Colon cancer is characterized by high inter-patient variability and spatial heterogeneity, which can impact prognosis and treatment response. Previous studies have suggested a role for hydrogen sulfide in the development of colon cancer, and explored its potential as a therapeutic target. However, no systematic analysis has been conducted to investigate the prognostic and treatment response value of hydrogen sulfide-related genes in colon cancer. In this study, we identified 12 hydrogen sulfide-related genes significantly associated with colon cancer prognosis, and used these genes to classify colon cancer into three stable molecular subtypes. These subtypes exhibited significant differences in prognosis, immune landscape, and treatment response. Our findings have important implications for clinical diagnosis, personalized treatment planning, and new drug development in colon cancer.
Previous research has partially elucidated the roles of prognosis-related HSRGs in cancer occurrence and development, as well as their potential as targets for cancer treatment. CD36 is a transmembrane glycoprotein involved in various biological processes, including lipid uptake, immune recognition, inflammation, molecular adhesion, and cell apoptosis. CD36 has been demonstrated to promote tumor metastasis, therapy resistance, angiogenesis, and mediate tumor immune tolerance [17]. Glutathione S-transferase mu 1 (GSTM1) is significantly downregulated in colon cancer and its expression level is significantly associated with dendritic cells, B cells, neutrophils, and macrophages [18]. Additionally, GSTM1 gene mutations are associated with colorectal cancer risk [19]. Leptin (LEP), the most famous adipokine highly expressed in colorectal cancer is related to the sensitivity of chemotherapy drug 5-fluorouracil (5-FU) [20, 21]. Tissue metalloprotease inhibitor I (TIMP1) has been widely confirmed as a prognostic biomarker for colon cancer. It can regulate colon cancer progression and metastasis by modulating FAK-PI3K/AKT and MAPK pathways [22]. Increased expression of long non-coding RNA H19 is associated with colorectal cancer recurrence [23], and its overexpression induces resistance to 1,25(OH)2D3 in colon cancer [24]. Recent studies have shown that cancer-associated fibroblasts promote the stemness and chemoresistance of colorectal cancer through transferring exosomal lncRNA H19. High methylation of the microtubule-associated protein tau (MAPT) promoter region is linked to poor prognosis in patients with colorectal cancer [25]. MIR126 is a novel regulatory factor in colon cancer that targets multiple genes to control the migration and invasion of colon cancer cells [26].
Recent research has indicated that a reduction in endogenous H2S levels can facilitate the development of a favorable immune microenvironment in colorectal cancer tissues. Consequently, an investigation was conducted to assess differences in tumor immune cell infiltration among colon cancer molecular subtypes derived from HSRG. The results demonstrated varying degrees of infiltration by different immune cells across these subtypes, including plasma cells, CD4 and CD8 T cells, NK cells, and macrophages. These significant differences in the immune microenvironment are partly responsible for determining prognosis and treatment response [27], as evidenced by subsequent analyses of drug sensitivity and immune therapy response. Furthermore, the study revealed a noteworthy correlation between certain prognostic-related HSRG expressions and macrophage infiltration, such as CD36, LEP, MIR126,NOS2, and TIMP1. Previous studies have shown that high levels of CD36 expression are associated with M2-type MAMs infiltration within tumors, leading to highly immunosuppressive tumor microenvironments [28]. Additionally, miR-126 promotes the transition from M1 to M2 macrophage phenotypes via VEGFA and KLF4 [29]. Therefore, further exploration into the role of these HSRGs in shaping immune cell infiltration and tumor microenvironments is highly valuable.
Among the two most significant molecular subtypes in terms of prognosis, our study revealed that immune-related biological processes were significantly suppressed in the subtype with poorer prognosis, while processes related to Wnt signaling pathway regulation were significantly activated. The Wnt signaling pathway, also known as the Wnt/β-catenin signaling pathway, is a well-known driver of colorectal cancer and plays a crucial role in its pathogenesis [30]. Drugs targeting this pathway have been developed for treating colorectal cancer and are commonly used in clinical practice [30]. Activation of immune-related processes, such as B cell-mediated immunity and humoral immune response mediated by circulating immunoglobulin, helps establish a robust tumor immune microenvironment that improves treatment response and prognosis. Additionally, we observed significant suppression of cytokine-cytokine receptor interaction in the subtype with poor prognosis, which is associated with the survival ability of colon cancer cells [31]. These findings provide valuable insights for further basic experiments.
Finally, a prognostic risk feature derived from HSRG was constructed and employed to develop a colon cancer prognostic assessment nomogram model, which can provide more accurate prognostic predictions for colon cancer patients. Nonetheless, there are certain limitations to this study. Firstly, the prognostic risk model based on public databases lacks validation from prospective clinical trials. Furthermore, the roles and mechanisms of related biomarker genes in the pathogenesis of colorectal cancer require further elucidation through basic experiments.