Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal cancers worldwide. The poor survival may be due to a high proportions of tumor recurrence and metastasis. Kinesin family member C1 (KIFC1) is highly expressed in a variety of neoplasms and is a potential marker for non-small cell lung cancer or ovarian adenocarcinoma metastasis. Nevertheless, the role of KIFC1 in HCC metastasis remains obscure. We investigated this in the present study using HCC cell lines and clinical specimens. Our results indicated that increased levels of KIFC1 were associated with poor prognosis and metastasis in HCC. In addition, KIFC1 induced epithelial-to-mesenchymal transition (EMT) and HCC metastasis both in vitro and in vivo. This tumorigenic effect depended on gankyrin; inhibiting gankyrin activity reversed EMT via activation of protein kinase B (AKT)/Twist family BHLH transcription factor 1 (AKT/TWIST1). We also found that KIFC1 was directly regulated by the microRNA miR-532-3p, whose downregulation was associated with metastatic progression in HCC. These results denote that a decrease in miR-532-3p levels results in increased KIFC1 expression in HCC, leading to metastasis via activation of the gankyrin/AKT/TWIST1 signaling pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism
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Carcinoma, Hepatocellular / mortality
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Carcinoma, Hepatocellular / secondary*
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Cell Line, Tumor
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Down-Regulation
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Epithelial-Mesenchymal Transition / physiology*
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Heterografts
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Humans
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Kaplan-Meier Estimate
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Kinesins / antagonists & inhibitors
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Kinesins / physiology*
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism
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Liver Neoplasms / mortality
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Liver Neoplasms / pathology*
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Lung Neoplasms / physiopathology
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Lung Neoplasms / secondary*
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Male
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Mice, Inbred BALB C
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Mice, Nude
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MicroRNAs / biosynthesis
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MicroRNAs / genetics
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MicroRNAs / physiology*
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / physiology*
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Nuclear Proteins / physiology
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Prognosis
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Proteasome Endopeptidase Complex / physiology
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Proto-Oncogene Proteins / physiology
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Proto-Oncogene Proteins c-akt / physiology
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RNA Interference
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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RNA, Neoplasm / physiology*
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Signal Transduction
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Twist-Related Protein 1 / physiology
Substances
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KIFC1 protein, human
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MIRN532 microRNA, human
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MicroRNAs
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Neoplasm Proteins
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Nuclear Proteins
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PSMD10 protein, human
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Proto-Oncogene Proteins
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RNA, Neoplasm
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TWIST1 protein, human
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Twist-Related Protein 1
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AKT1 protein, human
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Proto-Oncogene Proteins c-akt
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Proteasome Endopeptidase Complex
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Kinesins