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Inhibition of PC cell-derived growth factor (PCDGF)/granulin-epithelin precursor (GEP) decreased cell proliferation and invasion through downregulation of cyclin D and CDK 4 and inactivation of MMP-2
Yulan Liu, Ling Xi, Guoning Liao, Wei Wang, Xun Tian, Beibei Wang, Gang Chen, Zhiqiang Han, Mingfu Wu, Shixuan Wang, Jianfeng Zhou, Gang Xu, Yunping Lu, Ding Ma
BMC Cancer , 2007, DOI: 10.1186/1471-2407-7-22
Abstract: PCDGF/GEP expression level in three human ovarian cancer cell lines of different invasion potential were detected by RT-PCR and western blot. Effects of inhibition of PCDGF expression on cell proliferation and invasion capability were determined by MTT assay and Boyden chamber assay. Expression levels of cyclin D1 and CDK4 and MMP-2 activity were evaluated in a pilot study.PCDGF mRNA and protein were expressed at a high level in SW626 and A2780 and at a low level in SKOV3. PCDGF expression level correlated well with malignant phenotype including proliferation and invasion in ovarian cancer cell lines. In addition, the proliferation rate and invasion index decreased after inhibition of PCDGF expression by antisense PCDGF cDNA transfection in SW626 and A2780. Furthermore expression of CyclinD1 and CDK4 were downregulated and MMP-2 was inactivated after PCDGF inhibition in the pilot study.PCDGF played an important role in stimulating proliferation and promoting invasion in ovarian cancer. Inhibition of PCDGF decreased proliferation and invasion capability through downregulation of cyclin D1 and CDK4 and inactivation of MMP-2. PCDGF could serve as a potential therapeutic target in ovarian cancer.PC cell-derived growth factor (PCDGF), also called epithelin/granulin precursor (GEP), is an 88-kDa secreted glycoprotein purified from the conditioned medium of the highly malignant mouse teratoma-derived cell line PC for its ability to stimulate proliferation in an autocrine fashion [1]. In teratoma cells, PCDGF expression was shown to be essential for tumorigenicity [2]. High levels of PCDGF expression are found in rapidly proliferating cells, such as skin cells, deep crypts of gastrointestinal tract, and immune cells. On the other hand, low levels of PCDGF expression are found in cells that are not mitotically active, such as muscle and liver cells [3,4]. Overexpression of PCDGF has been linked to the growth and tumorigenicity of human breast carcinomas and to the acquisitio
MMP-10/Stromelysin-2 Promotes Invasion of Head and Neck Cancer  [PDF]
Elsayed Mohamed Deraz, Yasusei Kudo, Maki Yoshida, Mariko Obayashi, Takaaki Tsunematsu, Hirotaka Tani, Samadarani B. S. M. Siriwardena, Mohammad Reza Kiekhaee, Guangying Qi, Shinji Iizuka, Ikuko Ogawa, Giuseppina Campisi, Lorenzo Lo Muzio, Yoshimitsu Abiko, Akira Kikuchi, Takashi Takata
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0025438
Abstract: Background Periostin, IFN-induced transmembrane protein 1 (IFITM1) and Wingless-type MMTV integration site family, member 5B (Wnt-5b) were previously identified as the invasion promoted genes of head and neck squamous cell carcinoma (HNSCC) by comparing the gene expression profiles between parent and a highly invasive clone. We have previously reported that Periostin and IFITM1 promoted the invasion of HNSCC cells. Here we demonstrated that Wnt-5b overexpression promoted the invasion of HNSCC cells. Moreover, stromelysin-2 (matrix metalloproteinase-10; MMP-10) was identified as a common up-regulated gene among Periostin, IFITM1 and Wnt-5b overexpressing HNSCC cells by using microarray data sets. In this study, we investigated the roles of MMP-10 in the invasion of HNSCC. Methods and Findings We examined the expression of MMP-10 in HNSCC cases by immunohistochemistry. High expression of MMP-10 was frequently observed and was significantly correlated with the invasiveness and metastasis in HNSCC cases. Next, we examined the roles of MMP-10 in the invasion of HNSCC cells in vitro. Ectopic overexpression of MMP-10 promoted the invasion of HNSCC cells, and knockdown of MMP-10 suppressed the invasion of HNSCC cells. Moreover, MMP-10 knockdown suppressed Periostin and Wnt-5b-promoted invasion. Interestingly, MMP-10 overexpression induced the decreased p38 activity and MMP-10 knockdown induced the increased p38 activity. In addition, treatment with a p38 inhibitor SB203580 in HNSCC cells inhibited the invasion. Conclusions These results suggest that MMP-10 plays an important role in the invasion and metastasis of HNSCC, and that invasion driven by MMP-10 is partially associated with p38 MAPK inhibition. We suggest that MMP-10 can be used as a marker for prediction of metastasis in HNSCC.
