Integrin signaling in the development and treatment of hepatocellular carcinoma
Introduction. Hepatocellular carcinoma (HCC) is the most prominent liver cancer worldwide. HCC begins with underlying liver cirrhosis or inflammation from viral infection, that lead to the formation of nodules that will eventually develop into cancer. The main risk factors for chronic liver disease and cirrhosis include hepatitis infection and alcohol.1 Integrins are receptor molecules on cells that sense the extracellular matrix and send signals inside the cell that alter both cytoskeletal properties of the cell and cell behavior. Integrins form adhesion complexes with cytoskeletal proteins and cell cycle proteins. It appears that in the absence of integrins, cells do not proceed through the cell cycle. Integrin adhesion complexes also directly stimulate MEK/Erk and the FAK-PI3-AKT pathway that allows cells to continue in the cell cycle.2 Several studies have been done to manipulate the beta-integrin pathway with much success in preventing carcinoma growth, four of these studies are discussed here. Methods. One study took nanoparticle delivered siRNA to knockdown beta-1 integrin in mice to observe the progression of the carcinoma.3 Another study used antibodies against the CD-98 transmembrane protein using HCC cell lines to note the interaction between CD-98 and beta-1 integrin in HCC progression.4 Antibodies were used in a following study in which mouse xenograft models were used to knockdown CD147 in mice and understand not only the relationship with beta-1 integrin but with radioresistance.5 HCC cell lines were also exposed EP1 receptor antagonists to determine the role between prostaglandins and beta-1 integrin.6 Results. With the siRNA knockdown of beta-integrin, HCC progression was limited significantly along with decreased expression of the MET oncogene.3 With antibody knockdown of CD-98, ICD infected cells had tumor cells that weighed less than those of the control group, and tumor volumes were less with ICD cells. Western Blot analysis showed that ICD infected cells had decreased beta-1 integrin expression, as well as those with pFAK and AKT, as well as shown on immunohistochemical staining, as well as decreased expression of cell proliferation marker Ki-67. This showed that CD98-ICD inhibits malignant behaviors of HCC cells. Major contributors to integrin-dependent signaling pAKT and pFAK were decreased in liver cell lines with CD98-ICD, along with decreased beta-1 integrin, and indicates that CD98-ICD could interact with beta-1 integrin and inhibit downstream integrin signaling.4 HCC cells that had CD147 knocked down exhibited cell cycle arrest and increased apoptosis, enhancing radiosensitivity.5 Knockout of EP1 receptor reduced the basal level of beta-1 integrin protein, even with the presence of PGE2. The study also showed that adding an NF-kB inhibitor could block PGE2 mediated beta-1 integrin expression in HCC cells.6 Conclusions There is now potential for the siRNA mediated inhibition of integrins, CD98-ICD, CD147 integrin interaction, and targeting the PGE2/EP1/PKC/NF-kB/FoxC2/beta-1 integrin pathway to represent new therapeutic strategies for the treatment of HCC.
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- Bogorad RL, Yin H, Zeigerer A, et al. Nanoparticle-formulated siRNA targeting integrins inhibits hepatocellular carcinoma progression in mice. Nature Communications. 2014;5. doi:10.1038/ncomms4869.
- Wu B, Zhou Y, Wang Y, et al. Dominant Suppression of β1 Integrin by Ectopic CD98-ICD Inhibits Hepatocellular Carcinoma Progression. International Journal of Molecular Sciences. 2016;17(11):1882. doi:10.3390/ijms17111882.
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