title: Interleukin-12 inhibits the hepatocellular carcinoma growth by inducing macrophage polarization to the M1-like phenotype through downregulation of Stat-3.
abstract: Hepatocellular carcinoma is the third most common cause of cancer death worldwide. Novel early detection biomarkers and efficacious therapy strategies are needed. Macrophages recruited from circulation monocytes are the major component of solid cancer and play an important role in the carcinogenesis. Whether overexpression of L-12 in monocytes could induce the phenotype directional differentiation into tumoricidal M1 macrophages and inhibit HCC growth in tumor microenvironment was investigated in this study. For the establishment of the monocyte/IL-12 and polarization of M1-like macrophage, the IL-12 overexpressing recombinant monocyte/IL-12 cells were established by infecting with pAd5F35-CMV/IL-12 adenovirus and co-cultured with HCC SMMC-7721 and Hep3B cells. It was found that the phenotype of monocyte/IL-12 polarized to M1-like macrophages with CD197high IL-12high CD206low IL-10low, and decreased expression of TGF-β, VEGF-A, and MMP-9. In order to explore the mechanism underlying the macrophages polarization, we detected the Stat-3 pathway and its downstream transcription factor c-myc, and found that the p-Stat-3 and c-myc were down-regulated. To evaluate the effects of monocyte/IL-12 on inhibiting HCC growth, various assays including CCK8, flow cytometry, colony-forming and Transwell assays in vitro, and xenograft mouse models and immunohistochemical analyses in vivo were used to detect the HCC growth and relative markers. Treated with IL-12 overexpressing monocytes, the xenograft tumor growth was significantly inhibited in vivo. These results have proven that IL-12-overexpressed monocytes could directionally differentiate to M1-like macrophages through downregulation of Stat-3 and result in the inhibition of HCC growth.
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Cheng
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
authors.forename: Ting-Ting
authors.initials: TT
authors.lastname: Ma
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
authors.forename: Hai-Yu
authors.initials: HY
authors.lastname: Xiong
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
authors.forename: Zi-Wei
authors.initials: ZW
authors.lastname: Li
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
authors.forename: Chang-Li
authors.initials: CL
authors.lastname: Xie
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China.
authors.forename: Cui-Ying
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Key Laboratory of Diagnostic Medicine Designated by the Chinese Ministry of Education, Chongqing Medical University, Chongqing, 400016, China. tuzhiguang@aliyun.com.
authors.forename: Zhi-Guang
authors.initials: ZG
authors.lastname: Tu
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D045744:Cell Line, Tumor; D016764:Cell Polarity; D049109:Cell Proliferation; D018920:Coculture Techniques; D015536:Down-Regulation; D006801:Humans; D018664:Interleukin-12 / Q000502:physiology*; D008113:Liver Neoplasms / Q000473:pathology*; D008264:Macrophages / Q000473:pathology*; D009361:Neoplasm Invasiveness; D050796:STAT3 Transcription Factor / Q000502:physiology*
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D018664:Interleukin-12
keywords: CD197; CD206; Hepatocellular carcinoma; IL-12; M1 macrophages