1 was identified as a differentially expressed gene, with its overexpression significantly correlating with poor relapse-free and overall survival. Mechanistically, elevated SLC14A1 levels enhanced CRC cell invasiveness and migratory abilities, corroborated by upregulated TGF-β/Smad signaling and Epithelial-Mesenchymal Transition. SLC14A1 interacted with TβRII and stabilized TβRII protein, impeding its Smurf1-mediated K48-linked ubiquitination and degradation, amplifying TGF-β/Smad signaling. Furthermore, TGF-β1 reciprocally elevated SLC14A1 mRNA expression, with Snail identified as a transcriptional regulator, binding downstream of SLC14A1's transcription start site, establishing a positive feedback loop. Clinically, SLC14A1, phosphorylated Smad2, and Snail were markedly upregulated in CRC patients with metachronous liver metastasis, underscoring their potential as prognostic markers.
Our findings unveil SLC14A1 as a critical regulator in CRC metachronous liver metastasis, providing novel insights into the molecular crosstalk between SLC14A1 and TGF-β/Smad signaling. These discoveries not only enhance our understanding of CRC metachronous liver metastasis pathogenesis, but also highlight SLC14A1 as a promising target for therapeutic intervention and predictive marker.
结直肠癌（CRC）异时性肝转移是一个重大的临床挑战，主要归因于晚期发现和分子机制的复杂性，这些机制仍知之甚少。本研究旨在阐明溶质载体家族 14 成员 1（SLC14A1）在 CRC 异时性肝转移发生和进展中的作用。
我们对来自癌症基因组图谱和 GSE40967 数据库的 CRC 患者数据进行了全面分析，重点关注与非异时性肝转移和异时性肝转移相关的基因的差异表达。我们进行了体外和体内功能测定，以评估 SLC14A1 调节对 CRC 细胞的生物学影响。我们对临床标本进行了基因集富集分析、分子测定和免疫组织化学分析，以揭示 SLC14A1 发挥作用的潜在机制。
SLC14A1 被鉴定为差异表达基因，其过表达与较差的无复发生存率和总体生存率显著相关。在机制上，升高的 SLC14A1 水平增强了 CRC 细胞的侵袭性和迁移能力，这与 TGF-β/Smad 信号的上调和上皮间质转化一致。SLC14A1 与 TβRII 相互作用并稳定 TβRII 蛋白，阻止其 Smurf1 介导的 K48 连接泛素化和降解，放大 TGF-β/Smad 信号。此外，TGF-β1 反过来上调 SLC14A1 mRNA 表达，Snail 被鉴定为转录调节剂，结合 SLC14A1 转录起始位点下游，建立正反馈环。临床上，CRC 患者中 SLC14A1、磷酸化 Smad2 和 Snail 在异时性肝转移中明显上调，表明它们具有作为预后标志物的潜力。
我们的研究结果揭示了 SLC14A1 是 CRC 异时性肝转移的关键调节因子，为 SLC14A1 与 TGF-β/Smad 信号之间的分子相互作用提供了新的见解。这些发现不仅增强了我们对 CRC 异时性肝转移发病机制的理解，还强调了 SLC14A1 作为治疗干预和预测标志物的潜力。