Overexpression of human sperm protein 17 increases migration and decreases the chemosensitivity of human epithelial ovarian cancer cells
Fang-qiu Li, Yan-ling Han, Qun Liu, Bo Wu, Wen-bin Huang, Su-yun Zeng
BMC Cancer , 2009, DOI: 10.1186/1471-2407-9-323
Abstract: Immunohistochemistry and immunocytochemistry were used to identify HSp17 in paraffin embedded ovarian malignant tumor specimens and peritoneal metastatic malignant cells. Then we examined the effect of HSp17 overexpression on the proliferation, migration, and chemoresistance of ovarian cancer cells to carboplatin and cisplatin in a human ovarian carcinoma cell line, HO8910.We found that HSp17 was aberrantly expressed in 43% (30/70) of the patients with primary epithelial ovarian carcinomas, and in all of the metastatic cancer cells of ascites from 8 patients. The Sp17 expression was also detected in the metastatic lesions the same as in ovarian lesions. None of the 7 non-epithelial tumors primarily developed in the ovaries was immunopositive for HSp17. Overexpression of HSp17 increased the migration but decreased the chemosensitivity of ovarian carcinoma cells to carboplatin and cisplatin.HSp17 is aberrantly expressed in a significant proportion of epithelial ovarian carcinomas. Our results strongly suggest that HSp17 plays a role in metastatic disease and resistance of epithelial ovarian carcinoma to chemotherapy.Ovarian cancer is the fifth or sixth most common cause of gynecologic cancer morbidity and mortality in developed countries [1]. Most deaths from ovarian cancer are caused by metastases that are resistant to conventional therapies. Although ovarian cancers metastasize primarily by exfoliation followed by peritoneal implantation, about 40% of patients with advanced ovarian cancer show lymph node metastasis and/or extra-abdominal metastasis. The factors that regulate the metastatic process and chemoresistance of ovarian cancer remain poorly understood.Recent studies suggest that the enhanced expression and activation of matrix metalloproteinases MMP-2 and MMP-9 may play a role in ovarian cancer cell migration [2]. But other factors may also contribute to this malignant behavior. One candidate is human sperm protein 17 (HSp17), a normal tissue specific protei
Membrane-Type-3 Matrix Metalloproteinase (MT3-MMP) Functions as a Matrix Composition-Dependent Effector of Melanoma Cell Invasion  [PDF]
Olga Tatti, Mariliina Arjama, Annamari Ranki, Stephen J. Weiss, Jorma Keski-Oja, Kaisa Lehti
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0028325
Abstract: In primary human melanoma, the membrane-type matrix metalloproteinase, MT3-MMP, is overexpressed in the most aggressive nodular-type tumors. Unlike MT1-MMP and MT2-MMP, which promote cell invasion through basement membranes and collagen type I-rich tissues, the function of MT3-MMP in tumor progression remains unclear. Here, we demonstrate that MT3-MMP inhibits MT1-MMP-driven melanoma cell invasion in three-dimensional collagen, while yielding an altered, yet MT1-MMP-dependent, form of expansive growth behavior that phenocopies the formation of nodular cell colonies. In melanoma cell lines originating from advanced primary or metastatic lesions, endogenous MT3-MMP expression was associated with limited collagen-invasive potential. In the cell lines with highest MT3-MMP expression relative to MT1-MMP, collagen-invasive activity was increased following stable MT3-MMP gene silencing. Consistently, MT3-MMP overexpression in cells derived from less advanced superficially spreading melanoma lesions, or in the MT3-MMP knockdown cells, reduced MT1-MMP-dependent collagen invasion. Rather than altering MT1-MMP transcription, MT3-MMP interacted with MT1-MMP in membrane complexes and reduced its cell surface expression. By contrast, as a potent fibrinolytic enzyme, MT3-MMP induced efficient invasion of the cells in fibrin, a provisional matrix component frequently found at tumor-host tissue interfaces and perivascular spaces of melanoma. Since MT3-MMP was significantly upregulated in biopsies of human melanoma metastases, these results identify MT3-MMP as a matrix-dependent modifier of the invasive tumor cell functions during melanoma progression.
