記述言語：英語   掲載種別：研究論文（学術雑誌）  

Our previous study revealed that metastasis‑associated protein 1 (MTA1), which is expressed in vascular endothelial cells, acts as a tube formation promoting factor. The present study aimed to clarify the importance of MTA1 expression in tube formation using MTA1‑knockout (KO) endothelial cells (MTA1‑KO MSS31 cells). Tube formation was significantly suppressed in MTA1‑KO MSS31 cells, whereas MTA1‑overexpression MTA1‑KO MSS31 cells regained the ability to form tube‑like structures. In addition, western blotting analysis revealed that MTA1‑KO MSS31 cells showed significantly higher levels of phosphorylation of non‑muscle myosin heavy chain IIa, which resulted in suppression of tube formation. This effect was attributed to a decrease of MTA1/S100 calcium‑binding protein A4 complex formation. Moreover, inhibition of tube formation in MTA1‑KO MSS31 cells could not be rescued by stimulation with vascular endothelial growth factor (VEGF). These results demonstrated that MTA1 may serve as an essential molecule for angiogenesis in endothelial cells and be involved in different steps of the angiogenic process compared with the VEGF/VEGF receptor 2 pathway. The findings showed that endothelial MTA1 and its pathway may serve as promising targets for inhibiting tumor angiogenesis, further supporting the development of MTA1‑based antiangiogenic therapies.

DOI： 10.3892/mmr.2021.12527

リポジトリ公開URL： https://hdl.handle.net/2324/7173588

記述言語：日本語  

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sunitinib, a tyrosine kinase inhibitor, is among the first‑line treatments for metastatic or advanced stage renal cell carcinoma (RCC). However, patients with RCC develop resistance to sunitinib. We have previously demonstrated that lysosome‑associated membrane protein 2 (LAMP‑2), which has three splice variants with different functions (LAMP‑2A, LAMP‑2B, and LAMP‑2C), is involved in RCC. In the present study, we examined which splice variants of LAMP‑2 contributed to sunitinib resistance in RCC cells. In vitro analysis using ACHN, human RCC cell line, revealed that the IC50 of sunitinib was significantly increased by overexpression of LAMP‑2A and LAMP‑2B, but not LAMP‑2C (P<0.01). Kaplan‑Meier survival analysis using clinical samples revealed an association between shorter survival and high expression of LAMP‑2A and LAMP‑2B, but not LAMP‑2C, in patients with RCC treated with sunitinib (P=0.01). Furthermore, high expression of LAMP‑2A and LAMP‑2B in RCC revealed a weak to moderate inverse correlation with the tumor shrinkage rate and progression‑free survival, respectively. Thus, high expression of LAMP‑2A and LAMP‑2B contributed to the acquisition of sunitinib resistance, indicating that the expression of these two variants can predict the efficacy of sunitinib treatment in patients with RCC.

DOI： 10.3892/or.2020.7752

リポジトリ公開URL： https://hdl.handle.net/2324/7178659

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: The onset mechanism for bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been reported, with a focus on bone remodeling, biofilm formation, and epithelial cell proliferation and migration. However, the involvement of stromal cells, especially fibroblasts, in the oral cavity is unclear. Therefore, this study was focused on how bisphosphonates (BPs) affect orthotopic periodontal ligament fibroblasts from the viewpoint of oxidative stress compared with ectopically obtained fibroblasts. METHODS: Normal human periodontal ligament fibroblasts (HPdLFs) and normal human dermal fibroblasts (NHDFs) were used to gain insight into the functional differences in sensitivity and reactions to BPs. Cell growth assay, measurement of reactive oxygen species (ROS) and nitric oxide (NO) production, and wound-healing assay in vitro were performed. Maxillary first molars were extracted in C57BL/6 mice and either BP, N-acetyl-cysteine (NAC), and BP or saline were administered. RESULTS: BP-induced IC50 values were significantly lower in HPdLFs (30.6 µM) than in NHDFs (109.7 µM). BP resulted in an increase in ROS, but not NO generation in HPdLFs. BPs also inhibited proliferation and migration of HPdLFs but not NHDFs, while the addition of a ROS inhibitor, NAC, reversed those inhibitions. A BRONJ mouse model in which BP was administered and then the tooth was extracted, impaired wound healing of the socket was observed. When NAC was administered before tooth extraction, wound healing was significantly improved. CONCLUSION: These results suggest that BP causes fibroblasts obtained from the oral cavity but not from skin to generate ROS and that the subsequent ROS-mediated inhibition of fibroblast growth and migration definitely delays wound healing, thereby contributing to BRONJ pathogenesis.

