神戸大学 · 医学研究科/医学部

研究关键词Wnt5a-Ror1-Dvl2 signaling・lung adenocarcinoma・keratinocyte wound repair・ferroptosis regulation・Rho family GTPases・cell polarity proteins・membrane NADH metabolism・cancer progression

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• Rho family small GTPase Rif regulates Wnt5a-Ror1-Dvl2 signaling and promotes lung adenocarcinoma progression2023 · Elsevier BV, 2023年09月, Journal of Biological Chemistry, 105248 - 105248
• α-Tocopherol promotes HaCaT keratinocyte wound repair through the regulation of polarity proteins leading to the polarized cell migration2017 · In many developed countries including Japan, how to care the bedridden elderly people with chronic wounds such as decubitus becomes one of the most concerned issues. Although antioxidant micronutrients including vitamin E, especially α-tocopherol (α-Toc), are reported to shorten a period of wound closure, the promoting effect of α-Toc on wound healing independent of its antioxidant activity remains to be fully elucidated. The aim of this study was to examine whether α-Toc affects wound-mediated HaCaT keratinocyte polarization process including the recruitment of polarity regulating proteins, leading to wound repair independently of its antioxidant activity. We investigated the effects of α-Toc and other antioxidants such as Trolox, a cell-permeable α-Toc analog on the migration, proliferation, and cell polarization of HaCaT keratinocytes after wounding. We analyzed the localization and complex formation of polarity proteins, partitioning defective 3 (Par3), and atypical protein kinase C (aPKC), and aPKC activity by immunohistochemistry, immunoprecipitation analyses, and in vitro kinase assays, respectively. α-Toc but not other antioxidants enhanced the wound closure and cell polarization in HaCaT keratinocytes after wounding. α-Toc regulated the localization and complex formation of Par3 and aPKC during wound healing. Knockdown of aPKC or Par3 abrogated α-Toc-mediated promotion of the wound closure and cell polarization in HaCaT keratinocytes. Furthermore, aPKC kinase activity was significantly increased in α-Toc-treated cells through activation of phosphatidylinositol 3-kinase/Akt signaling pathway. These results suggest that α-Toc promotes HaCaT keratinocyte wound repair by regulating the aPKC kinase activity and the formation of aPKC-Par3 complex. © 2017 BioFactors, 44(2):180-191, 2018.
• Role of noncanonical Wnt ligands and Ror‐family receptor tyrosine kinases in the development, regeneration, and diseases of the musculoskeletal systemThe Ror-family receptor tyrosine kinases (RTKs), consisting of Ror1 and Ror2, play crucial roles in morphogenesis and formation of various tissues/organs, including the bones and skeletal muscles, the so-called musculoskeletal system, during embryonic development, by acting as receptors or coreceptors for a noncanonical Wnt protein Wnt5a. Furthermore, several lines of evidence have indicated that Ror1 and/or Ror2 play critical roles in the regeneration and maintenance of the musculoskeletal system in adults. Considering the anatomical and functional relationship between the skeleton and skeletal muscles, their structural and functional association might be tightly regulated during their embryonic development, development after birth, and their regeneration after injury in adults. Importantly, in addition to their congenital anomalies, much attention has been paid onto the age-related disorders of the musculoskeletal system, including osteopenia and sarcopenia, which affect severely the quality of life. In this article, we overview recent advances in our understanding of the roles of Ror1- and/or Ror2-mediated signaling in the embryonic development, regeneration in adults, and congenital and age-related disorders of the musculoskeletal system and discuss possible therapeutic approaches to locomotive syndromes by modulating Ror1- and/or Ror2-mediated signaling.
• Oncogenic E6 and/or E7 proteins drive proliferation and invasion of human papilloma virus‑positive head and neck squamous cell cancer through upregulation of Ror2 expression.Ror2 (receptor tyrosine kinase like orphan receptor 2) is highly expressed in various types of cancers; in the majority of these cancers, Ror2 expression is associated with more aggressive disease states. Recently, it has been reported that Ror2 is highly expressed in human papilloma virus (HPV)‑positive head and neck squamous cell cancer (HNSCC) cell lines, presumably indicating that Ror2 plays a critical role in HPV‑related cancers. However, the function of Ror2 in HPV‑positive HNSCC is currently unknown. Here, we first examined the expression levels of Ror2 in clinical specimens from patients with HPV‑negative and HPV‑positive oropharyngeal squamous cell cancer (OPSCC) via immunohistochemical analysis. We found that Ror2 was expressed in both HPV‑negative and HPV‑positive OPSCC tissues. We then confirmed that HPV‑positive HNSCC cell line, UPCI:SCC152 cells, express Ror2 higher than HPV‑negative cell lines as previously reported. Suppressed expression of HPV E6/7 resulted in reduced expression levels of Ror2. We also revealed that Ror2 downregulation significantly inhibited the proliferation of UPCI:SCC152 cells without inducing apoptosis. Moreover, Ror2 knockdown decelerated G1/S phase progression and abrogated invasive migration of UPCI:SCC152 cells. These results provide strong evidence that E6 and/or E7 oncoproteins regulate the progression of HPV‑positive HNSCC by upregulating Ror2 expression, suggesting that Ror2 could potentially be a novel target in HPV‑related cancers.

• Rifによる膵がん細胞のFerroptosis抵抗メカニズムの解明 紙崎 孝基 日本学術振興会, 科学研究費助成事業, 若手研究, 神戸大学, 2024年04月01日 - 2027年03月31日2024 · KUID parsed section
• 難治がんのフェロトーシス抑制機構におけるRifシグナルの解明 兵庫県健康財団, 令和6年度兵庫県健康財団 がん研究奨励賞, 2024年04月 - 2025年03月2024 · KUID parsed section
• 膵がんの進展におけるRif-Ror1シグナルの機能解析 メディカルトランスフォーメーション研究センター, 令和６年度メディカルトランスフォーメーション研究センター 若手共同研究プロジェクト, 2024年04月 - 2025年03月2024 · KUID parsed section
• 膵癌におけるWnt5a-Ror1シグナルの機能解析 メディカルトランスフォーメーション研究センター, 令和5年度メディカルトランスフォーメーション研究センター 若手共同研究プロジェクト, 2023年04月 - 2024年03月2023 · KUID parsed section

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