Limits...
Testes-specific protease 50 promotes cell invasion and metastasis by increasing NF-kappaB-dependent matrix metalloproteinase-9 expression.

Song ZB, Ni JS, Wu P, Bao YL, Liu T, Li M, Fan C, Zhang WJ, Sun LG, Huang YX, Li YX - Cell Death Dis (2015)

Bottom Line: Mechanistic studies revealed that NF-κB signaling pathway was required for TSP50-induced cell migration and metastasis, and further results indicated that TSP50 overexpression enhanced expression and secretion of MMP9, a target gene of NF-κB signaling.In addition, knockdown of MMP9 resulted in inhibition of cell migration and invasion in vitro and lung metastasis in vivo.Furthermore, we found that some breast cancer diagnosis-associated features such as tumor size, tumor grade, estrogen receptors (ER) and progesterone receptors (PR) levels, were correlated well with TSP50/p65 and TSP50/MMP9 expression status.

View Article: PubMed Central - PubMed

Affiliation: 1] National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China [2] Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun 130024, China.

ABSTRACT
The high mortality in breast cancer is often associated with metastatic progression in patients. Previously we have demonstrated that testes-specific protease 50 (TSP50), an oncogene overexpressed in breast cancer samples, could promote cell proliferation and tumorigenesis. However, whether TSP50 also has a key role in cell invasion and cancer metastasis, and the mechanism underlying the process are still unclear. Here we found that TSP50 overexpression greatly promoted cell migration, invasion, adhesion and formation of the stellate structures in 3D culture system in vitro as well as lung metastasis in vivo. Conversely, TSP50 knockdown caused the opposite changes. Mechanistic studies revealed that NF-κB signaling pathway was required for TSP50-induced cell migration and metastasis, and further results indicated that TSP50 overexpression enhanced expression and secretion of MMP9, a target gene of NF-κB signaling. In addition, knockdown of MMP9 resulted in inhibition of cell migration and invasion in vitro and lung metastasis in vivo. Most importantly, immunohistochemical staining of human breast cancer samples strongly showed that the coexpression of TSP50 and p65 as well as TSP50 and MMP9 were correlated with increased metastasis and poor survival. Furthermore, we found that some breast cancer diagnosis-associated features such as tumor size, tumor grade, estrogen receptors (ER) and progesterone receptors (PR) levels, were correlated well with TSP50/p65 and TSP50/MMP9 expression status. Taken together, this work identified the TSP50 activation of MMP9 as a novel signaling mechanism underlying human breast cancer invasion and metastasis.

Show MeSH

Related in: MedlinePlus

The correlation of TSP50/p65 and TSP50/MMP9 levels with some clinical and pathological parameters in human breast carcinoma. (a) The correlation between TSP50/p65 level and tumor sizes in the 206 breast cancer samples was analyzed by Fisher's exact test. Each data point represents an individual sample. (b) The correlation between TSP50/MMP9 level and tumor sizes in the 206 breast cancer samples was analyzed by Fisher's exact test. Each data point represents an individual sample. (c) The correlation between TSP50/p65 level and pathologic grade in the 206 breast cancer samples was analyzed by Fisher's exact test. (d) The correlation between TSP50/MMP9 level and pathologic grade in the 206 breast cancer samples was analyzed by Fisher's exact test. (e) Immunohistochemistry of TSP50, p65, MMP9, ER, and PR in the 206 breast cancer samples. (f) The correlation between TSP50/p65 level and ER expression was analyzed by Fisher's exact test. Scale bar, 200 μm. (g) The correlation between TSP50/MMP9 level and ER expression was analyzed by Fisher's exact test. (h) The correlation between TSP50/p65 level and PR expression was analyzed by Fisher's exact test. (i) The correlation between TSP50/MMP9 level and PR expression was analyzed by Fisher's exact test. **P<0.01
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4385939&req=5

fig8: The correlation of TSP50/p65 and TSP50/MMP9 levels with some clinical and pathological parameters in human breast carcinoma. (a) The correlation between TSP50/p65 level and tumor sizes in the 206 breast cancer samples was analyzed by Fisher's exact test. Each data point represents an individual sample. (b) The correlation between TSP50/MMP9 level and tumor sizes in the 206 breast cancer samples was analyzed by Fisher's exact test. Each data point represents an individual sample. (c) The correlation between TSP50/p65 level and pathologic grade in the 206 breast cancer samples was analyzed by Fisher's exact test. (d) The correlation between TSP50/MMP9 level and pathologic grade in the 206 breast cancer samples was analyzed by Fisher's exact test. (e) Immunohistochemistry of TSP50, p65, MMP9, ER, and PR in the 206 breast cancer samples. (f) The correlation between TSP50/p65 level and ER expression was analyzed by Fisher's exact test. Scale bar, 200 μm. (g) The correlation between TSP50/MMP9 level and ER expression was analyzed by Fisher's exact test. (h) The correlation between TSP50/p65 level and PR expression was analyzed by Fisher's exact test. (i) The correlation between TSP50/MMP9 level and PR expression was analyzed by Fisher's exact test. **P<0.01

