Research Papers:

Paracrine regulation of matrix metalloproteinases contributes to cancer cell invasion by hepatocellular carcinoma-secreted 14-3-3σ

Chia-Chia Liu _, Tzu-Ching Chang, Yi-Ting Lin, Yen-Ling Yu, Bor-Sheng Ko, Li-Ying Sung and Jun-Yang Liou

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Oncotarget. 2016; 7:36988-36999. https://doi.org/10.18632/oncotarget.9234

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Chia-Chia Liu1,2,* Tzu-Ching Chang3,4,*, Yi-Ting Lin1,5, Yen-Ling Yu1, Bor-Sheng Ko6, Li-Ying Sung2, Jun-Yang Liou1,7,8

1Institute of Cellular and System Medicine, National Health Research Institutes, Zhunan 350, Taiwan

2Institute of Biotechnology, National Taiwan University, Taipei 106, Taiwan

3Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan

4Metabolomic Medicine Research Center, China Medical University, Taichung 404, Taiwan

5Institute of Structural Biology, National Tsing Hua University, Hsinchu 300, Taiwan

6Department of Internal Medicine, National Taiwan University Hospital, Taipei 100, Taiwan

7Graduate Institute of Basic Medical Science, China Medical University, Taichung 404, Taiwan

8PhD. Program for Aging, China Medical University, Taichung 404, Taiwan

*These authors have contributed equally to this work

Correspondence to:

Jun-Yang Liou, email: [email protected]

Li-Ying Sung, email: [email protected]

Keywords: 14-3-3σ, hepatocellular carcinoma, invasion, matrix metalloproteinase, paracrine

Received: November 24, 2015    Accepted: April 23, 2016    Published: May 09, 2016


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.

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