KLK6/PAR1 Axis Promotes Tumor Growth and Metastasis by Regulating Cross-Talk between Tumor Cells and Macrophages

Yo Sep Hwang; Hee Jun Cho; Eun Sun Park; Jeewon Lim; Hyang Ran Yoon; Jong-Tae Kim; Suk Ran Yoon; Haiyoung Jung; Yong-Kyung Choe; Yong-Hoon Kim; Chul-Ho Lee; Yong Tae Kwon; Bo Yeon Kim; Hee Gu Lee

doi:10.3390/cells11244101

KLK6/PAR1 Axis Promotes Tumor Growth and Metastasis by Regulating Cross-Talk between Tumor Cells and Macrophages

Cells. 2022 Dec 16;11(24):4101. doi: 10.3390/cells11244101.

Authors

Yo Sep Hwang^{1

2}, Hee Jun Cho¹, Eun Sun Park^{1

2}, Jeewon Lim^{1

2}, Hyang Ran Yoon¹, Jong-Tae Kim¹, Suk Ran Yoon¹, Haiyoung Jung¹, Yong-Kyung Choe¹, Yong-Hoon Kim³, Chul-Ho Lee³, Yong Tae Kwon⁴, Bo Yeon Kim⁵, Hee Gu Lee^{1

2}

Affiliations

¹ Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
² Department of Biomolecular Science, University of Science and Technology (UST), Daejeon 34113, Republic of Korea.
³ Laboratory Animal Resource Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon 34141, Republic of Korea.
⁴ Protein Metabolism Medical Research Center, Department of Biomedical Science, College of Medicine, Seoul National University, Seoul 110-799, Republic of Korea.
⁵ Anticancer Agent Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheong won, Cheongju 28116, Republic of Korea.

Abstract

Kallikrein-related peptidase (KLK)6 is associated with inflammatory diseases and neoplastic progression. KLK6 is aberrantly expressed in several solid tumors and regulates cancer development, metastatic progression, and drug resistance. However, the function of KLK6 in the tumor microenvironment remains unclear. This study aimed to determine the role of KLK6 in the tumor microenvironment. Here, we uncovered the mechanism underlying KLK6-mediated cross-talk between cancer cells and macrophages. Compared with wild-type mice, KLK6-/- mice showed less tumor growth and metastasis in the B16F10 melanoma and Lewis lung carcinoma (LLC) xenograft model. Mechanistically, KLK6 promoted the secretion of tumor necrosis factor-alpha (TNF-α) from macrophages via the activation of protease-activated receptor-1 (PAR1) in an autocrine manner. TNF-α secreted from macrophages induced the release of the C-X-C motif chemokine ligand 1 (CXCL1) from melanoma and lung carcinoma cells in a paracrine manner. The introduction of recombinant KLK6 protein in KLK6-/- mice rescued the production of TNF-α and CXCL1, tumor growth, and metastasis. Inhibition of PAR1 activity suppressed these malignant phenotypes rescued by rKLK6 in vitro and in vivo. Our findings suggest that KLK6 functions as an important molecular link between macrophages and cancer cells during malignant progression, thereby providing opportunities for therapeutic intervention.

Keywords: KLK6; PAR1; macrophage; metastasis; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Kallikreins* / metabolism
Macrophages / metabolism
Melanoma*
Mice
Receptor, PAR-1* / metabolism
Tumor Microenvironment
Tumor Necrosis Factor-alpha

Substances

Kallikreins
Receptor, PAR-1
Tumor Necrosis Factor-alpha
Prss18 protein, mouse

Grants and funding

This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2020R1A2C2010321, 2020R1A5A1019023, 2021R1A2B5B03002614, and 2021R1A2C1011174). This work was also funded by the R&D Convergence Program (CAP21022-000) and KRIBB Research Initiative Program (1711170625).