Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells

Miyoshi, Anderson; Kitajima, Yoshihiko; Sumi, Kazuya; Sato, Kotaro; Hagiwara, Akeo; Koga, Yasuo; Miyazaki, Kohji

doi:10.1038/sj.bjc.6601685

Cited by 252 publications

(201 citation statements)

References 37 publications

(48 reference statements)

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“…As a result, we found that Ecadherin expression was repressed in the Snail transfectant, furthermore, EMT was dramatically induced and invasion activity was increased about 10-fold compared with that of mock transfectant cells. We further discovered that MMP-1, MMP-2, MMP-7, and MT1-MMP expressions were significantly upregulated by Snail introduction (Miyoshi et al, 2004). The MMP family is known to play a key role in tumour invasion of various human r = 0.256 cancers including HCC (Yamamoto et al, 1997;Harada et al, 1998;Nabeshima et al, 2002).…”

Section: Discussionmentioning

confidence: 89%

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Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma

et al. 2005

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We have previously demonstrated in an in vitro study that Snail increased the invasion activity of hepatoma cells by upregulating matrix metalloproteinase (MMP) gene expression. In the present study, we examined whether Snail gene expression correlates with cancer invasion and prognosis of patients with hepatocellular carcinoma (HCC). Quantitative reverse transcription -polymerase chain reaction (RT -PCR) was performed to evaluate Snail, E-cadherin, and MMP mRNA expressions in eight nodule-in-nodule tumours and 47 ordinary HCC tissues. In the nodule-in-nodule tumours, Snail expression significantly increased with tumour dedifferentiation (P ¼ 0.047). In the ordinary HCC tissues, Snail expression was significantly correlated with portal vein invasion (P ¼ 0.035) and intrahepatic metastasis (P ¼ 0.050); it also showed a significant correlation with MT1-MMP expression (r ¼ 0.572, Po0.001). In recurrence-free survival, the group with high Snail expression showed significantly poorer prognosis (P ¼ 0.035). Moreover, high Snail expression was an independent risk factor for early recurrence after curative resection. During the progression of HCC, Snail expression may be induced and accelerate invasion activity by upregulating MMP expression, resulting in portal invasion, intrahepatic metastasis, and poor prognosis. British Journal of Cancer (2005) Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies in the world and a frequent cause of cancer fatalities in Japan. Improvements in early diagnosis, surgical techniques, and perioperative management have contributed to decreases in mortality and morbidity among patients with HCC (Okuda et al, 1985;Fran et al, 1999). However, the long-term prognosis of patients with HCC after hepatectomy has been still poor because of a high incidence of recurrence after initial treatment (Fong et al, 1999;Poon et al, 2000b). Several centres have reported a cumulative 5-year recurrence rate ranging from 75 to 100% (Chen et al, 1994;Fong et al, 1999;Poon et al, 2000b). Pathological and genetic analyses have indicated two features in HCC recurrence: multicentric occurrence of new tumours (MO) and intrahepatic metastasis of the original tumour (im) (Tsuda et al, 1992;Matsumoto et al, 2001). It has been reported that MO is significantly influenced by the underlying liver status, such as the presence of active hepatitis (Belghiti et al, 1991;Ko et al, 1996). On the other hand, im is thought to be more closely associated with tumour factors, especially portal vein invasion (vp) (Vauthey et al, 1995;Shimada et al, 1999). Several published studies have demonstrated that vp plays an important role in the im process and influences the survival rate of patients with HCC (Fuster et al, 1996;Mitsunobu et al, 1996; The Liver Cancer Study Group of Japan, 1994). Therefore, it is important to elucidate the molecular mechanisms of vp and im; the subsequent establishment of markers for predicting vp and im may contribute to improvement in the prognosis of patients with HCC.Recently, the z...

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Section: Discussionmentioning

confidence: 89%

“…We have demonstrated in an in vitro study using HCC cell lines that Snail not only represses E-cadherin but also increases gene expression of the matrix metalloproteinase (MMP) family, which is thought to accelerate cancer invasion (Miyoshi et al, 2004).…”

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confidence: 99%

Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma

et al. 2005

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“…A similar suppressive impact of Snail downregulation on loss of adhesion was obtained using a tetracycline-inducible Snail shRNA system in DU145 cells exposed to 10 Â 2 Gy fIR (Figures 3d and e). Furthermore, genes known to be positively regulated by Snail, such as MMP-7, 18 or negatively, for example, integrin alpha2 (ITGA2 19 ), laminin alpha3 (LAMA3), laminin gamma2 (LAMC2 20 ) and E-cadherin (CDH1 21,22 ) were consistently altered in irradiated non-adherent DU145 cells (Figure 2f), indicating Snail activity. Indeed, knockdown of Snail led to decreased MMP-7 and increased ITGA2, LAMA3, LAMC2 and E-cadherin (Figure 2g).…”

