Functional analysis of Ror1-Rif signaling in malignant progression of non-small cell lung cancer cells

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08634
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Fukushima Medical University (2019); Kobe University (2017-2018)
• Principal Investigator: Nishita Michiru 福島県立医科大学, 医学部, 教授 (30379359)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 非小細胞肺がん / Ror1受容体型チロシンキナーゼ / Rif低分子量Gタンパク質 / フィロポディア / がん細胞浸潤

Outline of Final Research Achievements

We studied the role of Ror1 in invasive properties of non-small cell lung cancer (NSCLC) cells. We have shown that, in PC-9 NSCLC cells, Ror1 induces formation of polarized filopodia through the Rho-family small GTPase, Rif, in 3D-Matrigel. These filopodia were spacially associated with degradation of Matrigel. Suppressed expression of Ror1 or Rif inhibited both filopodia formation and Matrigel degradation. We have also shown that PC-9 cells express high levels of Wnt5a, leading to constitutively activated Wnt5a-Ror1-Dvl signaling, which is required for their invasiveness. Furthermore, SmgGDS was identified as a Rif-binding partner that promotes Rif-induced filopodia formation and invasion in PC-9 cells. Taken together, these results suggest that Wnt5a-Ror1 signaling mediated by SmgGDS and Rif regulates filopodia formation to promote invasion of NSCLC cells.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本研究によってRor1、Rif、SmgGDSを介した新たなフィロポディア形成機構が見いだされたことは、細胞生物学的知見として重要ある。また、がん細胞浸潤におけるフィロポディアの役割を見いだしたことは、社会的にも意義が多きい。特に、肺がんは本邦におけるがんによる死亡原因の１位であり、中でも肺がんの８割を占める非小細胞肺がんでは、化学療法や放射線治療が有効でないことが治療の大きな障害になっていることから、本研究成果は、有効な治療方法を開発する上でも重要な知見である。