Significance of plasminogen activator inhibitor 2 as a prognostic marker in primary lung cancer: association of decreased plasminogen activator inhibitor 2 with lymph node metastasis

Yoshino, Hiroshi; Endo, Yuichi; Watanabe, Y; Sasaki, Takuma

doi:10.1038/bjc.1998.588

Cited by 38 publications

(29 citation statements)

References 26 publications

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“…The proposed new Rb-associated activity for PAI-2 ( Fig. 7) may explain many of the diverse phenotypes described for cells and tissues expressing PAI-2 (11,12,17,31,34,37,53). Both the Rb family of proteins and PAI-2 are associated with tumor suppression (17,21,31,33,34,37,53), promotion of differentiation (21,31,33,49,54), inhibition of apoptosis (11,21,33,44), and transcriptional regulation (12, 21, 33) ( Fig.…”

Section: Discussionmentioning

confidence: 97%

“…A growing number of studies (2,6,11,12,26,39,40,44,45,49,54,55) have suggested that PAI-2, like other ov-serpins (45), may have an intracellular function distinct from its extracellular role as a uPA inhibitor, since the consequences of PAI-2 expression are often difficult to associate with uPA inhibition. PAI-2 expression by cancer cells has been associated repeatedly with a lower incidence of metastases and an improved prognosis (17,34,37,53), whereas expression of PAI-1, also an effective inhibitor of uPA, largely fails to correlate with an improved prognosis. PAI-2 expression during keratinocyte differentiation is also difficult to link with uPA inhibition, since the extracellular uPA is normally restricted to the basal and suprabasal keratinocytes (31), whereas PAI-2 is usually intracellular and largely restricted to the differentiating squamous epithelial cells (6,31).…”

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confidence: 99%

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Inhibition of Retinoblastoma Protein Degradation by Interaction with the Serpin Plasminogen Activator Inhibitor 2 via a Novel Consensus Motif

Darnell¹,

Antalis

Johnstone

et al. 2003

Molecular and Cellular Biology

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Section: Discussionmentioning

confidence: 97%

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confidence: 99%

Inhibition of Retinoblastoma Protein Degradation by Interaction with the Serpin Plasminogen Activator Inhibitor 2 via a Novel Consensus Motif

Darnell¹,

Antalis

Johnstone

et al. 2003

Molecular and Cellular Biology

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“…Clinical results reveal that a lower level of SERPINB2 expression is associated with poor prognosis and outcome in gastric (8,9), breast (10) and lung cancers (11 to completely inhibit soluble and cell-surface bound plasminogen activator activity, resulting in the suppression of the metastasis of melanoma cells in SCID mice (12). SERPINB5 (MASPIN) has been well studied and was confirmed to be a tumor-suppressor gene, which suppresses tumor growth, invasion and metastasis in different types of cancers, and has potential therapeutic perspectives (13)(14)(15).…”

Section: Introductionmentioning

confidence: 99%

Suppression of the invasion and migration of cancer cells by SERPINB family genes and their derived peptides

