Department of Biliary-Pancreatic SurgeryRenji HospitalSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina.
The University of Queensland Diamantina InstituteThe University of QueenslandBrisbaneQueenslandAustralia.
Hepatology. 2021 Feb;73(2):692-712. doi: 10.1002/hep.31304. Epub 2020 Nov 26.
The wide prevalence of chemoresistance and compromised early diagnosis of gallbladder cancer (GBC) has led to poor patient prognosis, requiring sustained efforts for the identification of effective biomarkers and therapeutic intervention. Ceramides have emerged as intracellular signaling molecules linked to tumorigenesis and therapeutic response in cancers. However, the clinical relevance of ceramides with GBC has not been investigated.
In the present study, we revealed aberrant gene expressions (e.g., serine palmitoyltransferase 1 [SPTLC1] and ceramide synthase 2 [CERS2]) of de novo ceramide biosynthesis and length-specific ceramide production in GBC tissues. Analyses of serum ceramide pattern in healthy controls, gallbladder stone, and GBC patients identified C24-Ceramide as a potential diagnostic biomarker for patients with GBC. Importantly, elevation of SPTLC1, CERS2, and its product, C24-Ceramide, was associated with tumor staging, distal metastasis, and worse prognosis. In line with this, C -Ceramide promoted GBC cell proliferation and migration in vitro and in vivo. Mechanistically, C24-Ceramide directly bound to phosphatidylinositol 5-phosphate 4-kinase type-2 gamma (PIP4K2C), a regulator of mammalian target of rapamycin (mTOR), to facilitate mTOR complex formation and activation. C6-Ceramide, an analogue of natural ceramide, competed with C24-Ceramide for PIP4K2C binding, thereby abrogating C24-Ceramide-mediated mTOR signaling activation and oncogenic activity. Furthermore, stimulation with C6-Ceramide significantly suppressed the proliferative and metastatic capacity of GBC cells in vitro and in vivo, which was dependent on PIP4K2C.
Our findings highlight the clinical relevance of ceramide metabolism with GBC progression and identify C24-Ceramide as a diagnostic biomarker for GBC. We propose that PIP4K2C is indispensable for C6-Ceramide as a potential therapeutic intervention for GBC through a direct competition with C24-Ceramide.
由于化疗耐药性广泛存在，胆囊癌（GBC）早期诊断水平有限，导致患者预后较差，因此需要持续努力寻找有效的生物标志物和治疗干预靶点。神经酰胺作为细胞内信号分子，与癌症的发生和治疗反应有关。然而，神经酰胺与 GBC 的临床相关性尚未得到研究。
本研究揭示了 GBC 组织中从头合成神经酰胺和特定长度神经酰胺产生的异常基因表达（如丝氨酸棕榈酰转移酶 1 [SPTLC1]和神经酰胺合酶 2 [CERS2]）。对健康对照、胆囊结石和 GBC 患者血清神经酰胺谱的分析表明，C24-神经酰胺是 GBC 患者的潜在诊断生物标志物。重要的是，SPTLC1、CERS2 及其产物 C24-神经酰胺的升高与肿瘤分期、远处转移和预后不良相关。与此一致的是，C24-神经酰胺在体外和体内促进 GBC 细胞的增殖和迁移。在机制上，C24-神经酰胺直接与磷酸肌醇 5-磷酸 4-激酶 2 型 γ（PIP4K2C）结合，后者是哺乳动物雷帕霉素靶蛋白（mTOR）的调节剂，促进 mTOR 复合物的形成和激活。C6-神经酰胺是神经酰胺的类似物，与 PIP4K2C 竞争结合，从而阻断 C24-神经酰胺介导的 mTOR 信号激活和致癌活性。此外，体外和体内刺激 C6-神经酰胺显著抑制 GBC 细胞的增殖和转移能力，这依赖于 PIP4K2C。
本研究结果强调了神经酰胺代谢与 GBC 进展的临床相关性，并确定 C24-神经酰胺作为 GBC 的诊断生物标志物。我们提出 PIP4K2C 对于 C6-神经酰胺作为 GBC 的潜在治疗干预是不可或缺的，这是通过与 C24-神经酰胺的直接竞争实现的。
