Tian Shuo, Hui Xiwu, Fan Zhenzhen, Li Qinshan, Zhang Junwen, Yang Xia, Ma Xiaoli, Huang Bingren, Chen Deng, Chen Hong
National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China; and.
National Laboratory of Medical Molecular Biology, Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing, China; and CSPC ZhongQi Pharmaceutical Technology, Shijiazhuang, China.
FASEB J. 2014 Aug;28(8):3528-39. doi: 10.1096/fj.14-250704. Epub 2014 Apr 25.
Hepatocellular carcinoma (HCC) is a common cancer associated with chronic hepatitis B virus (HBV) infection. Conventional interferon-α (IFN-α) and pegylated IFNs (PEG-IFNs) approved for chronic HBV infection treatment can reduce the risk of HCC but are not suitable for the majority of patients and cause significant side effects. IFN-λ1 is a type III IFN with antiviral, antiproliferative, and immunomodulatory functions similar to type I IFNs but with fewer side effects. However, the tolerability and antitumor activity of PEG-IFN-λ1 in HCC xenograft mice are unknown. In vitro IFN-λ1 treatment of Hep3B and Huh7 human hepatoma cell lines increased MHC class I expression, activated JAK-STAT signaling pathways, induced IFN-stimulated gene expression, and inhibited hepatitis B surface antigen (HBsAg) expression. IFN-λ1 treatment also caused 23.2 and 19.9% growth inhibition of Hep3B and Huh7 cells, respectively, and promoted cellular apoptosis. PEG-IFN-λ1, but not IFN-λ1 treatment, significantly suppressed tumor growth (P=0.002) and induced tumor cell apoptosis in a Hep3B cell xenograft mouse model without significant weight loss or toxicity. PEG-IFN-λ1 also significantly inhibited (P=0.000) serum HBsAg secretion from Hep3B xenograft tumors in vivo. Thus, PEG-IFN-λ1 can suppress Hep3B xenograft tumor growth and inhibit HBsAg production and may be a potential treatment for HBV-related HCC.
肝细胞癌（HCC）是一种与慢性乙型肝炎病毒（HBV）感染相关的常见癌症。批准用于治疗慢性HBV感染的传统干扰素-α（IFN-α）和聚乙二醇化干扰素（PEG-IFNs）可降低HCC风险，但不适用于大多数患者且会引起显著副作用。IFN-λ1是一种III型干扰素，具有与I型干扰素相似的抗病毒、抗增殖和免疫调节功能，但副作用较少。然而，PEG-IFN-λ1在HCC异种移植小鼠中的耐受性和抗肿瘤活性尚不清楚。在体外，用IFN-λ1处理Hep3B和Huh7人肝癌细胞系可增加MHC I类表达，激活JAK-STAT信号通路，诱导干扰素刺激基因表达，并抑制乙型肝炎表面抗原（HBsAg）表达。IFN-λ1处理还分别导致Hep3B和Huh7细胞生长抑制23.2%和19.9%，并促进细胞凋亡。在Hep3B细胞异种移植小鼠模型中，PEG-IFN-λ1而非IFN-λ1处理可显著抑制肿瘤生长（P=0.002）并诱导肿瘤细胞凋亡，且无明显体重减轻或毒性。PEG-IFN-λ1还可显著抑制（P=0.000）体内Hep3B异种移植肿瘤的血清HBsAg分泌。因此，PEG-IFN-λ1可抑制Hep3B异种移植肿瘤生长并抑制HBsAg产生，可能是治疗HBV相关HCC的一种潜在疗法。