et al. 2011

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Abstract.Apart from SERPINB2 and SERPINB5, the roles of the remaining 13 members of the human SERPINB family in cancer metastasis are still unknown. In the present study, we demonstrated that most of these genes are differentially expressed in tumor tissues compared to matched normal tissues from lung or breast cancer patients. Overexpression of each SERPINB gene effectively suppressed the invasiveness and motility of malignant cancer cells. Among all of the genes, the SERPINB1, SERPINB5 and SERPINB7 genes were more potent, and the inhibitory effect was further enhanced by co-expression of any two of them. In addition, single treatment of the synthetic peptides corresponding to the P5-P5' sequences of the reactive center loop (RCL) of SERPINB1, SERPINB5 or SERPINB7 markedly suppressed the invasive and migratory properties of the cancer cells in a dose-dependent manner. More significantly, combination treatment of these peptides in cancer cells further improved the suppressive effect by 20-40%. Here, we determined the expression of all SERPINB family members in lung and breast cancer patients, and identified those members with potent inhibitory ability toward invasion and migration, and designed RCL-derived peptides to suppress the malignancy of cancer cells. Forced re-expression of these anti-invasive SERPINB genes or application of the SERPINB RCL-peptides may provide a reasonable strategy against lethal cancer metastasis. IntroductionCancer metastasis is the leading cause of morbidity and mortality in cancer patients. It is a highly complex process, including cell detachment, migration, invasion, circulation in blood vessels, adhesion, colonization at other sites and formation of secondary tumors (1). Prior to tumor cell detachment from the primary site, which leads to cell migration and invasion in the metastasis process, the extracellular matrix (ECM) microenvironment must be degraded by proteases, such as urokinase plasminogen activator (uPA), uPA receptor (uPAR) and the plasmin network (2,3) and matrix metalloproteinases (MMPs) (4). On the other hand, protease inhibitors negatively regulate the proteolysis process in cancer metastasis, e.g. plasminogen activator inhibitors (PAIs), PAI-1 (SERPINE1) and PAI-2 (SERPINB2) against uPA/uPAR/plasmin network and the tissue inhibitor of matrix metalloproteinases (TIMPs), TIMP-1 to TIMP-4 against MMPs.Serine protease inhibitors (serpins) regulate many physiological processes, such as blood coagulation, fibrinolysis, inflammation, complement activation and cell migration (5). Based on their phylogenic relationships, the superfamily is divided into 16 different clades (A-P), in which human serpins are the first 9 clades (A-I) (6). The clade B serpins (SERPINB family) is the largest one within the human serpin superfamily. It contains 13 genes located on chromosome 6p25 (SERPINB1, SERPINB6 and SERPINB9) and 18q21 (the remaining members of the family). Unlike circulating serpins, the SERPINB family genes lack the N and C terminus extension regions common to other serpin...

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“…This novel association could explain the correlation of PAI-2 with a better prognosis in many human tumors (26)(27)(28)(29).…”

Section: Discussionmentioning

confidence: 82%

Adenovirus E1A orchestrates the urokinase-plasminogen activator system and upregulates PAI-2 expression, supporting a tumor suppressor effect

Fernández-Soria

Lleonart²,

Díaz-Fuertes³

et al. 2006

Int J Oncol

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Abstract. Invasiveness and metastatic potential are the two most important properties defining malignancy. The adenovirus E1A (Ad-E1A) gene has a dual effect as a proliferative gene and as a tumor-suppressor gene, decreasing tumor growth and the metastatic potential of malignant cells. In order to study genes related with the antimetastatic effect of Ad-E1A in human cells, we performed a microarray analysis using OncoChip™. In three independent experiments, NIH3T3, IMR90 and MDA MB 435 cells were infected with pLPC retroviruses carrying the adenovirus 12S E1A gene or the GFP gene. We analyzed cDNA expression by using the CNIO OncoChipTM, a cDNA microarray containing a total of 6386 genes represented by 7237 clones. uPA, uPAr, tPA, PAI-1 and PAI-2 were also studied at RNA and protein levels. Microarrays of cDNA expression, RT-PCR and Western blot performed in IMR90 E1A-expressing cells showed downregulation of uPA, uPAr, tPA, PAI-1 and upregulation of PAI-2. These results were confirmed in NIH3T3 and MDA MB 435 breast carcinoma cells, with PAI-2 upregulation by RT-PCR and Western blot. In addition, zymographic analysis demonstrated that E1A expression greatly reduced the gelatinase activity of the pro-MMP2 and -MMP9 proteins. We propose that adenovirus E1A may orchestrate the expression of most members of the urokinase-plasminogen activation system, downregulating potentially invasive genes and upregulating PAI-2, which is associated with a better prognosis in human tumors.

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Significance of plasminogen activator inhibitor 2 as a prognostic marker in primary lung cancer: association of decreased plasminogen activator inhibitor 2 with lymph node metastasis

Cited by 38 publications

References 26 publications

Inhibition of Retinoblastoma Protein Degradation by Interaction with the Serpin Plasminogen Activator Inhibitor 2 via a Novel Consensus Motif

Inhibition of Retinoblastoma Protein Degradation by Interaction with the Serpin Plasminogen Activator Inhibitor 2 via a Novel Consensus Motif

Suppression of the invasion and migration of cancer cells by SERPINB family genes and their derived peptides

Adenovirus E1A orchestrates the urokinase-plasminogen activator system and upregulates PAI-2 expression, supporting a tumor suppressor effect

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