PO.EN01.02 · 内分泌肿瘤
氧固醇磺基转移酶在前列腺癌抑制中的作用：细胞内在性与外在性角色
Oxysterol sulfotransferase in prostate cancer inhibition: Cell-intrinsic and -extrinsic roles
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
氧固醇磺基转移酶（SULT2B）介导氧固醇的酶促磺化。SULT2B可通过干扰氧固醇诱导的LXR核受体激活来调节脂质代谢，因为磺化的氧固醇对LXR是惰性的。原发性前列腺癌中SULT2B降低与不良生存相关，而在去势抵抗性前列腺癌（CRPC）的临床转移灶中该酶检测不到。SULT2B缺失的CRPC异种移植瘤生长加速，而SULT2B高表达的肿瘤则生长受抑，表现出肿瘤发射的生物发光减少并持续凋亡。SULT2B沉默的细胞更具侵袭性——这从EMT样诱导、激活的ERK生存信号以及增强的侵袭中可见。为获得机制性见解，我们检测了PC3 CRPC细胞因异位表达SULT2B所导致的细胞内在性和外在性变化。
结果：对SULT2B高表达的PC3（SA）与对照PC3（VA）细胞进行单细胞RNA测序，揭示了SULT2B使神经内分泌样PC3从间充质向上皮性状转变。UMAP显示一群SA细胞（cluster 7）在空间上与所有其他cluster清晰分离。对cluster 7细胞的生物信息学探究显示其富含上皮标志物而缺乏间充质标志物。cluster 7中的下调基因包括FOXA2、SOX4、MMP16、Fibronectin 1——它们均为致死性CRPC的驱动因素。值得注意的是，CD59——一种含唾液酸的细胞表面糖蛋白——在cluster 7以及所有SA cluster合并中均为下调基因。CD59是Siglec-9的配体，Siglec-9是一种结合唾液酸的凝集素，存在于巨噬细胞（MΦ）及其他髓系细胞上。CD59与Siglec-9的结合可能有助于免疫逃逸，因为阻断Siglec-9与唾液酸化糖蛋白的相互作用可阻止免疫细胞浸润前列腺肿瘤并抑制PC异种移植瘤（PMID 39436703）。炎症基因——如NFκB1以及CXCL1、CXCL8趋化因子——在cluster 7细胞及所有SA细胞cluster合并中被诱导。RT-qPCR证实了这些变化。AKR1C3——一种关键的雄激素生物合成驱动酶——在体外SULT2B沉默的C4-2B CRPC细胞中升高。多重免疫荧光显示CD86⁺ M1MΦ（促炎、免疫增强）与SA异种移植瘤中SULT2B⁺细胞共定位，而CD163⁺/CD206⁺ M2MΦ（抗炎、免疫抑制）浸润到VA异种移植瘤的AKR1C3⁺肿瘤细胞。AKR1C3在VA异种移植瘤中大量表达，与M2MΦ共定位，而在富含M1MΦ的SA异种移植瘤中明显减少。AKR1C3与SULT2B的互逆表达与我们的发现相一致，即AKR1C3受氧固醇-LXR信号上调。
结论：结果凸显了SULT2B对CRPC的双重影响——既调控癌细胞代谢，又通过改变肿瘤微环境中MΦ的动态来塑造癌症-免疫细胞的相互作用。对SULT2B细胞内在性和外在性角色的深入分子洞察，可能会揭示限制前列腺癌致死性进展的新途径。
查看英文原文 English abstract
Oxysterol sulfotransferase (SULT2B) mediates enzymatic sulfation of oxysterols. SULT2B can modulate lipid metabolism by interfering with oxysterol-induced activation of the LXR nuclear receptor, since sulfated oxysterols are LXR inert. Poor survival is linked to reduced SULT2B in primary prostate cancer, and the enzyme is undetectable in clinical metastases of castration resistant prostate cancer (CRPC). SULT2B-null CRPC xenografts show escalated growth while SULT2B-high tumors are growth suppressed, show reduced tumor-emitted bioluminescence and sustain apoptosis. SULT2B silenced cells are more aggressive - evident from EMT-like induction; activated ERK survival signal; and enhanced invasion. To gain mechanistic insight, we probed PC3 CRPC cells for cell-intrinsic and -extrinsic changes due to ectopic SULT2B expression.
Results: Single-cell RNA sequences of SULT2B-high PC3 (SA) & control PC3 (VA) cells revealed transition of neuroendocrine-like PC3 from mesenchymal to epithelial traits afforded by SULT2B. UMAP showed a cluster of SA cells (cluster 7) spatially well-resolved from all other clusters. Bioinformatic probing of cluster 7 cells showed them enriched in epithelial markers and deficient in mesenchymal markers. Down genes in cluster 7 include FOXA2, SOX4, MMP16, Fibronectin 1 - all drivers of lethal CRPC. Notably, CD59 - a sialic acid containing cell surface glycoprotein - is a down gene in cluster 7 and in all SA clusters combined. CD59 is a ligand for Siglec-9 - a lectin that binds sialic acid and resides on macrophages (MΦ) & other myeloids. CD59 binding to Siglec-9 may aid immune evasion since blocking Siglec-9 interaction with sialylated glycoproteins prevented immune cells infiltration to prostate tumor and inhibited PC xenograft (PMID 39436703). Inflammatory genes - such as for NFκB1 & CXCL1, CXCL8 chemokines - are induced in cluster 7 cells and in all SA cell clusters together. RT-qPCR confirmed the changes. AKR1C3 - a key androgen biosynthesis driving enzyme - was elevated in SULT2B-silenced C4-2B CRPC cells in vitro . Multiplex immunofluorescence showed colocalization of CD86 + M1MΦ (pro-inflammatory, immune-boosting) with SULT2B+ cells of SA xenograft, and CD163 + /CD206 + M2MΦ (anti-inflammatory, immune-suppressive) infiltration to AKR1C3 + tumor cells of VA xenograft. AKR1C3 is expressed copiously in VA xenograft, colocalizing with M2MΦ, while it is markedly reduced in M1MΦ-enriched SA xenograft. Reciprocal AKR1C3 and SULT2B expression is consistent with our finding that AKR1C3 is upregulated by oxysterol-LXR signaling.
Conclusion: Results highlight dual impacts of SULT2B on CRPC - regulating cancer cell metabolism and also shaping cancer-immune cells interplay by altering MΦ dynamics at tumor microenvironment. In depth molecular insights into cell-intrinsic and -extrinsic roles of SULT2B may uncover new avenue(s) for limiting lethal progression of prostate cancer
利益披露 Disclosure
B. Park, None..
Z. Zhang, None..
C. Wang, None..
M. Patel, None..
Y. Liu, None..
C. Hung, None..
B. Chatterjee, None.