Human Hepatocellular Carcinoma (HCC) Cells Require Both α3β1 Integrin and Matrix Metalloproteinases Activity for Migration and Invasion

Giannelli, Gianluigi; Bergamini, Carlo; Fransvea, Emilia; Marinosci, Felice; Quaranta, Vito; Antonaci, Salvatore

doi:10.1038/labinvest.3780270

Cited by 133 publications

(146 citation statements)

References 49 publications

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“…Furthermore, in our model, it is very likely that both the a6b4 and a3b1 integrins are involved in the Ln-5 signal pathway since both anti-a3-and anti-a6-blocking antibodies inhibit Ln-5-mediated survival in cytotoxicity experiments. Thus, consistently with our previous work (Giannelli et al, 2001), in the HCC model, it is possible that either a3b1 or a6b4 are implicated in signal transduction, mainly depending on which receptor is predominantly expressed. Therefore, these data could contribute to explain the discrepancy in the literature between the involvement of a3b1 and a6b4 in cancer aggressiveness.…”

Section: Discussionsupporting

confidence: 88%

“…However, this Ln-5 activity was completely inhibited by anti-a3 but not by anti-a6 integrin-blocking antibodies in HLF cells, and was completely inhibited by anti-a6 in Alexander cells. These results are consistent with our previous work reporting a strong expression of a3 integrin in HLF, while Alexander cells were a3 integrin negative but intensely a6 positive (Giannelli et al, 2001).…”

Section: Extracellular Matrix Proteins Modulate Gefitinib Effectivenesssupporting

confidence: 93%

“…Cells were trypsinised once a week with trypsin/ethylenediaminetetraacetic acid (EDTA) (0.25%/ 0.02%) and the medium was changed twice a week (Giannelli et al, 2001). …”

Section: Cell Culturementioning

confidence: 99%

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Laminin-5 offsets the efficacy of gefitinib (‘Iressa’) in hepatocellular carcinoma cells

Giannelli

Azzariti²,

Fransvea

et al. 2004

Br J Cancer

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Prognosis and survival of patients with hepatocellular carcinoma (HCC) is still very poor, and no therapies are currently available to inhibit tumour growth and metastases. Recently, we reported that the expression of an extracellular matrix component (ECM), namely , is directly related to poor prognosis in HCC patients. The aim of our study is to investigate the preclinical effect of gefitinib in an in vitro HCC model. We found that the IC 50 of gefitinib in HCC cells ranged from 0.7 to 10.0 mM, whereas Ln-5 inhibited the activity of gefitinib in a dose-dependent manner. Complete inhibition of phosphorylated (p)-EGFR (epidermal growth factor receptor) was obtained within 6 h exposure to gefitinib and complete restoration of the receptor status was obtained after 24 h. A downstream effect yields a decrease in p-Akt and p-Erk 1/2. The addition of exogenous Ln-5 has no effect on p-EGFR, whereas it restores p-Erk 1/2 and p-Akt. Consistently, Ln-5 induces recovery of HCC cells from Gefitinib-induced apoptosis. In conclusion, gefitinib inhibits HCC cell growth and we report for the first time that Ln-5, but not other ECM molecules, reduces the ability of gefitinib to inhibit cell growth via Akt. As patients with HCC have different Ln-5 expression levels, these results may help to better understand which patients might benefit from gefitinib treatment.

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Section: Discussionsupporting

confidence: 88%

Section: Extracellular Matrix Proteins Modulate Gefitinib Effectivenesssupporting

confidence: 93%

See 1 more Smart Citation

Laminin-5 offsets the efficacy of gefitinib (‘Iressa’) in hepatocellular carcinoma cells

Giannelli

Azzariti²,

Fransvea

et al. 2004

Br J Cancer

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“…22-25 (b) In some cells carcinogenesis is associated with a switch in integrin expression; for example, the major integrins a5b1 and a6b1 on normal hepatocytes are replaced by a1b1, a2b1 and a3b1, which are abundantly expressed in cancer cells. [26][27][28] This switch of integrin expression is associated with the acquisition of the migratory capacity, suggesting an important role for these integrins in cancer cell motility. Furthermore, several growth factors, which are abundantly expressed in the tumor microenvironment, are considered potent stimulators of the integrin expression.…”

