Complement components C1r and C1s promote oral squamous cell carcinoma cell proliferation

Thinh Thi Kim Truong; Tatsufumi Fujimoto; Shinsuke Fujii; Kari J. Kurppa; Kana Hasegawa; Yudai Tajiri; Masafumi Moriyama; Tamotsu Kiyoshima

doi:10.1016/j.job.2025.100691

Complement components C1r and C1s promote oral squamous cell carcinoma cell proliferation

Thinh Thi Kim Truong
, Tatsufumi Fujimoto
, Shinsuke Fujii^*
, Kari J. Kurppa
, Kana Hasegawa
, Yudai Tajiri
, Masafumi Moriyama
, Tamotsu Kiyoshima

^*Corresponding author for this work

Turku Bioscience Centre

Research output: Contribution to journal › Article › Scientific › peer-review

Abstract

Objectives: Oral squamous cell carcinoma (OSCC), the most frequent cancer of the oral cavity, mostly arises from the mucosal epithelium and rarely from the odontogenic epithelium. However, it is unclear whether they share the same mechanisms of OSCC development. Recently, we clarified comprehensive gene expression patterns in pathological specimens of two types of OSCC (odontogenic epithelial and mucosal epithelial origin). In addition, the enrichment analysis demonstrated that the “COMPLEMENT” gene set was elevated in these tumor lesions. However, the role of this system in OSCC tumorigenesis remains unclear. Here, we aimed to investigate the involvement of complement components in OSCC development. Methods: siRNA and shRNA were used to examine OSCC cell proliferation in vitro and in vivo and assess activation of intracellular signaling using western blotting technics. An MEK1/2-specific inhibitor was used to verify its effects on the expression of C1r and/or C1s, components of the classical complement pathway. C1s expression in OSCC pathological specimens was investigated using immunohistochemical analysis. Results: C1r and/or C1s expression regulated ERK and/or AKT activation and promoted OSCC cell growth. In addition, activated ERK regulated the expression of C1r and C1s via a negative-feedback loop. Immunohistochemically, C1s was expressed in the tumor lesions and frequently showed high expression levels of both phosphorylated ERK and Ki-67, but not in the non-tumor regions of OSCC specimens. Conclusions: The complement system may be a common molecular mechanism for OSCC tumorigenesis, which arises from different origins: odontogenic and mucosal epithelium. Elevated C1r/C1s expression contributes to OSCC cell proliferation.

Original language	English
Article number	100691
Journal	Journal of Oral Biosciences
Volume	67
Issue number	4
DOIs	https://doi.org/10.1016/j.job.2025.100691
Publication status	Published - Dec 2025
MoE publication type	A1 Journal article-refereed

Funding

This work was supported by JSPS KAKENHI Grants to S.F. (2023–2025) (JP22KK0262), (2024–2027) (JP24K02615) and T.K. (2023–2026) (JP23H03102), Takeda Science Foundation, Japan, The Shinnihon Foundation of Advanced Medical Treatment Research, Japan, The Mochida Memorial Foundation for Medical and Pharmaceutical Research, Japan, TERUMO LIFE SCIENCE FOUNDATION, Japan, The Ube Industries Foundation and Kakiharakagaku, Japan to S.F., The Shinnihon Foundation of Advanced Medical Treatment Research, Takeda Science Foundation, Fukuoka Public Health Promotion Organization Cancer Research Fund, Japan and Kaibara Morikazu Medical Science Promotion Foundation, Japan to K.H. This work was supported by JSPS KAKENHI Grants to S.F. (2023–2025) (JP22KK0262), (2024–2027) (JP24K02615) and T.K. (2023–2026) (JP23H03102), Takeda Science Foundation, Japan, The Shinnihon Foundation of Advanced Medical Treatment Research, Japan, The Mochida Memorial Foundation for Medical and Pharmaceutical Research, Japan, TERUMO LIFE SCIENCE FOUNDATION, Japan, The Ube Industries Foundation and Kakiharakagaku, Japan to S.F., The Shinnihon Foundation of Advanced Medical Treatment Research, Takeda Science Foundation, Fukuoka Public Health Promotion Organization Cancer Research Fund, Japan and Kaibara Morikazu Medical Science Promotion Foundation, Japan to K.H.We would like to thank Brian Quinn, managing editor of Japan Medical communication (www.japan-mc.co.jp), for editing our manuscript. The authors thank Drs. Y, Nakako, D, Alkahatib, C, Ting, S, Kawano and Mr H. Otoba for valuable technical support in this research. The authors also thank the Research Support Center, Graduate School of Medical Sciences, Kyushu University, Japan. We appreciate the technical assistance from The Joint Use Laboratories, Faculty of Dental Science, Kyushu University.

Keywords

C1r
C1s
Cell proliferation
Oral squamous cell carcinoma

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10.1016/j.job.2025.100691

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title = "Complement components C1r and C1s promote oral squamous cell carcinoma cell proliferation",

abstract = "Objectives: Oral squamous cell carcinoma (OSCC), the most frequent cancer of the oral cavity, mostly arises from the mucosal epithelium and rarely from the odontogenic epithelium. However, it is unclear whether they share the same mechanisms of OSCC development. Recently, we clarified comprehensive gene expression patterns in pathological specimens of two types of OSCC (odontogenic epithelial and mucosal epithelial origin). In addition, the enrichment analysis demonstrated that the “COMPLEMENT” gene set was elevated in these tumor lesions. However, the role of this system in OSCC tumorigenesis remains unclear. Here, we aimed to investigate the involvement of complement components in OSCC development. Methods: siRNA and shRNA were used to examine OSCC cell proliferation in vitro and in vivo and assess activation of intracellular signaling using western blotting technics. An MEK1/2-specific inhibitor was used to verify its effects on the expression of C1r and/or C1s, components of the classical complement pathway. C1s expression in OSCC pathological specimens was investigated using immunohistochemical analysis. Results: C1r and/or C1s expression regulated ERK and/or AKT activation and promoted OSCC cell growth. In addition, activated ERK regulated the expression of C1r and C1s via a negative-feedback loop. Immunohistochemically, C1s was expressed in the tumor lesions and frequently showed high expression levels of both phosphorylated ERK and Ki-67, but not in the non-tumor regions of OSCC specimens. Conclusions: The complement system may be a common molecular mechanism for OSCC tumorigenesis, which arises from different origins: odontogenic and mucosal epithelium. Elevated C1r/C1s expression contributes to OSCC cell proliferation.",