Mentions: On the basis of the above findings, we next investigated the clinical significance of TSP50/p65 and TSP50/MMP9 expression in another 206 human breast cancer samples. We first examined whether coexpression of TSP50 and 65 as well as TSP50 and MMP9 were correlated with tumor size and pathologic grade. Our data indicated that the TSP50+/p65+ or TSP50+/MMP9+ tumor were much larger than other tumors from the patients (Figures 8a and b). Similar results were obtained when the correlation of TSP50/p65 and TSP50/MMP9 expression with tumor grade was tested (Figures 8c and d). Especially, (58/90) 64% of breast tumors of pathologic grade III were TSP50+/p65+, and (57/90) 63% were TSP50+/MMP9+ (Supplementary Table1). As ERs and PRs could influence breast cancer prognosis, and testing the tumor for both estrogen and progesterone receptors is a standard part of a breast cancer diagnosis,24 we next analyzed whether expression of TSP50/p65 and TSP50/MMP9 were associated with these two clinical molecules in breast cancer patients (Figure 8e). As shown in Figures 8f and g, 72% (78/108) of TSP50+/ p65+tumors and 78% (80/102) of TSP50+/MMP9+ tumors were negative for ER expression. In contrast, 72% (18/25) of TSP50−/p65−tumors and 63% (17/27) of TSP50−/MMP9− tumors were positive for ER expression (Supplementary Table 1), and the similar results were obtained when PR expression was examined (Figures 8h and i). Taken together, our results suggested that expression status of TSP50/p65 as well as TSP50/MMP9 may be taken as a potential diagnostic, prognosis and therapeutic marker for human breast carcinoma in early stage.


Testes-specific protease 50 promotes cell invasion and metastasis by increasing NF-kappaB-dependent matrix metalloproteinase-9 expression.

Song ZB, Ni JS, Wu P, Bao YL, Liu T, Li M, Fan C, Zhang WJ, Sun LG, Huang YX, Li YX - Cell Death Dis (2015)

The correlation of TSP50/p65 and TSP50/MMP9 levels with some clinical and pathological parameters in human breast carcinoma. (a) The correlation between TSP50/p65 level and tumor sizes in the 206 breast cancer samples was analyzed by Fisher's exact test. Each data point represents an individual sample. (b) The correlation between TSP50/MMP9 level and tumor sizes in the 206 breast cancer samples was analyzed by Fisher's exact test. Each data point represents an individual sample. (c) The correlation between TSP50/p65 level and pathologic grade in the 206 breast cancer samples was analyzed by Fisher's exact test. (d) The correlation between TSP50/MMP9 level and pathologic grade in the 206 breast cancer samples was analyzed by Fisher's exact test. (e) Immunohistochemistry of TSP50, p65, MMP9, ER, and PR in the 206 breast cancer samples. (f) The correlation between TSP50/p65 level and ER expression was analyzed by Fisher's exact test. Scale bar, 200 μm. (g) The correlation between TSP50/MMP9 level and ER expression was analyzed by Fisher's exact test. (h) The correlation between TSP50/p65 level and PR expression was analyzed by Fisher's exact test. (i) The correlation between TSP50/MMP9 level and PR expression was analyzed by Fisher's exact test. **P<0.01
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4385939&req=5