CSE1L/CAS, the cellular apoptosis susceptibility protein, enhances invasion and metastasis but not proliferation of cancer cells
Ching-Fong Liao, Shue-Fen Luo, Li-Tzu Li, Chuang-Yu Lin, Ying-Chun Chen, Ming-Chung Jiang
Journal of Experimental & Clinical Cancer Research , 2008, DOI: 10.1186/1756-9966-27-15
Abstract: We enhanced or reduced CAS expression by transfecting CAS or anti-CAS expression vectors into human MCF-7 breast cancer cells. The proliferations of cells were determined by trypan blue exclusion assay and flow cytometry analysis. Invasion of cancer cells were determined by matrigel-based invasion assay.Our studies showed that increased CAS expression was unable to enhance cancer cell proliferation. Immunofluorescence showed CAS was distributed in cytoplasm areas near cell membrane and cell protrusions. CAS was localized in cytoplasmic vesicle and immunogold electronmicroscopy showed CAS was located in vesicle membrane. CAS overexpression enhanced matrix metalloproteinase-2 (MMP-2) secretion and cancer cell invasion. Animal experiments showed CAS reduction inhibited the metastasis of B16-F10 melanoma cells by 56% in C57BL/6 mice.Our results indicate that CAS increases the invasion but not the proliferation of cancer cells. Thus, CAS plus ECM-degradation proteinases may be used as the markers for predicting the advance of tumour metastasis.The cellular apoptosis susceptibility (CAS) protein is highly expressed in various cancers including melanomas, lymphomas, breast cancers, hepatomas, ovarian carcinomas, endometrial carcinomas, and colorectal cancers [1-8]. Also, the expression of CAS is correlated positively with high stage and high-grade cancers as well as worse outcome of the cancer patients [1-8]. Thus, CAS may play an important role in regulating cancer development and progression.CAS is the human homologue of the yeast chromosome segregation gene, CSE1 [9]. CAS is associated with microtubules and mitotic spindles, the cellular organelles for cell cycle mitosis division; hence CAS is speculated to play a role in cell proliferation and is regarded as a proliferation-associated protein [1,10]. Consequently, many pathological studies demonstrated that the expression of CAS in tumors is related with tumor proliferation in cancer development [2-5]; although there i
Lewis Y Promotes Growth and Adhesion of Ovarian Carcinoma-Derived RMG-I Cells by Upregulating Growth Factors  [PDF]
Feifei Li,Bei Lin,Yingying Hao,Yan Li,Juanjuan Liu,Jianping Cong,Liancheng Zhu,Qing Liu,Shulan Zhang
International Journal of Molecular Sciences , 2010, DOI: 10.3390/ijms11103748
Abstract: Lewis y (LeY) antigen is a difucosylated oligosaccharide carried by glycoconjugates on the cell surface. Overexpression of LeY is frequently observed in epithelial-derived cancers and has been correlated to the pathological staging and prognosis. However, the effects of LeY on ovarian cancer are not yet clear. Previously, we transfected the ovarian cancer cell line RMG-I with the α1,2-fucosyltransferase gene to obtain stable transfectants, RMG-I-H, that highly express LeY. In the present study, we examined the proliferation, tumorigenesis, adhesion and invasion of the cell lines with treatment of LeY monoclonal antibody (mAb). Additionally, we examined the expression of TGF-β1, VEGF and b-FGF in xenograft tumors. The results showed that the proliferation and adhesion in vitro were significantly inhibited by treatment of RMG-I-H cells with LeY mAb. When subcutaneously inoculated in nude mice, RMG-I-H cells produced large tumors, while mock-transfected cells RMG-I-C and the parental cells RMG-I produced small tumors. Moreover, the tumor formation by RMG-I-H cells was inhibited by preincubating the cells with LeY mAb. Notably, the expression of TGF-β1, VEGF and b-FGF all increased in RMG-I-H cells. In conclusion, LeY plays an important role in promoting cell proliferation, tumorigenecity and adhesion, and these effects may be related to increased levels of growth factors. The LeY antibody shows potential application in the treatment of LeY-positive tumors.
