Abstract：
BACKGROUND: Until 2021, colon cancer was a leading cancer globally. Early detection improves outcomes; however, advanced cases still having poor prognosis. Therefore, an understanding of associated molecular mechanisms is crucial for developing new preventive and therapeutic strategies for colon cancer.
METHODS: The TCGA database was analyzed to assess melanocortin 1receptor (MC1R) expression in colon cancer and its link with patient prognosis. Further, models and diverse experimental techniques were employed to investigate the impact of MC1R on colon cancer progression and its underlying mechanism was elucidated.
RESULTS: In a follow-up study of clinical patients, the important role of MC1R was identified in the development of colon cancer. First, MC1R was expressed more highly in colon tumor tissues than in adjacent tissues. In addition, MC1R was associated with colon cancer prognosis, and higher expression of MC1R tended to predict a worse prognosis. This conclusion was verified in MC1R-/- mice, which showed a greater resistance to tumor growth than wild-type mice, as expected. Further investigation revealed a significant change in the portion of Tregs in MC1R-/- mice, while the portion of CD4 + and CD8 + T cells remained unchanged. The in vitro experiments revealed a weaker ability of the MC1R-/- T cells to differentiate into Tregs. Previous studies report that the functional integrity of Tregs is interwoven with cellular metabolism. Therefore, MC1R was deduced to regulate the differentiation of Tregs by reprogramming the metabolism. As expected, MC1R-/- T cells exhibited weaker mitochondrial function and a lower aerobic oxidation capacity. Concurrently, the MC1R-/- T cells had stronger limiting effects on colon cancer cells. According to these results, the MC1R inhibitor was hypothesized as a potential therapeutic agent to suppress colon cancer. The results showed that upon MC1R suppression, the tumors in the mice developed more slowly, and the mice survived longer, potentially providing a novel strategy to treat clinical colon cancer.
CONCLUSIONS: By regulating Tregs differentiation, MC1R overexpression in colon cancer correlates with poor prognosis, while MC1R inhibition shows potential as a therapeutic approach to slow tumor growth and enhance survival.
METHODS: The TCGA database was analyzed to assess melanocortin 1receptor (MC1R) expression in colon cancer and its link with patient prognosis. Further, models and diverse experimental techniques were employed to investigate the impact of MC1R on colon cancer progression and its underlying mechanism was elucidated.
RESULTS: In a follow-up study of clinical patients, the important role of MC1R was identified in the development of colon cancer. First, MC1R was expressed more highly in colon tumor tissues than in adjacent tissues. In addition, MC1R was associated with colon cancer prognosis, and higher expression of MC1R tended to predict a worse prognosis. This conclusion was verified in MC1R-/- mice, which showed a greater resistance to tumor growth than wild-type mice, as expected. Further investigation revealed a significant change in the portion of Tregs in MC1R-/- mice, while the portion of CD4 + and CD8 + T cells remained unchanged. The in vitro experiments revealed a weaker ability of the MC1R-/- T cells to differentiate into Tregs. Previous studies report that the functional integrity of Tregs is interwoven with cellular metabolism. Therefore, MC1R was deduced to regulate the differentiation of Tregs by reprogramming the metabolism. As expected, MC1R-/- T cells exhibited weaker mitochondrial function and a lower aerobic oxidation capacity. Concurrently, the MC1R-/- T cells had stronger limiting effects on colon cancer cells. According to these results, the MC1R inhibitor was hypothesized as a potential therapeutic agent to suppress colon cancer. The results showed that upon MC1R suppression, the tumors in the mice developed more slowly, and the mice survived longer, potentially providing a novel strategy to treat clinical colon cancer.
CONCLUSIONS: By regulating Tregs differentiation, MC1R overexpression in colon cancer correlates with poor prognosis, while MC1R inhibition shows potential as a therapeutic approach to slow tumor growth and enhance survival.
摘要：
背景：直到2021年，结肠癌一直是全球领先的癌症。早期检测可改善结果；然而，晚期病例仍有不良预后。因此,了解相关的分子机制对于开发新的结肠癌预防和治疗策略至关重要.
方法：分析TCGA数据库以评估黑皮质素1受体（MC1R）在结肠癌中的表达及其与患者预后的联系。Further,采用模型和多种实验技术研究MC1R对结肠癌进展的影响，并阐明其潜在机制。
结果：在对临床患者的随访研究中，MC1R在结肠癌发生发展中的重要作用。首先,MC1R在结肠肿瘤组织中的表达高于癌旁组织。此外,MC1R与结肠癌预后相关,MC1R的高表达倾向于预测预后较差。这一结论在MC1R-/-小鼠中得到了验证,比野生型小鼠对肿瘤生长有更大的抵抗力，如预期。进一步的调查显示MC1R-/-小鼠中Tregs的部分发生了显着变化，而CD4+和CD8+T细胞部分保持不变。体外实验显示MC1R-/-T细胞分化为Tregs的能力较弱。先前的研究报道Tregs的功能完整性与细胞代谢交织在一起。因此,推断MC1R通过重编程代谢来调节Tregs的分化。不出所料,MC1R-/-T细胞表现出较弱的线粒体功能和较低的有氧氧化能力。同时,MC1R-/-T细胞对结肠癌细胞有较强的限制作用。根据这些结果,MC1R抑制剂被认为是抑制结肠癌的潜在治疗剂.结果表明，在MC1R抑制下，小鼠体内的肿瘤发展更慢，老鼠存活的时间更长，可能提供一种治疗临床结肠癌的新策略。
结论：通过调节Tregs分化，结肠癌中MC1R过表达与不良预后相关,而MC1R抑制显示出作为减缓肿瘤生长和提高生存率的治疗方法的潜力。
方法：分析TCGA数据库以评估黑皮质素1受体（MC1R）在结肠癌中的表达及其与患者预后的联系。Further,采用模型和多种实验技术研究MC1R对结肠癌进展的影响，并阐明其潜在机制。
结果：在对临床患者的随访研究中，MC1R在结肠癌发生发展中的重要作用。首先,MC1R在结肠肿瘤组织中的表达高于癌旁组织。此外,MC1R与结肠癌预后相关,MC1R的高表达倾向于预测预后较差。这一结论在MC1R-/-小鼠中得到了验证,比野生型小鼠对肿瘤生长有更大的抵抗力，如预期。进一步的调查显示MC1R-/-小鼠中Tregs的部分发生了显着变化，而CD4+和CD8+T细胞部分保持不变。体外实验显示MC1R-/-T细胞分化为Tregs的能力较弱。先前的研究报道Tregs的功能完整性与细胞代谢交织在一起。因此,推断MC1R通过重编程代谢来调节Tregs的分化。不出所料,MC1R-/-T细胞表现出较弱的线粒体功能和较低的有氧氧化能力。同时,MC1R-/-T细胞对结肠癌细胞有较强的限制作用。根据这些结果,MC1R抑制剂被认为是抑制结肠癌的潜在治疗剂.结果表明，在MC1R抑制下，小鼠体内的肿瘤发展更慢，老鼠存活的时间更长，可能提供一种治疗临床结肠癌的新策略。
结论：通过调节Tregs分化，结肠癌中MC1R过表达与不良预后相关,而MC1R抑制显示出作为减缓肿瘤生长和提高生存率的治疗方法的潜力。
