Overexpression of cortactin is involved in motility and metastasis of hepatocellular carcinoma

Chuma, Makoto; Sakamoto, Michiie; Yasuda, Jun; Fujii, Gen; Nakanishi, Koji; Tsuchiya, Akira; Ohta, Tsutomu; Asaka, Masahiro; Hirohashi, Setsuo

doi:10.1016/j.jhep.2004.06.018

Cited by 109 publications

(103 citation statements)

References 40 publications

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“…Cortactin overexpression is known to be associated with the development of cancer (7)(8)(9)(10)(11). The overexpression of cortactin obtained by immunohistochemistry in 62.5% cases of colorectal cancer is consistent with previous findings.…”

Section: Discussionsupporting

confidence: 90%

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Localization of cortactin is associated with colorectal cancer development

Hirakawa

Shibata²,

Nakayama³

2009

Int J Oncol

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Abstract. Cortactin is a ubiquitously expressed actin filament (F-actin)-binding protein that stabilizes F-actin networks and promotes actin polymerization by activating the actinrelated protein 2/3 (Arp2/3) complex. Overexpression of cortactin in cancer cells stimulate cell migration, invasion, and experimental metastasis; however, the underlying mechanism in cortactin involvement in tumor progression is not fully understood. Recently, a direct interaction between zonula occludens-1 (ZO-1) and cortactin in epithelial cells was reported. The present study aimed to further clarify the significance of the interaction between cortactin and ZO-1 in cancer progression. Cortactin expression and localization in colorectal human cancer tissues were evaluated by immunohistochemistry and immunofluorescence. Co-immunoprecipitation and immunofluorescence analysis revealed cortactin and ZO-1 interaction and localization in cancer cells. In our study, the localization of cortactin is a crucial marker for lymph node metastasis in colorectal cancer. We show how the localization of cortactin effects cancer development. A molecular interaction between cortactin and ZO-1 in migrating or polarized cancer cells was revealed. This is the first report to show the interaction of cortactin and ZO-1 in colorectal cancer progression. We conclude that localization of cortactin in cancer cells and interaction between ZO-1 and cortactin are crucial for cancer progression.

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Section: Discussionsupporting

confidence: 90%

“…The C-terminal half is composed of an ·-helix domain of unknown function, followed by a proline-serine-threonine-rich region (PST) and Src homology 3 (SH3) domain (6). Gene amplification of CTTN and overexpression of cortactin have been reported in various cancers including colorectal cancer (7)(8)(9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Localization of cortactin is associated with colorectal cancer development

Hirakawa

Shibata²,

Nakayama³

2009

Int J Oncol

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“…Recently, many studies have documented a role for cortactin in promoting cancer cell motility and invasion, including a critical role in invadopodia, which are actin-rich subcellular protrusions associated with the degradation of the extracellular matrix by cancer cells [48,49]. Notably, orthotopic injection of HCC cells overexpressing cortactin into the liver resulted in an increased intrahepatic metastasis [50]. In the present study, we found that one of the mechanisms by which MPZL1 promoted HCC cell migration and tumor metastasis is through the phosphorylation and activation of cortactin.…”

Section: Discussionmentioning

confidence: 99%

Amplification of MPZL1/PZR promotes tumor cell migration through Src-mediated phosphorylation of cortactin in hepatocellular carcinoma

et al. 2013

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We have previously identified 1 241 regions of somatic copy number alterations (CNAs) in hepatocellular carcinoma (HCC). In the present study, we found that a novel recurrent focal amplicon, 1q24.1-24.2, targets the MPZL1 gene in HCC. Notably, there is a positive correlation between the expression levels of MPZL1 and intrahepatic metastasis of the HCC specimens. MPZL1 can significantly enhance the migratory and metastatic potential of the HCC cells. Moreover, we found that one of the mechanisms by which MPZL1 promotes HCC cell migration is by inducing the phosphorylation and activation of the pro-metastatic protein, cortactin. Additionally, we found that Src kinase mediates the phosphorylation and activation of cortactin induced by MPZL1 overexpression. Taken together, these findings suggest that MPZL1 is a novel pro-metastatic gene targeted by a recurrent region of copy number amplification at 1q24.1-24.2 in HCC.

