Identification of the metastatic mechanism of keratin 19 positive cancer stem cells and novel therapeutic targets in hepatocellular carcinoma

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K16305
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kyoto University
• Principal Investigator: Kawai Takayuki 京都大学, 医学研究科, 客員研究員 (00813867)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 肝細胞癌 / 癌幹細胞

Outline of Final Research Achievements

Hepatocellular carcinoma (HCC) is one of the most intractable malignancies worldwide. In this study, we investigated the metastatic mechanism of keratin 19 (K19) positive HCC cancer stem cells (CSCs). The results of three-dimensional culture of HCC cells using the decellularized liver derived from normal and fibrotic livers showed that K19-positive HCC-CSCs showed high invasive and metastatic potential in the decellularized fibrotic liver, suggesting that the activation of TGFb/Smad pathway via signals from the fibrotic liver extracellular matrix may be the mechanism. In addition, analysis of HCC clinical specimens revealed that K19 expression was significantly correlated with the progression of liver fibrosis, and mutations in genes involved in the regulation of the TGFb/Smad pathway occurred in K19-positive hepatocellular carcinoma.

Free Research Field

消化器外科学（肝胆膵領域の悪性腫瘍）

Academic Significance and Societal Importance of the Research Achievements

本研究では、K19陽性肝細胞癌癌幹細胞が線維化肝からのシグナルを介したTGFb/Smad pathwayの活性化により高い浸潤・転移形質を示す可能性が示唆された。また、肝細胞癌におけるK19発現は肝線維化進行度と相関しており、K19陽性肝細胞癌ではTGFb/Smad pathwayの調節に関わる遺伝子に変異を有していた。この成果により、K19陽性肝細胞癌の転移メカニズムの一端が明らかになり、TGFb/Smad pathwayという新規治療標的が同定された。肝細胞癌の約15%を占める特に予後不良なK19陽性症例に対する個別化治療の可能性が示されたと考えており、社会的意義を有すると思われる。