LH2 Promotes Tumor Progression in Oral Squamous Cell Carcinoma via EPHA7-AKT-VEGF Signaling.
- 1Department of Oral Science, Graduate School of Medicine, Chiba University, Chiba, Japan.
- 2Department of Dentistry and Oral-Maxillofacial Surgery, Chiba University Hospital, Chiba, Japan.
Abstract
Background
Lysyl hydroxylase 2 (LH2) specifically hydroxylates lysine residues in type I collagen telopeptides. Aberrant LH2 expression has been implicated as a driver of aggressive phenotypes in multiple cancers, including oral squamous cell carcinoma (OSCC). However, the intracellular signaling mechanisms activated by LH2 overexpression remain unclear.Methods
In this study, we performed a comprehensive expression analysis to clarify LH2-driven signaling and to identify potential therapeutic targets. Stable LH2-overexpressing (LH2 O/E) OSCC cell lines were generated using a CAG-driven full-length LH2 cDNA construct. Cell proliferation assays were performed to evaluate the effects of LH2 overexpression on cell growth. Expression profiling by RNA sequencing, followed by Ingenuity Pathway Analysis, was performed to identify LH2-regulated networks. Differentially expressed genes were validated by quantitative RT-PCR and immunoblot analyses. siRNA-mediated LH2 knockdown was performed for loss-of-function studies.Results
LH2 O/E cells displayed significantly increased proliferative capacity compared with control cells. RNA sequencing identified 3,415 differentially expressed genes (1,828 upregulated and 1,587 downregulated) associated with axonal guidance signaling. Among the genes within the axonal guidance signaling network, ephrin type-A receptor 7 (EPHA7) was markedly upregulated. Increased EPHA7 expression was associated with induction of vascular endothelial growth factors (VEGFs) and increased AKT phosphorylation. Knockdown of LH2 in LH2 O/E cells reduced EPHA7 and VEGF levels and attenuated cell proliferation, supporting a functional link between LH2 and the EPHA7-VEGF axis.Conclusion
Our findings demonstrate that LH2 overexpression drives an EPHA7-VEGF signaling cascade that promotes tumor progression in OSCC. These results provide mechanistic insight into LH2-associated oncogenesis and identify a potential therapeutic target for OSCC.
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BibTeX
@article{nishimura2026promotes,
title = {{LH2 Promotes Tumor Progression in Oral Squamous Cell Carcinoma via EPHA7-AKT-VEGF Signaling.}},
author = {Yuki Nishimura and Atsushi Kasamatsu and Reo Fukushima and Tomoaki Saito and Suguru Okoshi and Isao Miyamoto and Dai Nakashima and Katsuhiro Uzawa},
journal = {Journal of Cancer},
year = {2026},
month = sep,
doi = {10.7150/jca.141338},
url = {https://europepmc.org/article/MED/42910375},
note = {CC BY},
}
RIS
TY - JOUR
TI - LH2 Promotes Tumor Progression in Oral Squamous Cell Carcinoma via EPHA7-AKT-VEGF Signaling.
AU - Yuki Nishimura
AU - Atsushi Kasamatsu
AU - Reo Fukushima
AU - Tomoaki Saito
AU - Suguru Okoshi
AU - Isao Miyamoto
AU - Dai Nakashima
AU - Katsuhiro Uzawa
PY - 2026
DA - 2026/09/28
JO - Journal of Cancer
DO - 10.7150/jca.141338
UR - https://europepmc.org/article/MED/42910375
AB - Background Lysyl hydroxylase 2 (LH2) specifically hydroxylates lysine residues in type I collagen telopeptides. Aberrant LH2 expression has been implicated as a driver of aggressive phenotypes in multiple cancers, including oral squamous cell carcinoma (OSCC). However, the intracellular signaling mechanisms activated by LH2 overexpression remain unclear.Methods In this study, we performed a comprehensive expression analysis to clarify LH2-driven signaling and to identify potential therapeutic targets. Stable LH2-overexpressing (LH2 O/E) OSCC cell lines were generated using a CAG-driven full-length LH2 cDNA construct. Cell proliferation assays were performed to evaluate the effects of LH2 overexpression on cell growth. Expression profiling by RNA sequencing, followed by Ingenuity Pathway Analysis, was performed to identify LH2-regulated networks. Differentially expressed genes were validated by quantitative RT-PCR and immunoblot analyses. siRNA-mediated LH2 knockdown was performed for loss-of-function studies.Results LH2 O/E cells displayed significantly increased proliferative capacity compared with control cells. RNA sequencing identified 3,415 differentially expressed genes (1,828 upregulated and 1,587 downregulated) associated with axonal guidance signaling. Among the genes within the axonal guidance signaling network, ephrin type-A receptor 7 (EPHA7) was markedly upregulated. Increased EPHA7 expression was associated with induction of vascular endothelial growth factors (VEGFs) and increased AKT phosphorylation. Knockdown of LH2 in LH2 O/E cells reduced EPHA7 and VEGF levels and attenuated cell proliferation, supporting a functional link between LH2 and the EPHA7-VEGF axis.Conclusion Our findings demonstrate that LH2 overexpression drives an EPHA7-VEGF signaling cascade that promotes tumor progression in OSCC. These results provide mechanistic insight into LH2-associated oncogenesis and identify a potential therapeutic target for OSCC.
SN - 1837-9664
ER -