DOI： 10.1002/JPER.19-0385

リポジトリ公開URL： https://hdl.handle.net/2324/7178695

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Extensive studies on metastasis-associated proteins, S100A4 and MTA1, have been carried out for over two decades, but correlation of both proteins remains obscure. Here we show evidence for the correlation in angiogenesis. First, silencing of each protein by siRNA-mediated knockdown in mouse endothelial MSS31 cells resulted in the inhibition of tube formation. Unexpectedly, the knockdown of MTA1 affected not only its own expression but also the expression of S100A4, whereas silencing of S100A4 did not affect the MTA1 expression. Additionally, non-muscle myosin IIA (NMIIA) phosphorylation, which was partly controlled by S100A4, was found to be upregulated by knockdown of both proteins in MSS31 cells. Moreover, cycloheximide treatment of MSS31 cells revealed that the rate of S100A4 degradation was accelerated by MTA1 knockdown. This finding, together with our observation that cytoplasmic MTA1, but not nuclear MTA1, was colocalized with S100A4, suggested the involvement of MTA1 in S100A4 stability. The direct in vivo angiogenesis assay showed that both protein siRNAs provoked a significant inhibition of new blood vessel formation induced by angiogenic factors, indicating their anti-angiogenic activities. Treatment of human pancreatic tumor (PANC-1) xenograft in mice with mMTA1 siRNA resulted in tumor regression via suppression of angiogenesis in vivo, as also observed in the case of human prostate cancer xenograft treated with mS100A4 siRNA. Taken together, these data led us to conclude that the MTA1-S100A4-NMIIA axis exists in endothelial cells as a novel pathway in promoting tumor vascular formation and could be a target for suppressing tumor growth and metastasis.

DOI： 10.1038/s41388-019-0748-z

リポジトリ公開URL： https://hdl.handle.net/2324/7178658

記述言語：日本語  

血管内皮細胞に発現しているMTA1はS100A4を介する事で新たな腫瘍血管新生の阻害標的になりうる

リポジトリ公開URL： https://hdl.handle.net/2324/7237094

記述言語：英語  

血管内皮細胞におけるMTA1発現の抑制はS100A4発現抑制を介した血管新生阻害による抗腫瘍効果を引き起こす(Silencing of MTA1 in endothelial cells induced anti-tumor effect by inhibiting angiogenesis via downregulation of S100A4)

リポジトリ公開URL： https://hdl.handle.net/2324/7237092

記述言語：英語  

血管内皮細胞におけるMTA1発現は血管新生阻害の標的分子となりうる(MTA1 expressed in endothelial cells is a candidate target molecule for inhibiting angiogenesis)

リポジトリ公開URL： https://hdl.handle.net/2324/7237094

記述言語：英語  

血管内皮細胞におけるMTA1の抑制はS100A4抑制を介した血管新生阻害による腫瘍退縮を引き起こす

リポジトリ公開URL： https://hdl.handle.net/2324/7236793

記述言語：英語  

血管内皮細胞におけるMTA1の抑制はS100A4抑制を介した血管新生阻害による腫瘍退縮を引き起こす

リポジトリ公開URL： https://hdl.handle.net/2324/7236792