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“…28,29 IM is thought to develop through tumor cell dissemination through the portal vein. 30 Previous studies using the mouse IM model indicate activation of RhoA 21 and AKT, 31 and overexpression of cortactin 32 Reduced TGFBR2 expression correlated with portal vain invasion in HCC cases, and poorly differentiated HCC cells showed lower TGFBR2 expression compared with well-differentiated cells. This suggests that HCC cells, with reduced TGFBR2 expression, seem to be more invasive and may promote IM.…”

Section: Tgfbr2 Expression In Hccsmentioning

confidence: 92%

Reduced transforming growth factor-β receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis

Mamiya

Yamazaki

Masugi

et al. 2010

Laboratory Investigation

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Hepatocellular carcinoma (HCC) occurs mainly in the liver associated with chronic hepatitis and hepatic cirrhosis as a result of prolonged viral infection. Transforming growth factor-b (TGF-b) induces the fibrosis in hepatic cirrhosis, although it is also an inhibitor of hepatocyte proliferation. To understand the role of TGF-b signaling in HCC progression, we analyzed gene expression in HCC cells in relation to TGF-b signaling using a two-way clustering algorithm. By the analysis, five HCC cell lines were classified into two groups according to their metastatic capacity. TGF-b receptor II (TGFBR2) was downregulated in metastatic cells, which did not show a response to TGF-b. Immunohistochemistry demonstrated clear membrane distribution of TGFBR2 in noncancerous hepatocytes, whereas reduced TGFBR2 expression was observed in 34 of 136 HCCs. In clinical cases, reduced TGFBR2 expression correlated with larger tumor size (Po0.001), poor differentiation (Po0.001), portal vein invasion (P ¼ 0.002), intrahepatic metastasis (IM) (Po0.001), and shorter recurrence-free survival (P ¼ 0.022). In conclusion, reduced TGFBR2 expression was associated with aggressive features of HCC such as IM, and may represent an immunohistochemical biomarker to detect aggressive HCC. Hepatocellular carcinoma (HCC) is a common cause of death from cancer worldwide. 1 Prolonged infection with hepatitis virus often causes chronic hepatitis, followed by liver cirrhosis. 2 During the development of these liver diseases, transforming growth factor-b (TGF-b) has an important role in fibrosis of the lesions. 3 HCCs mainly occur in those injured livers with activated TGF-b signaling, although TGF-b inhibits hepatocyte cell growth in the normal liver. 4,5 TGF-b signaling is activated when a TGF-b ligand binds to its receptor on the cell membrane. The downstream effectors, SMAD2 and SMAD3, together with SMAD4, translocate to the nucleus and regulate the expression of various genes, including cyclin-dependent kinase inhibitor 1A (CDKN1A), which is involved in cell growth arrest. 6,7 TGF-b signaling is also suggested to be involved in the malignant progression of tumors. TGF-b can induce epithelial-mesenchymal transition and promote tumor cell invasion, and may also have angiogenic and immunosuppressive effects on the tumor microenvironment, all of which promote metastasis. 8 Mutations in the TGF-b superfamily genes have been found in various cancers. The TGF-b receptor II (TGFBR2) gene is frequently mutated in colon cancers, 9,10 gastric cancers, 10,11 and in gliomas 12 with microsatellite instability. SMAD4 mutations occur mainly in pancreatic cancers, in which the SMAD4 gene was first identified as a tumorsuppressor gene. 13 In HCCs, however, mutations in TGF-b superfamily genes are rare, 14,15 and alteration of TGF-b signaling is still unclear and controversial. To investigate alterations of TGF-b signaling in HCC progression, we compared the expression profiles of TGF-b signalingrelated genes in HCC cells exhibiting different metastatic potential. We...

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Overexpression of cortactin is involved in motility and metastasis of hepatocellular carcinoma

Cited by 109 publications

References 40 publications

Localization of cortactin is associated with colorectal cancer development

Localization of cortactin is associated with colorectal cancer development

Amplification of MPZL1/PZR promotes tumor cell migration through Src-mediated phosphorylation of cortactin in hepatocellular carcinoma

Reduced transforming growth factor-β receptor II expression in hepatocellular carcinoma correlates with intrahepatic metastasis

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