한빛사논문
- 조회391
Seul Gi Lee 1,2,8, Seon Min Woo 1,8, Seung Un Seo 1, Chan-Hyeong Lee 3, Moon-Chang Baek 3, Se Hwan Jang 4, Zee Yong Park 4, Simmyung Yook 5, Ju-Ock Nam 6 and Taeg Kyu Kwon 1,7,*
1Department of Immunology, School of Medicine, Keimyung University, Daegu, Republic of Korea.
2Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
3Department of Molecular Medicine, CMRI, Exosome Convergence Research Center (ECRC), School of Medicine, Kyungpook National University, Daegu, Republic of Korea.
4School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Korea.
5Department of Biopharmaceutical Convergence, Sungkyunkwan University, Suwon, Republic of Korea.
6Department of Food Science and Biotechnology, Kyungpook National University, Daegu, Republic of Korea.
7Center for Forensic Pharmaceutical Science, Keimyung University, Daegu, Republic of Korea.
8These authors contributed equally: Seul Gi Lee, Seon Min Woo.
*Corresponding author: correspondence to Taeg Kyu Kwon
Abstract
M2-like tumor-associated macrophages (TAMs) are risk factors for cancer progression and metastasis. However, the mechanisms underlying their polarization are still not fully understood. Although cathepsin D (Cat D) has been reported as a procarcinogenic factor, little is known about the functional role of Cat D in the tumor microenvironment (TME). This study aimed to explore the effect and molecular mechanisms of Cat D in the TME. Cat D knockout (KO) altered the cytokine secretion pattern and induced TAM reprogramming from the M2 to M1 subtype, thereby preventing epithelial-mesenchymal transition and tumor metastasis. Mechanistically, we identified transforming growth factor beta-induced protein (TGFBI) as a Cat D target protein that is specifically associated with TAM polarization. Elevated TGFBI expression in Cat D KO cancer cells resulted in a decline in M2-like TAM polarization. Our RNA-sequencing results indicated that the cancer cell-secreted chemokine CCL20 is a major secretory chemokine for Cat D-TGFBI-mediated TAM polarization. In contrast, Cat D overexpression accelerated TAM polarization into M2-like cells by suppressing TGFBI expression. In addition, the double Cat D and TGFBI KO rescued the inhibitory effects of Cat D KO on tumor metastasis by controlling TAM and T-cell activation. These findings indicated that Cat D contributes to cancer metastasis through TGFBI-mediated TAM reprogramming. Cat D deletion inhibits M2-like TAM polarization through TGFBI-mediated CCL20 expression, reprogramming the immunosuppressive TME. Our results open a potential new avenue for therapy focused on eliminating tumor metastasis.
논문정보
- Research article
- 2024년 02월 (BRIC 등록일 2024-02-02)
- 국내(교신)+국외 연구진
- 생명과학 > 세포생물학
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