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The Potential Role of the Paxillin Paralog Hic-5 in Progression Of Wen-Sheng Wu. et al. Medical Research Archives vol 6 issue 3. March issue 3 Medical Research Archives RESEARCH ARTICLE The potential role of the paxillin paralog Hic-5 in progression of hepatocellular carcinoma Authors Jia-Ru Wu&,Chi-Tan Hu#, Ren-In You&, Chi-Wen Chen%, Wen-Sheng Wu&1 Affiliations: # Research Centre for Hepatology, Department of Internal Medicine, Buddhist Tzu Chi General Hospital. School of Medicine, Tzu Chi University, Hualien, Taiwan. &Institute of Medical Sciences, Department of Laboratory Medicine and Biotechnology, College of Medicine, Tzu Chi University, Hualien, Taiwan. % School of Chinese Medicine, China Medical University, Taiwan Correspondence: Wen-Sheng Wu. Institute of medical biotechnology, college of Medicine, Tzu Chi University No. 701, Chung Yang Rd, Sec 3, Hualien 970, Taiwan. E-mail: [email protected] ；Phone: 8867-03-8565301 ext 2327；Fax: 8867-03-8571917 ABSTRACT Hepatocellular carcinoma (HCC) is one of the most common causes of death from cancer worldwide. The poor prognosis of HCC is due to high recurrence rate mainly caused by intrahepatic metastasis. Paxillin was known to be a central adaptor protein for mediating focal adhesion (FA) signal required for HCC progression. However, target therapy aiming at paxillin seems unfeasible due to its ubiquitous tissue expression and essential biological functions. Within the paxillin superfamily, hydrogen peroxide inducible clone-5 (Hic-5) is the most homologous to paxillin. This review summarises the recent findings relevant to the differential biochemical and biological roles of Hic-5 and paxillin. Given the structure similarity between Hic-5 and paxillin, Hic-5 shares many of the characteristics of paxillin, including the localization of Hic-5 at focal adhesions and similar FA binding factors. However, some of the regulatory mechanisms and molecular functions of Hic-5 are rather different from those of paxillin. These might explain the differential roles of both adaptors in regulating various pathophysiological processes. Interestingly, both adaptors might play distinct but complementary roles in tumor progression. Due to the more limited tissue distribution of Hic-5, it can be a more suitable therapeutic target for preventing HCC progression. Key words: Hepatocellular carcinoma; Metastasis; Paxillin; Hic-5; focal adhesions. Copyright 2018 KEI Journals. All Rights Reserved Wen-Sheng Wu.et al. Medical Research Archives vol 6 issue 3. March 2018 issue Page 2 of 17 Introduction Hepatocellular carcinoma (HCC) is one of the metastatic factors [27]. The role of paxillin in most common causes of death from cancer tumor progression of HCC has been worldwide. The mortality rate is very high in demonstrated in a lot of studies. Paxillin China, Taiwan and Southeast Asia[1]. Recently, phosphorylation at Ser178 mediated by Jun N- the incidence of HCC was increasing in terminal kinase (JNK) was involved in the HGF countries such as Japan, Italy, France, [30] and P21-activated protein kinase (PAK) Switzerland, United Kingdom and the United triggered tumor progression of HCC [31]. States[2]. The poor prognosis of HCC is due to Recently, paxillin was found to be a mediator high recurrence rate mainly caused by for the actopaxin-triggered HCC metastasis intrahepatic metastasis (about 80%) or [25]. extrahepatic metastasis (about 20%)[3]. Therefore, prevention of metastasis is critical Within the paxillin superfamily, Hic-5 for HCC management. To address the issue, the (hydrogen peroxide inducible clone-5), is the suitable molecular targets within the molecular most homologous to paxillin. Hic-5 was initially pathways leading to HCC metastasis are needed identified as one of the TGF1 and hydrogen to be identified. peroxide-inducible genes [32]. As paxillin, Hic Tumor metastasis occurs via complicated 5 is also an adaptor molecule essential for processes, including epithelial mesenchymal triggering progression of tumors [33, 34] transition (EMT), migration and invasion of including HCC [35]. This review summarizes primary tumor, followed by intravasation, the recent findings relevant to differential extravasation and colonization at the metastatic biochemical and biological roles between Hic-5 loci. The tumor microenvironment in HCC and paxillin in mediating a lot of cellular contains a lot of metastatic factors produced by phenotypes. Specifically the complementary interaction of primary cell with inflammatory role of both adaptors in tumor progression is cells, stromal cell and extracellular matrix [4, addressed. Moreover, the possibility of Hic-5 to 5]. Some of the metastatic factors including be a promising therapeutic target for prevention transforming growth factor (TGF) [6], of HCC metastasis