Toll-like receptor 4 promotes bladder cancer progression upon S100A8/A9 binding, which requires TIRAP-mediated TPL2 activation

• Published in: Biochemical and biophysical research communications 2022-12, Vol.634, p.83-91
• Main Authors: Herik Rodrigo, Acosta Gonzalez, Tomonobu, Nahoko, Yoneda, Haruka, Kinoshita, Rie, Mitsui, Yosuke, Sadahira, Takuya, Terawaki, Shin-ichi, Gohara, Yuma, Gede Yoni Komalasari, Ni Luh, Jiang, Fan, Murata, Hitoshi, Yamamoto, Ken-ichi, Futami, Junichiro, Yamauchi, Akira, Kuribayashi, Futoshi, Inoue, Yusuke, Kondo, Eisaku, Toyooka, Shinichi, Nishibori, Masahiro, Watanabe, Masami, Nasu, Yasutomo, Sakaguchi, Masakiyo
• Format: Article
• Language: English
• Subjects: Bladder cancer; S100A8/A9; TLR4; TPL2
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2022.09.116

Bladder cancer is an often widely disseminated and deadly cancer. To block the malignant outgrowth of bladder cancer, we must elucidate the molecular-level characteristics of not only bladder cancer cells but also their surrounding milieu. As part of this effort, we have long been studying extracellular S100A8/A9, which is elevated by the inflammation associated with certain cancers. Extracellularly enriched S100A8/A9 can hasten a shift to metastatic transition in multiple types of cancer cells. Intriguingly, high-level S100A8/A9 has been detected in the urine of bladder-cancer patients, and the level increases with the stage of malignancy. Nonetheless, S100A8/A9 has been investigated mainly as a potential biomarker of bladder cancers, and there have been no investigations of its role in bladder-cancer growth and metastasis. We herein report that extracellular S100A8/A9 induces upregulation of growth, migration and invasion in bladder cancer cells through its binding with cell-surface Toll-like receptor 4 (TLR4). Our molecular analysis revealed the TLR4 downstream signal that accelerates such cancer cell events. Tumor progression locus 2 (TPL2) was a key factor facilitating the aggressiveness of cancer cells. Upon binding of S100A8/A9 with TLR4, TPL2 activation was enhanced by an action with a TLR4 adaptor molecule, TIR domain-containing adaptor protein (TIRAP), which in turn led to activation of the mitogen-activated protein kinase (MAPK) cascade of TPL2. Finally, we showed that sustained inhibition of TLR4 in cancer cells effectively dampened cancer survival in vivo. Collectively, our results indicate that the S100A8/A9-TLR4-TPL2 axis influences the growth, survival, and invasive motility of bladder cancer cells. •TLR4 is upregulated in bladder cancer cells.•S100A8/A9-TLR4 axis plays a crucial role in bladder cancer progression.•TPL2 is required for bladder cancer progression under TLR4 upon S100A8/A9 binding.•TPL2 requires TIRAP adaptor protein for its activation.