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Expression Analysis of JCAD and IL-33 in Gingival Cancer Tumor Angiogenesis
by
, , , , , , and
Tatsuya Shirai
1, 
Yasumasa Kakei
1,
Yumi Muraki
1,
Tatsuya Nagano
2,
Ratoe Suraya
2,
Kaito Uryu
1,
Daisuke Takeda
1,
Manabu Shigeoka
1,3,
Akira Kimoto
1,
Takumi Hasegawa
1,
Tetsuya Hara
4,
Noriaki Emoto
4 and
Masaya Akashi
1,* 1
Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
2
Division of Respiratory Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
3
Division of Molecular and Genomic Pathology, Department of Pathology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan
4
Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakitamachi, Higashinada-ku, Kobe 658-8558, Japan
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(23), 3732; https://doi.org/10.3390/cancers17233732
Submission received: 15 October 2025
/
Revised: 13 November 2025
/
Accepted: 14 November 2025
/
Published: 21 November 2025
(This article belongs to the Special Issue The Biomarkers of Oral Cancer)
Simple Summary
Tumor angiogenesis, the process by which new blood vessels form to support tumor growth, plays a critical role in oral squamous cell carcinoma (OSCC). We focused on a protein called junctional cadherin 5-associated (JCAD), which is involved in abnormal blood vessel formation, and interleukin-33 (IL-33), a molecule that regulates inflammation. Using genetically modified mice and human tissue samples, we examined how JCAD and IL-33 contribute to tumor-related angiogenesis. We found that loss of JCAD disrupted normal blood vessel formation and that, in human tumors, JCAD was highly expressed where IL-33 was reduced. Moreover, JCAD controlled the response of vascular cells to inflammatory signals. These results suggest that JCAD contributes to abnormal vessel growth in OSCC and may become a promising target for controlling tumor angiogenesis.
Abstract
Background: Tumor angiogenesis is a key step in oral squamous cell carcinoma (OSCC) development. Here, we evaluated the expression patterns of junctional cadherin 5-associated (JCAD), a pathological angiogenesis protein, and interleukin-33 (IL-33) in OSCC to investigate their roles in pathological angiogenesis. Methods: Wound healing assays were performed to evaluate pathological angiogenesis in JCAD knockout (JCAD-KO) mice. In human mandibular gingival SCC and lymph nodes specimens, the numbers of blood vessels positive for CD34 (a vascular endothelial cell marker), CD105 (a well-established tumor angiogenesis marker), JCAD, and IL-33 were counted. We also evaluated the effects of tumor necrosis factor-α (TNF-α) stimulation as a pro-angiogenic factor on human umbilical vein endothelial cells (HUVECs) with JCAD knockdown. Results: In JCAD-KO mouse skin, wound healing and angiogenesis were significantly disturbed. In the clinical samples, the number of microvessels in which CD105 and JCAD were expressed but intranuclear IL-33 expression was lost significantly increased in the intratumoral area compared with the normal area. JCAD knockdown restored the TNF-α-induced loss of intranuclear IL-33 expression in HUVECs. Conclusions: Our combined assessment of JCAD and IL-33 supports the evaluation of tumor angiogenesis in OSCC. JCAD is a potential target for controlling tumor angiogenesis mediated by TNF-α.
Keywords:
JCAD; IL-33; tumor angiogenesis; gingival cancer
