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Int. J. Mol. Sci. 2016, 17(11), 1882;

Dominant Suppression of β1 Integrin by Ectopic CD98-ICD Inhibits Hepatocellular Carcinoma Progression

National Translational Science Center for Molecular Medicine, Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi’an 710032, China
Department of Oncology, State Key Discipline of Cell Biology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, China
Institute of Stomatology, Chinese People’s Liberation Army General Hospital, Beijing 100853, China
These authors contributed equally to this work.
Authors to whom correspondence should be addressed.
Academic Editor: Johannes Haybaeck
Received: 30 September 2016 / Revised: 28 October 2016 / Accepted: 1 November 2016 / Published: 10 November 2016
(This article belongs to the Collection Molecular Mechanisms of Human Liver Diseases)
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Hepatocellular carcinoma (HCC) is currently the third most common cause of cancer-related death in the Asia-Pacific region. Our previous work showed that knockdown of CD98 significantly inhibits malignant HCC cell phenotypes in vitro and in vivo. The level of CD98 in the membrane is tightly regulated to mediate complex processes associated with cell–cell communication and intracellular signaling. In addition, the intracellular domain of CD98 (CD98-ICD) seems to be of vital importance for recycling CD98 to the membrane after it is endocytosed. The intracellular and transmembrane domains of CD98 associate with β-integrins (primarily β1 but also β3), and this association is essential for CD98 mediation of integrin-like signaling and complements dominant suppression of β1-integrin. We speculated that isolated CD98-ICD would similarly suppress β1-integrin activation and inhibit the malignant behaviors of cancer cells. In particular, the exact role of CD98-ICD has not been studied independently in HCC. In this study, we found that ectopic expression of CD98-ICD inhibited the malignant phenotypes of HCC cells, and the mechanism possibly involves β1-integrin suppression. Moreover, the expression levels of CD98, β1-integrin-A (the activated form of β1-integrin) and Ki-67 were significantly increased in HCC tissues relative to those of normal liver tissues. Therefore, our preliminary study indicates that ectopic CD98-ICD has an inhibitory role in the malignant development of HCC, and shows that CD98-ICD acts as a dominant negative mutant of CD98 that attenuates β1-integrin activation. CD98-ICD may emerge as a promising candidate for antitumor treatment. View Full-Text
Keywords: CD98 heavy chain; carcinoma; hepatocellular; disease progression; integrins; protein transport CD98 heavy chain; carcinoma; hepatocellular; disease progression; integrins; protein transport

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Wu, B.; Zhou, Y.; Wang, Y.; Yang, X.-M.; Liu, Z.-Y.; Li, J.-H.; Feng, F.; Chen, Z.-N.; Jiang, J.-L. Dominant Suppression of β1 Integrin by Ectopic CD98-ICD Inhibits Hepatocellular Carcinoma Progression. Int. J. Mol. Sci. 2016, 17, 1882.

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