Department of General Surgery, Pancreatic Disease Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, 197 Ruijin 2Nd Road, Shanghai, 200025, China.
Research Institute of Pancreatic Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China.
J Transl Med. 2023 Nov 21;21(1):838. doi: 10.1186/s12967-023-04702-6.
LIPH, a membrane-associated phosphatidic acid-selective phospholipase A1a, can produce LPA (Lysophosphatidic acid) from PA (Phosphatidic acid) on the outer leaflet of the plasma membrane. It is well known that LIPH dysfunction contributes to lipid metabolism disorder. Previous study shows that LIPH was found to be a potential gene related to poor prognosis with pancreatic ductal adenocarcinoma (PDAC). However, the biological functions of LIPH in PDAC remain unclear.
Cell viability assays were used to evaluate whether LIPH affected cell proliferation. RNA sequencing and immunoprecipitation showed that LIPH participates in tumor glycolysis by stimulating LPA/LPAR axis and maintaining aldolase A (ALDOA) stability in the cytosol. Subcutaneous, orthotopic xenograft models and patient-derived xenograft PDAC model were used to evaluate a newly developed Gemcitabine-based therapy.
LIPH was significantly upregulated in PDAC and was related to later pathological stage and poor prognosis. LIPH downregulation in PDAC cells inhibited colony formation and proliferation. Mechanistically, LIPH triggered PI3K/AKT/HIF1A signaling via LPA/LPAR axis. LIPH also promoted glycolysis and de novo synthesis of glycerolipids by maintaining ALDOA stability in the cytosol. Xenograft models show that PDAC with high LIPH expression levels was sensitive to gemcitabine/ki16425/aldometanib therapy without causing discernible side effects.
LIPH directly bridges PDAC cells and tumor microenvironment to facilitate aberrant aerobic glycolysis via activating LPA/LPAR axis and maintaining ALDOA stability, which provides an actionable gemcitabine-based combination therapy with limited side effects.
LIPH 是一种膜相关的选择性磷酸脂酶 A1a，能够在外质膜的外层将 PA（磷酸脂）转化为 LPA（溶血磷脂酸）。众所周知，LIPH 功能障碍与脂质代谢紊乱有关。先前的研究表明，LIPH 被发现是与胰腺导管腺癌（PDAC）预后不良相关的潜在基因。然而，LIPH 在 PDAC 中的生物学功能仍不清楚。
细胞活力测定用于评估 LIPH 是否影响细胞增殖。RNA 测序和免疫沉淀表明，LIPH 通过刺激 LPA/LPAR 轴并维持细胞质中醛缩酶 A（ALDOA）的稳定性，参与肿瘤糖酵解。皮下、原位异种移植模型和患者来源的异种移植 PDAC 模型用于评估新开发的基于吉西他滨的治疗方法。
LIPH 在 PDAC 中显著上调，与晚期病理分期和不良预后相关。PDAC 细胞中 LIPH 的下调抑制了集落形成和增殖。在机制上，LIPH 通过 LPA/LPAR 轴触发 PI3K/AKT/HIF1A 信号通路。LIPH 还通过维持细胞质中 ALDOA 的稳定性促进糖酵解和甘油磷脂的从头合成。异种移植模型表明，高表达 LIPH 的 PDAC 对吉西他滨/ki16425/aldometanib 治疗敏感，而没有引起明显的副作用。
LIPH 通过激活 LPA/LPAR 轴和维持 ALDOA 稳定性，直接连接 PDAC 细胞和肿瘤微环境，促进异常的有氧糖酵解，为基于吉西他滨的联合治疗提供了一种可行的方法，副作用有限。