Section: Resultsmentioning

confidence: 98%

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

et al. 2014

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Fractionated ionizing radiation combined with surgery or hormone therapy represents the first-choice treatment for medium to high-risk localized prostate carcinoma. One of the main reasons for the failure of radiotherapy in prostate cancer is radioresistance and further dissemination of surviving cells. In this study, exposure of four metastasis-derived human prostate cancer cell lines (DU145, PC-3, LNCaP and 22RV1) to clinically relevant daily fractions of ionizing radiation (35 doses of 2 Gy) resulted in generation of two radiation-surviving populations: adherent senescent-like cells expressing common senescenceassociated markers and non-adherent anoikis-resistant stem cell-like cells with active Notch signaling and expression of stem cell markers CD133, Oct-4, Sox2 and Nanog. While a subset of the radiation-surviving adherent cells resumed proliferation shortly after completion of the irradiation regimen, the non-adherent cells started to proliferate only on their reattachment several weeks after the radiation-induced loss of adhesion. Like the parental non-irradiated cells, radiation-surviving re-adherent DU145 cells were tumorigenic in immunocompromised mice. The radiation-induced loss of adhesion was dependent on expression of Snail, as siRNA/shRNA-mediated knockdown of Snail prevented cell detachment. On the other hand, survival of the non-adherent cells required active Erk signaling, as chemical inhibition of Erk1/2 by a MEK-selective inhibitor or Erk1/2 knockdown resulted in anoikis-mediated death in the non-adherent cell fraction. Notably, whereas combined inhibition of Erk and PI3K-Akt signaling triggered cell death in the non-adherent cell fraction and blocked proliferation of the adherent population of the prostate cancer cells, such combined treatment had only marginal if any impact on growth of control normal human diploid cells. These results contribute to better understanding of radiation-induced stress response and heterogeneity of human metastatic prostate cancer cells, document treatment-induced plasticity and phenotypically distinct cell subsets, and suggest the way to exploit their differential sensitivity to radiosensitizing drugs in overcoming radioresistance. Cell Death and Differentiation (2015) 22, 898-911; doi:10.1038/cdd.2014.97; published online 11 July 2014Prostate carcinoma (CaP) is the most frequent type of cancer in men, and the sixth cause of cancer-associated death in men worldwide. 1 Despite the advances in diagnosis and therapy of CaP, the mortality has remained almost unchanged for the last decades. Currently, the most successful treatment for localized CaP is prostatectomy with postoperative fractionated radiotherapy, significantly improving metastasis-free and overall survival, where the median of a 15-year survival is around 47% of patients. 2,3 The rest of the patients develop a metastatic disease that is incurable due to the resistance of CaP to androgen ablation, radiotherapy and chemotherapy. Therefore, understanding the mechanisms of radioresistance and chemoresista...

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“…Strengthening these data, a diminution of vimentin expression following SIP1 siRNA transfection was also shown in BT549 breast tumor cells. Up to now, the implication of SIP1 in EMT phenomena associated with tumor cell invasion has been more particularly linked to its ability to repress E-cadherin, as shown in MDCK cells and in hepatocellular and colon epidermoid carcinoma cells transfected with SIP1 (Comijn et al, 2001;Miyoshi et al, 2004;Vandewalle et al, 2005). A repression of E-cadherin by SIP1 was accordingly observed in our cell systems.…”

Section: Discussionmentioning

confidence: 99%

“…Much less is known regarding the δEF1/ZEB family. Recent studies have nevertheless shown that SIP1-induced EMT in hepatocellular and in colon epidermoid carcinoma cells is also associated with an increased expression of N-cadherin and mesenchymal p120ctn isoforms (Vandewalle et al, 2005) as well as several members of the MMP family (Miyoshi et al, 2004). Thus, together with our observations that expression of endogenous vimentin and SIP1 associates with migratory/invasive abilities, these results suggest that SIP1 can contribute to the upregulation of vimentin transcription such as that occurs during epithelial cell migration/invasion.…”

Section: Discussionmentioning

confidence: 99%

Regulation of vimentin by SIP1 in human epithelial breast tumor cells

et al. 2006

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The expression of Smad interacting protein-1 (SIP1; ZEB2) and the de novo expression of vimentin are frequently involved in epithelial-to-mesenchynial transitions (EMTs) under both normal and pathological conditions. In the present study, we investigated the potential role of SIP1 in the regulation of vimentin during the EMT associated with breast tumor cell migration and invasion. Examining several breast tumor cell Unes displaying various degrees of invasiveness, we found SIP1 and vimentin expression only in invasive cell Unes. Also, using a model of cell migration with human mammary MCF10A cells, we showed that SIP1 is induced specifically in vimentin-positive migratory cells. Furthermore, transfection of SIP1 cDNA in MCF10A cells increased their vimentin expression both at the mRNA and protein levels and enhanced their migratory abilities in Boyden Chamber assays. Inversely, inhibition of SIP1 expression by RNAi strategies in BT-549 cells and MCF10A cells decreased vimentin expression. We also showed that SIP1 transfection did not activate the TOP-FLASH reporter system, suggesting that the β-catenin/ TCF pathway is not impUcated in the regulation of vimentin by SIP1. Our results therefore impUcate SIP1 in the regulation of vimentin observed in the EMT associated with breast tumor cell migration, a pathway that may contribute to the metastatic progression of breast cancer.

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Snail and SIP1 increase cancer invasion by upregulating MMP family in hepatocellular carcinoma cells

Cited by 252 publications

References 37 publications

Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma

Snail accelerates cancer invasion by upregulating MMP expression and is associated with poor prognosis of hepatocellular carcinoma

Radiotherapy-induced plasticity of prostate cancer mobilizes stem-like non-adherent, Erk signaling-dependent cells

Regulation of vimentin by SIP1 in human epithelial breast tumor cells

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