DLK1 Promotes Lung Cancer Cell Invasion through Upregulation of MMP9 Expression Depending on Notch Signaling  [PDF]
Lin Li, Jinjing Tan, Ying Zhang, Naijun Han, Xuebing Di, Ting Xiao, Shujun Cheng, Yanning Gao, Yu Liu
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0091509
Abstract: The transmembrane and secreted protein delta-like 1 homolog (DLK1) belongs to the EGF-like family. It is widely accepted that DLK1 plays important roles in regulating cell differentiation, such as adipogenesis and osteogenesis. Aberrant expression of DLK1 has been found in various types of human cancers, including lung cancer. A previous study in this lab has revealed that DLK1 is associated with tumor invasion, although the mechanism is still unknown. To explore the potential effects that DLK1 might have on invasion, DLK1 was overexpressed or knocked down in the human lung cancer cell lines. The protein's influences on cell invasion were subsequently evaluated. A transwell assay showed that DLK1 overexpression significantly promoted cancer cell invasion. Western blotting and gelatin zymography analysis indicated that DLK1 could affect both matrix metalloproteinase-9 (MMP9) expression and its extracellular activity. An analysis of NOTCH1 and HES1 gene expression and Notch intracellular domain (NICD) nuclear translocation during DLK1 stimulation or depletion demonstrated that DLK1 could activate Notch signaling in lung cancer cells. Additionally, the elevated expression of MMP9 induced by DLK1 stimulation could be significantly decreased by inhibiting Notch signaling using γ-secretase inhibitor (GSI). The data presented in this study suggest that DLK1 can promote the invasion of lung cancer cells by upregulating MMP9 expression, which depends on Notch signaling.
Macrophage Migration and Invasion Is Regulated by MMP10 Expression  [PDF]
Megan Y. Murray, Timothy P. Birkland, Jonathan D. Howe, Andrew D. Rowan, Mark Fidock, William C. Parks, Jelena Gavrilovic
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063555
Abstract: This study was designed to identify metalloproteinase determinants of macrophage migration and led to the specific hypothesis that matrix metalloproteinase 10 (MMP10/stromelysin-2) facilitates macrophage migration. We first profiled expression of all MMPs in LPS-stimulated primary murine bone marrow-derived macrophages and Raw264.7 cells and found that MMP10 was stimulated early (3 h) and down-regulated later (24 h). Based on this pattern of expression, we speculated that MMP10 plays a role in macrophage responses, such as migration. Indeed, using time lapse microscopy, we found that RNAi silencing of MMP10 in primary macrophages resulted in markedly reduced migration, which was reversed with exogenous active MMP10 protein. Mmp10?/? bone marrow-derived macrophages displayed significantly reduced migration over a two-dimensional fibronectin matrix. Invasion of primary wild-type macrophages into Matrigel supplemented with fibronectin was also markedly impaired in Mmp10?/? cells. MMP10 expression in macrophages thus emerges as an important moderator of cell migration and invasion. These findings support the hypothesis that MMP10 promotes macrophage movement and may have implications in understanding the control of macrophages in several pathologies, including the abnormal wound healing response associated with pro-inflammatory conditions.