fig8: The correlation of TSP50/p65 and TSP50/MMP9 levels with some clinical and pathological parameters in human breast carcinoma. (a) The correlation between TSP50/p65 level and tumor sizes in the 206 breast cancer samples was analyzed by Fisher's exact test. Each data point represents an individual sample. (b) The correlation between TSP50/MMP9 level and tumor sizes in the 206 breast cancer samples was analyzed by Fisher's exact test. Each data point represents an individual sample. (c) The correlation between TSP50/p65 level and pathologic grade in the 206 breast cancer samples was analyzed by Fisher's exact test. (d) The correlation between TSP50/MMP9 level and pathologic grade in the 206 breast cancer samples was analyzed by Fisher's exact test. (e) Immunohistochemistry of TSP50, p65, MMP9, ER, and PR in the 206 breast cancer samples. (f) The correlation between TSP50/p65 level and ER expression was analyzed by Fisher's exact test. Scale bar, 200 μm. (g) The correlation between TSP50/MMP9 level and ER expression was analyzed by Fisher's exact test. (h) The correlation between TSP50/p65 level and PR expression was analyzed by Fisher's exact test. (i) The correlation between TSP50/MMP9 level and PR expression was analyzed by Fisher's exact test. **P<0.01
Mentions: On the basis of the above findings, we next investigated the clinical significance of TSP50/p65 and TSP50/MMP9 expression in another 206 human breast cancer samples. We first examined whether coexpression of TSP50 and 65 as well as TSP50 and MMP9 were correlated with tumor size and pathologic grade. Our data indicated that the TSP50+/p65+ or TSP50+/MMP9+ tumor were much larger than other tumors from the patients (Figures 8a and b). Similar results were obtained when the correlation of TSP50/p65 and TSP50/MMP9 expression with tumor grade was tested (Figures 8c and d). Especially, (58/90) 64% of breast tumors of pathologic grade III were TSP50+/p65+, and (57/90) 63% were TSP50+/MMP9+ (Supplementary Table1). As ERs and PRs could influence breast cancer prognosis, and testing the tumor for both estrogen and progesterone receptors is a standard part of a breast cancer diagnosis,24 we next analyzed whether expression of TSP50/p65 and TSP50/MMP9 were associated with these two clinical molecules in breast cancer patients (Figure 8e). As shown in Figures 8f and g, 72% (78/108) of TSP50+/ p65+tumors and 78% (80/102) of TSP50+/MMP9+ tumors were negative for ER expression. In contrast, 72% (18/25) of TSP50−/p65−tumors and 63% (17/27) of TSP50−/MMP9− tumors were positive for ER expression (Supplementary Table 1), and the similar results were obtained when PR expression was examined (Figures 8h and i). Taken together, our results suggested that expression status of TSP50/p65 as well as TSP50/MMP9 may be taken as a potential diagnostic, prognosis and therapeutic marker for human breast carcinoma in early stage.

Bottom Line: Mechanistic studies revealed that NF-κB signaling pathway was required for TSP50-induced cell migration and metastasis, and further results indicated that TSP50 overexpression enhanced expression and secretion of MMP9, a target gene of NF-κB signaling.In addition, knockdown of MMP9 resulted in inhibition of cell migration and invasion in vitro and lung metastasis in vivo.Furthermore, we found that some breast cancer diagnosis-associated features such as tumor size, tumor grade, estrogen receptors (ER) and progesterone receptors (PR) levels, were correlated well with TSP50/p65 and TSP50/MMP9 expression status.

View Article: PubMed Central - PubMed

Affiliation: 1] National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130024, China [2] Research Center of Agriculture and Medicine Gene Engineering of Ministry of Education, Northeast Normal University, Changchun 130024, China.

ABSTRACT
The high mortality in breast cancer is often associated with metastatic progression in patients. Previously we have demonstrated that testes-specific protease 50 (TSP50), an oncogene overexpressed in breast cancer samples, could promote cell proliferation and tumorigenesis. However, whether TSP50 also has a key role in cell invasion and cancer metastasis, and the mechanism underlying the process are still unclear. Here we found that TSP50 overexpression greatly promoted cell migration, invasion, adhesion and formation of the stellate structures in 3D culture system in vitro as well as lung metastasis in vivo. Conversely, TSP50 knockdown caused the opposite changes. Mechanistic studies revealed that NF-κB signaling pathway was required for TSP50-induced cell migration and metastasis, and further results indicated that TSP50 overexpression enhanced expression and secretion of MMP9, a target gene of NF-κB signaling. In addition, knockdown of MMP9 resulted in inhibition of cell migration and invasion in vitro and lung metastasis in vivo. Most importantly, immunohistochemical staining of human breast cancer samples strongly showed that the coexpression of TSP50 and p65 as well as TSP50 and MMP9 were correlated with increased metastasis and poor survival. Furthermore, we found that some breast cancer diagnosis-associated features such as tumor size, tumor grade, estrogen receptors (ER) and progesterone receptors (PR) levels, were correlated well with TSP50/p65 and TSP50/MMP9 expression status. Taken together, this work identified the TSP50 activation of MMP9 as a novel signaling mechanism underlying human breast cancer invasion and metastasis.

Show MeSH
Related in: MedlinePlus