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This dissertation, Overexpression of PAK4 and Its Relevance in Hepatocellular Carcinoma by Haitao, Xu, 許海濤, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled OVEREXPRESSION OF PAK4 AND ITS RELEVANCE IN HEPATOCELLULAR CARCINOMA Submitted by XU Hai-tao for the degree of Master of Philosophy at the University of Hong Kong in October 2006 PAK4 (p21-activated protein kinase 4) is a member of the PAK protein kinase family which phosphorylates downstream substrates on serine/threonine residues. First identified as an important regulator of the cytoskeletal dynamics, PAK4 has also been shown to have a role in other cellular signaling pathways including cell migration, cell survival regulation and cellular transformation. On the other hand, overexpression of PAK4 has been reported in cancer cell lines derived from tumors of various tissue origins such as lung, ovary, CNS, leukemia, prostate, colon, renal, melanoma as well as breast. All these point to a tumorigenic potential of PAK4. Despite extensive research on PAK4 in different cancers, there is so far no such study in hepatocellular carcinoma (HCC). HCC is one of the commonest malignancies in the world. Although the risk factors have been clearly identified, the molecular mechanisms involved in hepatocarcinogenesis remain to be elucidated. In this study, we investigated the expression of PAK4 in clinical HCC tissue samples. As in a number of other tumors, PAK4 is significantly overexpressed in HCC tumor tissues, compared with the nontumorous counterparts. This overexpression is associated with a more aggressive tumor behavior, which is characterized by more frequent venous invasion and liver invasion, implying that PAK4 may have a role in HCC metastasis. We further studied the effects of PAK4 knockdown on HCC cell line. With the establishment of stable clones, we observed morphological changes and impaired migration in PAK4-depleted cells. However, cell proliferation was hardly affected. Our data suggested that in HCC PAK4 may exert its influence on tumor migration, rather than tumor growth. Together with the previously identified shorter isoform of PAK4 (which we named PAK4β), we studied the cellular localization of PAK4 in HCC cell line. A potential nuclear exporting sequence (NES) was identified from exon 2 of PAK4. It was found to confer cytoplasmic localization of PAK4α ( previously called wild type), while the NES-missing isoform PAK4β predominantly localized to the nucleus. Interestingly, in HCC tissue samples, PAK4 was found to be retained in the nucleus, implicating preferential expression of specific isoform in HCC. Taken together, our findings suggest PAK4 may play a role in HCC metastasis. An abstract of 357 words DOI: 10.5353/th_b3870394 Subjects: Gene expressionProtein kinasesMetastasisLiver - Cancer - Genetic aspects

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