Secalonic Acid-F, a Novel Mycotoxin, Represses the Progression of Hepatocellular Carcinoma via MARCH1 Regulation of the PI3K/AKT/β-catenin Signaling Pathway
Secalonic Acid-F, a Novel Mycotoxin, Represses the Progression of Hepatocellular Carcinoma via MARCH1 Regulation of the PI3K/AKT/β-catenin Signaling Pathway
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DOI：
10.3390/molecules24030393
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发表时间：
2019-01
期刊：
影响因子：
4.6
通讯作者：
Lulu Xie;Minjing Li;Desheng Liu;Xia Wang;Peiyuan Wang;Hanhan Dai;Wei Yang;Wei Liu;Xuemei Hu;Mingdong Zhao
中科院分区：
文献类型：
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作者：
Lulu Xie;Minjing Li;Desheng Liu;Xia Wang;Peiyuan Wang;Hanhan Dai;Wei Yang;Wei Liu;Xuemei Hu;Mingdong Zhao
肝癌是一种非常常见和严重的健康问题。因此，迫切需要强有力的分子靶向药物。以前，我们证明了secalonic acid-F（SAF）抑制肝细胞癌（HCC）细胞（HepG 2）的生长，但SAF对HCC的其他抗癌生物学功能和潜在机制尚不清楚。在这项研究中，我们发现SAF，这是从我们实验室鉴定为棘孢曲霉的真菌菌株中分离出来的，可以通过靶向MARCH 1来抑制肝细胞癌的进展，MARCH 1调节PI 3 K/AKT/β-catenin和抗凋亡Mcl-1/Bcl-2信号级联。首先，我们证实SAF以剂量依赖性方式降低肝癌细胞系（HepG 2和Hep 3B）的增殖和集落形成，促进细胞凋亡，并抑制HepG 2和Hep 3B细胞的细胞周期。此外，SAF处理的HepG 2和Hep 3B细胞的迁移和侵袭能力明显受到抑制。Western blot结果显示，SAF通过调节PI 3 K/AKT/β-catenin信号通路下调MARCH 1的表达。此外，通过靶向MARCH 1的小干扰RNA（siRNA）敲低MARCH 1也抑制HepG 2和Hep 3B细胞的增殖、集落形成、迁移和侵袭，并增加凋亡率。这些数据证实MARCH 1的下调可以抑制肝癌的进展，其机制可能是通过PI 3 K/AKT/β-catenin失活以及抗凋亡的Mcl-1/Bcl-2的下调。在体内，SAF下调MARCH 1显著抑制肿瘤生长，表明SAF部分阻断MARCH 1并进一步调节HCC裸鼠模型中PI 3 K/AKT/β-catenin和抗凋亡Mcl-1/Bcl-2信号级联。此外，在小鼠模型中，SAF治疗后肿瘤中的表观扩散系数（ADC）值（来自磁共振成像（MRI））增加。综上所述，我们的研究结果表明，MARCH 1是HCC治疗的潜在分子靶点，SAF是靶向MARCH 1治疗肝癌患者的有前途的药物。
Liver cancer is a very common and significant health problem. Therefore, powerful molecular targeting agents are urgently needed. Previously, we demonstrated that secalonic acid-F (SAF) suppresses the growth of hepatocellular carcinoma (HCC) cells (HepG2), but the other anticancer biological functions and the underlying mechanism of SAF on HCC are unknown. In this study, we found that SAF, which was isolated from a fungal strain in our lab identified as Aspergillus aculeatus, could inhibit the progression of hepatocellular carcinoma by targeting MARCH1, which regulates the PI3K/AKT/β-catenin and antiapoptotic Mcl-1/Bcl-2 signaling cascades. First, we confirmed that SAF reduced the proliferation and colony formation of HCC cell lines (HepG2 and Hep3B), promoted cell apoptosis, and inhibited the cell cycle in HepG2 and Hep3B cells in a dose-dependent manner. In addition, the migration and invasion of HepG2 and Hep3B cells treated with SAF were significantly suppressed. Western blot analysis showed that the level of MARCH1 was downregulated by pretreatment with SAF through the regulation of the PI3K/AKT/β-catenin signaling pathways. Moreover, knockdown of MARCH1 by small interfering RNAs (siRNAs) targeting MARCH1 also suppressed the proliferation, colony formation, migration, and invasion as well as increased the apoptotic rate of HepG2 and Hep3B cells. These data confirmed that the downregulation of MARCH1 could inhibit the progression of hepatocellular carcinoma and that the mechanism may be via PI3K/AKT/β-catenin inactivation as well as the downregulation of the antiapoptotic Mcl-1/Bcl-2. In vivo, the downregulation of MARCH1 by treatment with SAF markedly inhibited tumor growth, suggesting that SAF partly blocks MARCH1 and further regulates the PI3K/AKT/β-catenin and antiapoptosis Mcl-1/Bcl-2 signaling cascade in the HCC nude mouse model. Additionally, the apparent diffusion coefficient (ADC) values, derived from magnetic resonance imaging (MRI), were increased in tumors after SAF treatment in a mouse model. Taken together, our findings suggest that MARCH1 is a potential molecular target for HCC treatment and that SAF is a promising agent targeting MARCH1 to treat liver cancer patients.