Ding Lei, Wang Yong, Tang Zhentao, Ni Chenbo, Zhang Qian, Zhai Qidi, Liang Chao, Li Jie
Department of Urology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, 210009, Nanjing,, China.
Department of Urology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, 299 Qingyang Road, 214023, Suqian, China.
Nutr Metab (Lond). 2024 Apr 2;21(1):17. doi: 10.1186/s12986-024-00791-2.
Previous studies have unequivocally demonstrated that the vitamin D (VD) metabolism pathway significantly influences prognosis and sensitivity to hormone therapy in prostate cancer (PCa). However, the precise underlying mechanism remains unclear.
We performed molecular profiling of 1045 PCa patients, leveraging genes linked to VD synthesis and VD receptors. We then identified highly variable gene modules with substantial associations with patient stratification. Subsequently, we intersected these modules with differentially expressed genes between PCa and adjacent paracancerous tissues. Following a meticulous process involving single-factor regression and LASSO regression to eliminate extraneous variables and construct a prognostic model. Within the high-risk subgroup defined by the calculated risk score, we analyzed their differences in cell infiltration, immune status, mutation landscape, and drug sensitivity. Finally, we selected Apolipoprotein E (APOE), which featured prominently in this model for further experimental exploration to evaluate its potential as a therapeutic target.
The prognostic model established in this study had commendable predictive efficacy. We observed diminished infiltration of various T-cell subtypes and reduced expression of co-stimulatory signals from antigen-presenting cells. Mutation analysis revealed that the high-risk cohort harbored a higher frequency of mutations in the TP53 and FOXA genes. Notably, drug sensitivity analysis suggested the heightened responsiveness of high-risk patients to molecular inhibitors targeting the Bcl-2 and MAPK pathways. Finally, our investigation also confirmed that APOE upregulates the proliferative and invasive capacity of PCa cells and concurrently enhances resistance to androgen receptor antagonist therapy.
This comprehensive study elucidated the potential mechanisms through which this metabolic pathway orchestrates the biological behavior of PCa and findings hold promise in advancing the development of combination therapies in PCa.
先前的研究已明确表明，维生素D（VD）代谢途径显著影响前列腺癌（PCa）的预后和对激素治疗的敏感性。然而，确切的潜在机制仍不清楚。
我们对1045例PCa患者进行了分子谱分析，利用与VD合成和VD受体相关的基因。然后，我们确定了与患者分层有显著关联的高度可变基因模块。随后，我们将这些模块与PCa和相邻癌旁组织之间的差异表达基因进行交叉分析。经过单因素回归和LASSO回归这一细致过程以消除无关变量并构建预后模型。在由计算出的风险评分定义的高危亚组中，我们分析了它们在细胞浸润、免疫状态、突变图谱和药物敏感性方面的差异。最后，我们选择了在该模型中表现突出的载脂蛋白E（APOE）进行进一步的实验探索，以评估其作为治疗靶点的潜力。
本研究建立的预后模型具有值得称赞的预测效能。我们观察到各种T细胞亚型的浸润减少以及抗原呈递细胞共刺激信号的表达降低。突变分析显示，高危队列中TP53和FOXA基因的突变频率更高。值得注意的是，药物敏感性分析表明高危患者对靶向Bcl-2和MAPK途径的分子抑制剂反应性增强。最后，我们的研究还证实，APOE上调PCa细胞的增殖和侵袭能力，并同时增强对雄激素受体拮抗剂治疗的抗性。
这项全面的研究阐明了该代谢途径调控PCa生物学行为的潜在机制，其研究结果有望推动PCa联合治疗的发展。
