Research Papers:

Integrin β3 and LKB1 are independently involved in the inhibition of proliferation by lovastatin in human intrahepatic cholangiocarcinoma

Sheng-Huei Yang, Hung-Yun Lin, Chun A Changou, Chun-Han Chen, Yun-Ru Liu, Jinghan Wang, Xiaoqing Jiang, Frank Luh and Yun Yen _

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Oncotarget. 2016; 7:362-373. https://doi.org/10.18632/oncotarget.6238

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Sheng-Huei Yang1, Hung-Yun Lin1,2, Chun A Changou1,3,4, Chun-Han Chen1, Yun-Ru Liu5, Jinghan Wang6, Xiaoqing Jiang6, Frank Luh7,8, Yun Yen1

1PhD Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan

2Taipei Cancer Center, Taipei Medical University, Taipei, Taiwan

3Integrated Laboratory, Center of Translational Medicine, Taipei Medical University, Taipei, Taiwan

4Core Facility, Taipei Medical University, Taipei, Taiwan

5Office of Human Research, Taipei Medical University, Taipei, Taiwan

6The First Department of Biliary Surgery, Eastern Hepatobiliary Surgical Hospital, Second Military Medical University, Shanghai, China

7School of medicine, Taipei Medical University, Taipei, Taiwan

8Sino-American Cancer Foundation, Arcadia, California, United States

Correspondence to:

Yun Yen, e-mail: [email protected]

Keywords: bile duct cancer, HMG-CoA reductase inhibitor, integrin, LKB1, TGF-β1

Received: August 06, 2015     Accepted: October 14, 2015     Published: October 26, 2015


Human intrahepatic cholangiocarcinomas are one of the most difficult cancers to treat. In our study, Lovastatin, a 3-hydroxy-3-methylglutaryl-coenzyme-CoA (HMG-CoA) reductase inhibitor, demonstrated anticancer properties by inhibiting cancer cell proliferation, cell migration and cell adhesion. Lovastatin inhibited the expressions of transforming growth factor (TGF)-β1, cyclooxygenase (COX)-2, and intercellular adhesion molecule (ICAM)-1. Furthermore, lovastatin inhibited the expressions of integrin β1 and integrin β3 but not integrin αv or integrin β5. While Lovastatin’s inhibitory effects on TGFβ1, COX2, and ICAM-1 expression were independently controlled by the tumor suppressor LKB1, integrin β3 expression was not affected. Lovastatin’s inhibitory effect on cell adhesion was associated with the decreased expression of integrin β3 and cell surface heterodimer integrin αvβ3. Quantitative real time PCR, fluorescent microscopy, and cell migration assays all confirmed that Lovastatin inhibits integrin αvβ3 downstream signaling including FAK activation, and β-catenin, vimentin, ZO-1, and β-actin. Overall, Lovastatin reduced tumor cell proliferation and migration by modifying the expression of genes involved in cell adhesion and other critical cellular processes. Our study highlights novel anti-cancer properties of Lovastatin and supports further exploration of statins in the context of cholangiocarcinoma therapy.

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