keywords = "C1r, C1s, Cell proliferation, Oral squamous cell carcinoma, Oral squamous cell carcinoma, Cell proliferation, C1s, C1r",

author = "Truong, \{Thinh Thi Kim\} and Tatsufumi Fujimoto and Shinsuke Fujii and Kurppa, \{Kari J.\} and Kana Hasegawa and Yudai Tajiri and Masafumi Moriyama and Tamotsu Kiyoshima",

note = "Publisher Copyright: {\textcopyright} 2025 Japanese Association for Oral Biology",

year = "2025",

month = dec,

doi = "10.1016/j.job.2025.100691",

language = "English",

volume = "67",

journal = "Journal of Oral Biosciences",

issn = "1349-0079",

publisher = "Elsevier",

number = "4",

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TY - JOUR

T1 - Complement components C1r and C1s promote oral squamous cell carcinoma cell proliferation

AU - Truong, Thinh Thi Kim

AU - Fujimoto, Tatsufumi

AU - Fujii, Shinsuke

AU - Kurppa, Kari J.

AU - Hasegawa, Kana

AU - Tajiri, Yudai

AU - Moriyama, Masafumi

AU - Kiyoshima, Tamotsu

PY - 2025/12

Y1 - 2025/12

N2 - Objectives: Oral squamous cell carcinoma (OSCC), the most frequent cancer of the oral cavity, mostly arises from the mucosal epithelium and rarely from the odontogenic epithelium. However, it is unclear whether they share the same mechanisms of OSCC development. Recently, we clarified comprehensive gene expression patterns in pathological specimens of two types of OSCC (odontogenic epithelial and mucosal epithelial origin). In addition, the enrichment analysis demonstrated that the “COMPLEMENT” gene set was elevated in these tumor lesions. However, the role of this system in OSCC tumorigenesis remains unclear. Here, we aimed to investigate the involvement of complement components in OSCC development. Methods: siRNA and shRNA were used to examine OSCC cell proliferation in vitro and in vivo and assess activation of intracellular signaling using western blotting technics. An MEK1/2-specific inhibitor was used to verify its effects on the expression of C1r and/or C1s, components of the classical complement pathway. C1s expression in OSCC pathological specimens was investigated using immunohistochemical analysis. Results: C1r and/or C1s expression regulated ERK and/or AKT activation and promoted OSCC cell growth. In addition, activated ERK regulated the expression of C1r and C1s via a negative-feedback loop. Immunohistochemically, C1s was expressed in the tumor lesions and frequently showed high expression levels of both phosphorylated ERK and Ki-67, but not in the non-tumor regions of OSCC specimens. Conclusions: The complement system may be a common molecular mechanism for OSCC tumorigenesis, which arises from different origins: odontogenic and mucosal epithelium. Elevated C1r/C1s expression contributes to OSCC cell proliferation.

AB - Objectives: Oral squamous cell carcinoma (OSCC), the most frequent cancer of the oral cavity, mostly arises from the mucosal epithelium and rarely from the odontogenic epithelium. However, it is unclear whether they share the same mechanisms of OSCC development. Recently, we clarified comprehensive gene expression patterns in pathological specimens of two types of OSCC (odontogenic epithelial and mucosal epithelial origin). In addition, the enrichment analysis demonstrated that the “COMPLEMENT” gene set was elevated in these tumor lesions. However, the role of this system in OSCC tumorigenesis remains unclear. Here, we aimed to investigate the involvement of complement components in OSCC development. Methods: siRNA and shRNA were used to examine OSCC cell proliferation in vitro and in vivo and assess activation of intracellular signaling using western blotting technics. An MEK1/2-specific inhibitor was used to verify its effects on the expression of C1r and/or C1s, components of the classical complement pathway. C1s expression in OSCC pathological specimens was investigated using immunohistochemical analysis. Results: C1r and/or C1s expression regulated ERK and/or AKT activation and promoted OSCC cell growth. In addition, activated ERK regulated the expression of C1r and C1s via a negative-feedback loop. Immunohistochemically, C1s was expressed in the tumor lesions and frequently showed high expression levels of both phosphorylated ERK and Ki-67, but not in the non-tumor regions of OSCC specimens. Conclusions: The complement system may be a common molecular mechanism for OSCC tumorigenesis, which arises from different origins: odontogenic and mucosal epithelium. Elevated C1r/C1s expression contributes to OSCC cell proliferation.

KW - C1r

KW - C1s

KW - Cell proliferation

KW - Oral squamous cell carcinoma

KW - Cell proliferation

KW - C1s

KW - C1r

UR - https://www.scopus.com/pages/publications/105013387027

U2 - 10.1016/j.job.2025.100691

DO - 10.1016/j.job.2025.100691

M3 - Article

C2 - 41274675

AN - SCOPUS:105013387027

SN - 1349-0079

VL - 67

JO - Journal of Oral Biosciences

JF - Journal of Oral Biosciences

IS - 4

M1 - 100691

ER -

Complement components C1r and C1s promote oral squamous cell carcinoma cell proliferation

Abstract

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