is highlighted. hepatocyte growth factor (HGF) [7, 8], vascular endothelial growth factor (VEGF) and Comparison of the biochemical properties epidermal growth factor (EGF) [9] and integrin between Hic-5 and paxillin engagement [10-15], are capable of triggering Differential structure and binding properties HCC progression. A lot of signaling components in the FA such as RacGTPase [16, Paxillin comprises numerous discrete 17], focal adhesion kinase (FAK) [18-22], Src structural domains for scaffolding FA [23], Pyk2 [24] and paxillin [25] are known to components in response to integrin engagement be responsible for mediating HCC progression and growth factors [36]. The C-terminal half of triggered by these metastatic factors. paxillin contains four LIM domains, serving as binding sites for several structural and Among the aforementioned FA signal regulatory proteins such as tubulin and the components, Paxillin is responsible for protein tyrosine phosphatase (PTP) PEST. The mediating signal cross talk between integrin and N-terminus of paxillin is composed of five Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Wen-Sheng Wu.et al. Medical Research Archives vol 6 issue 3. March 2018 issue Page 3 of 17 leucine- and aspartate-rich LD motifs (LD1- residues. However, phosphorylation of Hic-5 LD5), with multiple tyrosine, serine and may occur through PYK2 following threonine phosphorylation sites for recruiting a hyperosmotic stress [47] and platelet activation lot of signal molecules including Src tyrosine [48]. kinase, focal adhesion kinase (FAK), receptor for activated C kinase 1(RACK1), JNK, p-38 and Abl. Hic-5 shares the same 11-exon In addition to the discrepancies of the genomic organization as paxillin with minor molecular structure, interaction and differences in the number of LD domains in the phosphorylation pattern for FA signaling as N-terminal region (five for paxillin and four for described above, there are a lot of different HIC-5) [36]. biochemical properties between both Hic-5 and Given the structure similarity between Hic-5 paxillin including tissue specific distribution, and paxillin, Hic-5 shares many of the regulation of gene expression, interaction with characteristics of paxillin, including the critical signal cascade, and the impacts on localization at FA and similar FA binding cellular phenotypes. factors such as protein tyrosine kinase 2 beta (PYK2), c-Src tyrosine kinase (Csk), FAK, Arf Differential tissue specific distribution between GAP1 (GIT-1) [37] and PTP-PEST [38]. paxillin and Hic-5 However, there are paxillin interacting FA components such as Crk and Src which can not Tissue expression of paxillin is broader than that bind Hic5. One distinct binding activity of Hic-5 of Hic-5 was ascribed to its LIM domain by which Hic-5 Whereas paxillin is ubiquitously expressed in may form LIM-LIM hetero-oligomers with most tissue and cell types, Hic-5 is enriched LIM-only proteins such as PINCH or CRP2 only in certain tissue such as smooth muscle (in [41]. In contrast, LIM4 of paxillin cannot form particular the vasculature), large intestine and oligomers and does not interact with PINCH or uterus and relatively high in the lung and spleen CRP2 [41]. [33]. This implicates that the biological roles of paxillin are broader than Hic-5. Indeed, paxillin Differential phosphorylation pattern involved ablation causing early embryonic lethality, while in FA signaling Hic-5 knockout exhibits only very mild vascular defects [33]. The phosphorylation patterns of Hic-5 and paxillin induced by extracellular stimuli are also Differential pattern of inducible gene expression rather different. Upon integrin engagement, between paxillin and Hic-5 paxillin becomes tyrosine phosphorylated, primarily on tyrosine residues 31 and 118 (Y31 One distinct regulatory mechanism of Hic-5 is and Y118, respectively at LD1), in a FAK- and the inducible gene expression by a lot of Src-dependent manner, resulting in activation of extracellular stimuli. In the most early studies, a lot of critical signal cascades for cell spreading Hic-5 gene expression was found to be induced and motility [42, 43]. In contrast, Hic-5 does not by reactive oxygen species (ROS) [59], as its exhibit the aforementioned phosphorylation name suggests. Hic-5 expression can also be patterns probably due to lack of cognate tyrosine induced during TGF1-induced senescence of Copyright 2018 KEI Journals. All Rights Reserved http://journals.ke-i.org/index.php/mra Wen-Sheng Wu.et al. Medical Research Archives vol 6 issue 3. March 2018 issue Page 4 of 17 osteoblastic cell line [32], angiotensin II-induced (BMP) signaling [70]. In addition, Hic-5 may abdominal aortic aneurysm (AAA) development serve as a scaffold protein that specifically [60], methylmercury-induced ER
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