title: Paracrine regulation of matrix metalloproteinases contributes to cancer cell invasion by hepatocellular carcinoma-secreted 14-3-3σ.
abstract: 14-3-3σ overexpression results in enhanced hepatocellular carcinoma (HCC) cell migration and HCC tumor vascular-invasion is significantly associated with 14-3-3σ expression. However, increased expression of 14-3-3σ paradoxically suppresses in vitro cell invasion of HCC. We hypothesize that surrounding tumor-associated stromal cells play a crucial role in 14-3-3σ-regulated HCC cell invasion. In this study, H68 fibroblasts, THP-1 and phorbol-12-myristate-13-acetate (PMA)-treated THP-1 (PMA-THP-1) cells were incubated with conditioned media of control (control-CM) and 14-3-3σ-overepxressing cells (14-3-3σ-CM), followed by co-culture with HCC cells. Invasiveness of HCC cells was examined by a Boyden chamber assay. HCC cells co-cultured with 14-3-3σ-CM treated cells significantly enhanced their invasive ability compared with control-CM treated cells. Moreover, incubation with 14-3-3σ-CM induced differential expression profiles of matrix metalloproteinases (MMPs) in fibroblasts (MMP-1, MMP-2, MMP-9, MMP-12 and MMP-14), THP-1 (MMP-1 and MMP-12) and PMA-THP-1 cells (MMP-2, MMP-12 and MMP-14). In contrast, silencing of 14-3-3σ by siRNA significantly abolished 14-3-3σ-CM induced MMPs. In addition, treatment with recombinant 14-3-3σ (r14-3-3σ) protein exhibits a similar expression profile of MMPs induced by 14-3-3σ-CM in fibroblasts, THP-1 and PMA-THP-1 cells. Finally, knockdown of aminopeptidase N (APN) significantly abrogated r14-3-3σ induced expression of MMPs in HS68 fibroblasts. These results suggest that HCC-secreted 14-3-3σ promotes expression of MMPs in cancerous surrounding cells via an APN dependent mechanism. 14-3-3σ has a paracrine effect in educating stromal cells in tumor-associated microenvironment.
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.|Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Chia-Chia
authors.initials: CC
authors.lastname: Liu
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.|Metabolomic Medicine Research Center, China Medical University, Taichung 404, Taiwan.
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Chang
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.|Institute of Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Lin
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.
authors.forename: Yen-Ling
authors.initials: YL
authors.lastname: Yu
authors.affiliation: Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Bor-Sheng
authors.initials: BS
authors.lastname: Ko
authors.affiliation: Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan.
authors.forename: Li-Ying
authors.initials: LY
authors.lastname: Sung
authors.affiliation: Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan.|Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan.|PhD. Program for Aging, China Medical University, Taichung 404, Taiwan.
authors.forename: Jun-Yang
authors.initials: JY
authors.lastname: Liou
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D005095:Exoribonucleases / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology*; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D009361:Neoplasm Invasiveness / Q000473:pathology; D019899:Paracrine Communication / Q000502:physiology*; D059016:Tumor Microenvironment / Q000502:physiology
chemical_list: D048948:14-3-3 Proteins; D014408:Biomarkers, Tumor; D005095:Exoribonucleases; C413442:SFN protein, human; D020782:Matrix Metalloproteinases
keywords: 14-3-3σ; hepatocellular carcinoma; invasion; matrix metalloproteinase; paracrine