Sphingomyelin Phodiesterase Acid-Like 3A Promotes Hepatocellular Carcinoma Growth Through the Enhancer of Rudimentary Homolog.
Sphingomyelin Phodiesterase Acid-Like 3A Promotes Hepatocellular Carcinoma Growth Through the Enhancer of Rudimentary Homolog.
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鞘磷脂磷酸二酯酶酸样 3A 通过基本同系物的增强剂促进肝细胞癌生长
DOI：
10.3389/fonc.2022.852765
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发表时间：
2022
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
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作者：
肝细胞癌（Hepatocellular carcinoma，HCC）是世界范围内最常见的恶性肿瘤之一，其发病机制尚不清楚.鞘磷脂磷酸二酯酶酸性样3A（SMPDL 3A）影响细胞分化并参与免疫调节。然而，其在HCC中的分子生物学功能尚未阐明。分析180例肝癌患者肝癌组织中SMPDL 3A的表达与肝癌患者预后的关系。使用Crispr-Cas9双载体慢病毒敲除HCC细胞系中的SMPDL 3A。采用CCK-8法、克隆形成实验、细胞周期分析、细胞划痕实验、TUNEL实验和流式细胞术检测SMPDL 3A对细胞活力的影响。BALB/c裸鼠的异种移植瘤测定证实SMPDL 3A促进肿瘤生长和体内。SMPDL 3A相互作用蛋白的质谱分析和免疫共沉淀初步研究本研究表明SMPDL 3A在肝癌组织中的表达与癌旁组织不同。此外，高SMPDL 3A表达的患者的总生存率和无瘤生存率显著低于低SMPDL 3A表达的患者。SMPDL 3A表达与PIVKA-II诱导的蛋白水平、肝硬化、肿瘤直径、微血管浸润和巴塞罗那临床肝癌分期密切相关。因此，SMPDL 3A是影响HCC患者无瘤生存率和总生存率的独立危险因素。使用Crispr-Cas9基因组编辑技术的体外研究揭示了SMPDL 3A对细胞增殖、凋亡和迁移的敲除作用。细胞计数kit-8法和克隆形成实验显示sgSMPDL 3A抑制肿瘤细胞增殖和迁移。流式细胞术和TUNEL检测显示sgSMPDL 3A促进肿瘤细胞凋亡。此外，在裸鼠皮下肿瘤形成期间，sgSMPDL 3A抑制肿瘤生长。Ki 67和PNCA的免疫组织化学也表明sgSMPDL 3A抑制荷瘤裸鼠皮下肿瘤增殖。进一步的实验表明，SMPDL 3A与基本同源物增强子（ERH）相互作用。SMPDL 3A高表达与肝癌患者预后不良有关。SMPDL 3A基因敲除可抑制肝癌细胞的增殖和迁移，并促进肝癌细胞的迁移。SMPDL 3A与ERH相互作用影响肝癌的发生和发展。
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, with unclear pathogenesis. Sphingomyelin phodiesterase acid-like 3A (SMPDL3A) affects cell differentiation and participates in immune regulation. However, its molecular biological function in HCC has not yet been elucidated. Data from 180 HCC patients were analyzed the relationship between the expression of SMPDL3A in liver cancer tissues and the prognosis of liver cancer patients. Crispr-Cas9 dual vector lentivirus was used to knock out SMPDL3A in HCC cell lines. The effects of SMPDL3A on cell viability were determined by CCK8 assay, clone formation experiment, cell cycle assay, cell scratch, TUNEL experiment and flow cytometry. Xenograft tumor assays in BALB/c nude mice confirmed that SMPDL3A promoted tumor growth and in vivo. Preliminary exploration of SMPDL3A interacting protein by mass spectrometry analysis and co-immunoprecipitation. This study showed that the expression of SMPDL3A in HCC tissue differed from that in tumor-adjacent tissues. Moreover, the overall survival rate and tumor-free survival rate of patients with high-SMPDL3A expression were significantly lower than those with low-SMPDL3A expression. SMPDL3A expression was closely related to the level of protein induced by PIVKA-II, liver cirrhosis, tumor diameter, microvascular invasion, and Barcelona clinic liver cancer staging. Thus, SMPDL3A is an independent risk factor that affects the tumor-free survival rate and overall survival rate of HCC patients. In vitro study using Crispr-Cas9 genome editing technology revealed the knockout effect of SMPDL3A on cell proliferation, apoptosis, and migration. Cell counting kit-8 assay and clone formation experiment showed that sgSMPDL3A inhibited tumor cell proliferation and migration. Flow cytometry and TUNEL assay showed that sgSMPDL3A promoted apoptosis in tumors. Moreover, sgSMPDL3A inhibited tumor growth during subcutaneous tumor formation in nude mice. Immunohistochemistry of Ki67 and PNCA also indicated that sgSMPDL3A inhibited subcutaneous tumor proliferation in tumor-bearing nude mice. Further experiments showed that SMPDL3A interacts with the enhancer of rudimentary homolog (ERH). High-SMPDL3A expression was related to poor prognosis of patients with HCC. Knockout of SMPDL3A inhibited the proliferation and migration and accelerated the migration of HCC cells. SMPDL3A interacted with ERH to affect the tumorigenesis and progression of HCC.
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