Is DLK gene a trigger for neuroendocrine differentiation of lung cancer?

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15091
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Dokkyo Medical University
• Principal Investigator: Ishii Jun 獨協医科大学, 医学部, 助教 (80749599)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 神経内分泌形質 / 肺癌 / 悪性形質 / DLK1 / 増殖因子 / 増殖活性

Outline of Final Research Achievements

Neuro-Endocrine differentiation (NE-def) is involved in the malignancy of lung cancer. We have shown that the NE-def is triggered by the class 3/4 POU genes, but its expression mechanism is unknown. In this study we focused on the fact that the NE-def is suppressed by the Notch receptor signal, and that lung cancer cells with the NE-def highly express the Notch signal inhibitory ligand DLK1. From the above, we hypothesized and studied that there may be a cascade that "DLK1 → Notch inhibition → 3/4 POU genes → NE-def expression”. As a result, it was found that DLK1 expression has a limited effect on NE-def, but it is deeply involved in the growth of lung cancer cells by another route mediated by growth factors.

Free Research Field

実験病理学

Academic Significance and Societal Importance of the Research Achievements

肺癌は致死率の高い悪性腫瘍であり、その悪性化に関与するNE形質の発現機序や、増殖機序の解明は急務である。本研究により、NE形質を有する肺癌が高度に発現するDLK1が、NE形質やその誘導因子である3/4型POU遺伝子発現に大きくは影響しないことが明らかとなり、NE形質発現メカニズムの全貌解明に一歩近づいた。またMinor populationであるDLK1強発現肺癌細胞が、IGF2やNTSといった増殖因子の発現を介してNE形質を有する肺癌細胞集団全体の増殖に寄与する可能性が明らかにされた。本研究の発展により、増殖因子あるいはその供給細胞を標的とした新規治療への応用が期待される。