Tsai Kuei-Yen, Wei Po-Li, Lee Cheng-Chin, Zumbi Crystal Ngofi, Prince G M Shazzad Hossain, Batzorig Uyanga, Huang Chien-Yu, Chang Yu-Jia
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan.
Int J Med Sci. 2025 Mar 29;22(9):1992-2009. doi: 10.7150/ijms.109767. eCollection 2025.
Colorectal cancer (CRC) is one of the most prevalent cancers, posing a significant threat to human life. Although therapeutic approaches for advanced-stage patients have improved in recent years, there is still room for enhancing treatment response. Recent evidence suggests that dysregulation of nucleotide sugar transporters (NSTs) is associated with the development and progression of tumors. Therefore, this study aims to explore the potential therapeutic and prognostic implications of the solute carrier family 35 A (SLC35A) members in CRC. To achieve this, we performed integrative bioinformatics analysis using various publicly available databases, including GENT2, TCGA, UALCAN, cBioPortal, Kaplan-Meier plotter, The ROC plotter, GDSC, TISIDB, and TIMER. We compared gene expression profiles between CRC tumors and adjacent normal tissues, revealing that only SLC35A2 exhibited significant upregulation in tumors, while the other family members were downregulated. Additionally, higher SLC35A2 expression was found in microsatellite stable (MSS) colorectal tumors. Further analysis of TCGA and GEO datasets showed that patients with high SLC35A2 expression experienced poorer relapse-free survival. Next, we conducted gene set enrichment analysis (GSEA), and the results indicated that the upregulation of SLC35A2 is linked to cellular metabolism pathways, such as MYC Targets V2, Steroid Biosynthesis, Pentose Phosphate Pathway, and TCA Cycle. Furthermore, our CRC cell models revealed the tumor-promoting role of SLC35A2 and discovered that the upregulation of SLC35A2 is associated with chemoresistance against irinotecan. Additionally, we observed a negative correlation between SLC35A2 expression and the infiltration of immune cells, particularly cytotoxic CD8+ T cells and B cells. This suggests the immunomodulatory role of SLC35A2. In summary, SLC35A2 is abnormally upregulated in CRC, and patients with high SLC35A2 expression tend to have poor relapse-free survival. This may be due to its involvement in regulating cancer cell metabolic reprogramming, promoting tumor progression, modulating the immune landscape, and influencing treatment response. Consequently, SLC35A2 could serve as a significant prognostic factor and a potential therapeutic target in CRC.
结直肠癌（CRC）是最常见的癌症之一，对人类生命构成重大威胁。尽管近年来晚期患者的治疗方法有所改进，但在提高治疗反应方面仍有提升空间。最近的证据表明，核苷酸糖转运蛋白（NSTs）的失调与肿瘤的发生和发展有关。因此，本研究旨在探讨溶质载体家族35A（SLC35A）成员在结直肠癌中的潜在治疗和预后意义。为此，我们使用了各种公开可用的数据库进行综合生物信息学分析，包括GENT2、TCGA、UALCAN、cBioPortal、Kaplan-Meier plotter、ROC plotter、GDSC、TISIDB和TIMER。我们比较了结直肠癌肿瘤组织和相邻正常组织之间的基因表达谱，发现只有SLC35A2在肿瘤组织中显著上调，而其他家族成员则下调。此外，在微卫星稳定（MSS）的结直肠癌肿瘤中发现SLC35A2表达更高。对TCGA和GEO数据集的进一步分析表明，SLC35A2高表达的患者无复发生存期较差。接下来，我们进行了基因集富集分析（GSEA），结果表明SLC35A2的上调与细胞代谢途径有关，如MYC靶点V2、类固醇生物合成、磷酸戊糖途径和三羧酸循环。此外，我们的结直肠癌模型揭示了SLC35A2的促肿瘤作用，并发现SLC35A2的上调与对伊立替康的化疗耐药性有关。此外，我们观察到SLC35A2表达与免疫细胞的浸润之间存在负相关，特别是细胞毒性CD8+ T细胞和B细胞。这表明SLC35A2具有免疫调节作用。总之，SLC35A2在结直肠癌中异常上调，SLC35A2高表达的患者往往无复发生存期较差。这可能是由于它参与调节癌细胞代谢重编程、促进肿瘤进展、调节免疫格局以及影响治疗反应。因此，SLC35A2可作为结直肠癌的一个重要预后因素和潜在治疗靶点。