Finasteride Inhibits Human Prostate Cancer Cell Invasion through MMP2 and MMP9 Downregulation  [PDF]
Andrei Moroz, Flávia K. Delella, Rodrigo Almeida, Lívia Maria Lacorte, Wágner José Fávaro, Elenice Deffune, Sérgio L. Felisbino
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0084757
Abstract: Introduction The use of the 5-alpha reductase inhibitors (5-ARIs) finasteride and dutasteride for prostate cancer prevention is still under debate. The FDA recently concluded that the increased prevalence of high-grade tumors among 5-ARI-treated patients must not be neglected, and they decided to disallow the use of 5-ARIs for prostate cancer prevention. This study was conducted to verify the effects of finasteride on prostate cell migration and invasion and the related enzymes/proteins in normal human and tumoral prostatic cell lines. Materials and Methods RWPE-1, LNCaP, PC3 and DU145 cells were cultivated to 60% confluence and exposed for different periods to either 10 μM or 50 μM finasteride that was diluted in culture medium. The conditioned media were collected and concentrated, and MMP2 and MMP9 activities and TIMP-1 and TIMP-2 protein expression were determined. Cell viability, migration and invasion were analyzed, and the remaining cell extracts were submitted to androgen receptor (AR) detection by western blotting techniques. Experiments were carried out in triplicate. Results Cell viability was not significantly affected by finasteride exposure. Finasteride significantly downregulated MMP2 and MMP9 activities in RWPE-1 and PC3 cells and MMP2 in DU145 cells. TIMP-2 expression in RWPE-1 cells was upregulated after exposure. The cell invasion of all four tested cell lines was inhibited by exposure to 50 μM of finasteride, and migration inhibition only occurred for RWPE-1 and LNCaP cells. AR was expressed by LNCaP, RWPE-1 and PC3 cells. Conclusions Although the debate on the higher incidence of high-grade prostate cancer among 5-ARI-treated patients remains, our findings indicate that finasteride may attenuate tumor aggressiveness and invasion, which could vary depending on the androgen responsiveness of a patient’s prostate cells.
Autophagy Induced by HIF1α Overexpression Supports Trophoblast Invasion by Supplying Cellular Energy  [PDF]
Mikiko Yamanaka-Tatematsu, Akitoshi Nakashima, Naonobu Fujita, Tomoko Shima, Tamotsu Yoshimori, Shigeru Saito
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0076605
Abstract: Extravillous trophoblasts (EVTs) characterize the invasion of the maternal decidua under low oxygen and poor nutrition at the early feto-maternal interface to establish a successful pregnancy. We previously reported that autophagy in EVTs was activated under 2% O2 in vitro, and autophagy activation was also observed in EVTs at the early feto-maternal interface in vivo. Here, we show that autophagy is an energy source for the invasion of EVTs. Cobalt chloride (CoCl2), which induces hypoxia inducible factor 1α (HIF1α) overexpression, activated autophagy in HTR8/SVneo cells, an EVT cell line. The number of invading HTR8-ATG4BC74A cells, an autophagy-deficient EVT cell line, was markedly reduced by 81 percent with the CoCl2 treatment through the suppression of MMP9 level, although CoCl2 did not affect the cellular invasion of HTR8-mStrawberry cells, a control cell line. HTR8-ATG4BC74A cells treated with CoCl2 showed a decrease in cellular adenosine triphosphate (ATP) levels and a compensatory increase in the expression of purinergic receptor P2X ligand-gated ion channel 7 (P2RX7), which is stimulated with ATP, whereas HTR8-mStrawberry cells maintained cellular ATP levels and did not affect P2RX7 expression. Furthermore, the decreased invasiveness of HTR8-ATG4BC74A cells treated with CoCl2 was neutralized by ATP supplementation to the level of HTR8-ATG4BC74A cells treated without CoCl2. These results suggest that autophagy plays a role in maintaining homeostasis by countervailing HIF1α-mediated cellular energy consumption in EVTs.
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