Section: Introductionmentioning

confidence: 98%

DNAzymes to mouse β1 integrin mRNA in vivo: targeting the tumor vasculature and retarding cancer growth

et al. 2009

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Previously, we designed a DNAzyme (b1DE) targeting the human b1 integrin subunit, which efficiently digested the mRNA of the b1 integrin subunit and downregulated b1 integrin expression in endothelial cells. This DNAzyme blocked the adhesion of endothelial cells and abolished their ability to form microcapillary tubes in Matrigel. In our present study, we demonstrate that b1DE effectively inhibited neovascularization in Matrigel plugs (BALB/c mice, n ¼ 20) and solid human carcinoma tumors developed in nude mice (BALB/cA nude (nu-/-)-B6.Cg-Foxn1 nu ) (n ¼ 30) using prostate carcinoma cells PC-3 (n ¼ 15) and colon adenocarcinoma cells CX1.1 (n ¼ 15). When injected intratumorally, it significantly reduced the tumor size and number of microvessels developed by both CX1.1 and PC-3 cells within the 3 weeks of experiment duration. Thus, DNAzymes targeting b1 integrin genes can inhibit multiple key tumorigenic processes in vitro and in vivo and may serve as useful anti-cancer agents.

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“…Since it has been previously reported that HCCs make different matrix components from normal liver (Torbenson et al, 2002;Gulubova et al, 1997;Zhao et al, 1996;Koukoulis et al, 1995;Torimura et al, 1994;Grigioni et al, 1991;Jagirdar et al, 1985;Szendroi et al, 1985;Sell and Ruoslahti, 1982;Theret et al, 2001;Giannelli et al, 2001;Lebail et al, 1997;Kin et al, 1994;Tabarin et al, 1987), we examined the possibility that this relative resistance of HCC cell lines to prothrombin, could be attributable to an HCC matrix that was different from normal hepatocytes. We tested this idea by growing Hep3B human hepatoma cells to partial confluence and the HCC cells were then lysed in their tissue culture dishes.…”

Section: Discussionmentioning

confidence: 99%

Growth inhibitory actions of prothrombin on normal hepatocytes: Influence of matrix

Carr

Kar

Wang

et al. 2007

Cell Biology International

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Most hepatomas have a defect in prothrombin carboxylation, and can secrete under-carboxylated prothrombin or des-γ-carboxy-prothrombin (DCP), the function of which is unknown. We considered that prothrombin-DCP axis might also be involved in growth control. Hepatocytes and hepatoma cells were treated with prothrombin, and DNA synthesis and cytoskeleton were studied. Prothrombin inhibited DNA synthesis in hepatocytes on fibronectin, but not collagen matrix. Hepatoma cell lines were not inhibited. We found that hepatoma cell matrix conferred resistance to hepatocytes. Prothrombin decreased fibronectin but not collagen amounts, but only in the presence of hepatocytes and not hepatoma cells, indicating that it has a differential action on matrix proteins. It also caused changes in cell shape and actin depolymerization. In vivo, there was a decrease in plasma prothrombin activity after a partial hepatectomy (PH) concomitant with a peak of DNA synthesis by the hepatocyte at 24 h after PH. Injection of warfarin at the time of PH, further inhibited PT activity and enhanced this 24 h peak of DNA synthesis. Furthermore, repeated injection of prothrombin lowered the peak DNA synthesis after PH. The data support the hypothesis that prothrombin can act as a hepatocyte growth inhibitor, likely at the level of fibronectin loss and result in cytoskeletal changes. Hepatomas resist this action, possibly due to their different matrix proteins. This represents a novel mechanism for growth regulation and provides a possible biological significance for the tumor marker DCP.

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Human Hepatocellular Carcinoma (HCC) Cells Require Both α3β1 Integrin and Matrix Metalloproteinases Activity for Migration and Invasion

Cited by 133 publications

References 49 publications

Laminin-5 offsets the efficacy of gefitinib (‘Iressa’) in hepatocellular carcinoma cells

Laminin-5 offsets the efficacy of gefitinib (‘Iressa’) in hepatocellular carcinoma cells

DNAzymes to mouse β1 integrin mRNA in vivo: targeting the tumor vasculature and retarding cancer growth

Growth inhibitory actions of prothrombin on normal hepatocytes: Influence of matrix

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