| Summary: | 碩士 === 輔英科技大學 === 醫學檢驗生物技術系碩士班 === 102 === In Taiwan, hepatocellular carcinoma (HCC) is the second most common cause of cancer death and causes more than 7,500 deaths each year. Nevertheless, approximately 75% of patients with HCC have advanced unresectable diseases upon presentation. Alterations of histone deacetylases (HDACs) have been described in different human cancers and modulated different tumor-specific genes involved in growth control and cell migration. Human histone deacetylase 6 (HDAC6) is the only HDAC that possesses two functional deacetylase domains (DD). Cell motility and adhesion involves dynamic acetylation status of microtubule, regulated by HDAC6, a major cytoplasmic α-tubulin deacetylase. Our results showed that both cytoplasmic intensity and nuclear frequency of HDAC6 staining were decreased in 65.1% and 62.7%, respectively, of the 83 HCC cases. Nevertheless, an increased cytoplasmic HDAC6 staining was positively correlated with disease recurrence (p=0.002). In addition, patients with an increased nuclear HDAC6 frequency in cancerous lesions had a poor overall survival rate (p=0.004). Restoration of HDAC6 expression increased the proliferation, migration, and invasion of the Mahlavu cells. More interestingly, ectopic HDAC6 overexpression increased a ligand (i.e. EGF)-independent expression of β-catenin, and cyclin D, and subsequently promoted the entry of cytoplasmic β-catenin into the nucleus. EGFR, a dominant trigger of AKT signaling, was also increased upon HDAC6 restoration, and treatment with an EGFR-specific inhibitor attenuated the expression of β-catenin in Mahlavu cells. In conclusion, HDAC6 may server as a prognostic biomarker in HCC. A HDAC6-mediated ligand-independent EGFR signaling may be involved in its contribution to HCC development. Therapy with inhibition of HDAC6 activity may by pass the driver mutations of EGFR. Hopefully, the study will provide a better understanding of the carcinogenesis of HCC and provide useful information for the clinicians to decide the treatment for each individual HCC patient.
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