Our cell aggregation assay also showed that hypoxia inhibited hepatoma cell aggregation in our study (data not shown). To explore whether Tg737 is involved in invasion and migration induced by hypoxia, we examined the different expression

levels of Tg737 under normoxic and hypoxic conditions. The data confirmed that hypoxia induced the downregulation of Tg737 expression in HCC cell lines. In addition, hypoxia induced changes in adhesion, and the migration and invasion capacities of HCC cells were abrogated by restoring Tg737 expression levels. Taken together, these results suggest that hypoxia may increase the invasion and migration of HCC cells in a Tg737-dependent manner. The hypoxia-induced invasion and migration mediated by Tg737 is poorly understood. A hallmark of the invasion and migration of solid tumors is that this process requires cell-cell/matrix molecules that influence the adhesion, SB-715992 in vitro migration, and invasion of cancer cells [30]. Polycystin-1 is a large, plasma membrane receptor encoded by the PKD1 gene, which is mutated in autosomal-dominant polycystic kidney disease (ADPKD). Polycystin-1 is involved in several biological functions including proliferation, morphogenesis, and anti-apoptotic processes [31, 32]. Moreover, polycystin-1 appears to be associated with the focal adhesion

proteins talin, vinculin, FAK and paxillin [33]. Zhang et al. [9] also found that polycystin-1 influences the adhesion, migration, and invasion of cancer cells. As stated above, polycystin-1 is thought to be a cell adhesion molecule, Entinostat concentration possibly a member of the immunoglobulin superfamily of cell adhesion molecules. Furthermore, preliminary yeast 2-hybrid screens with Tg737 have identified several potential protein partners, including polycystin 1, catenin, P120 catenin, Snx1, and HNF4α [34]. Due to the importance of polycystin 1 in the adhesion, invasion

and migration of cancer cells and as a potential protein partner of Tg737, we hypothesized that Tg737-mediated hypoxia-induced increases in invasion and migration PAK6 require polycystin 1. As shown in our results, the expression of both Tg737 and polycystin 1 decreased after exposure of HCC cells to hypoxia. Moreover, the expression of polycystin 1 was restored under hypoxia by transfection of pcDNA3.1-Tg737. These data suggest that the effects of Tg737 on HCC cell migration and invasion under hypoxia may be at least partially mediated by the polycystin 1 pathway. A large amount of evidence suggests that some cytokines and chemokines secreted by cancer cells are important modulators of migration and invasion. Among these, IL-8 and TGF-β1 have important roles in the invasion and metastasis of many types of tumors [35, 36]. Furthermore, IL-8 and TGF-β1 signaling were recently investigated during the progression of ADPKD in PKD1 Savolitinib mouse mutant models [37, 38].