650

BMP2

bone morphogenetic protein 2;BMP2;bone morphogenetic protein 2

BMP-2A|bone morphogenetic protein 2A

20p12

protein-coding

Bladder cancer (BCa) remained a major health problem. Med19 was related to tumor growth of BCa. Bone morphogenetic proteins (BMPs) were reported to be critical in bone metastasis of cancer. We therefore investigated the relations between Med19 and BMPs in BCa and their effect on bone metastasis of BCa. Bladder cancer cell lines were cultured and interfered with Med19 shRNA and control. expressions of BMP-1, BMP-2, BMP-4, BMP-5, BMP-6, BMP-7, BMP-9, and BMP-15 were studied between 2 groups. Fifty-two BCa samples were included for immunohistochemical staining of Med19 and BMP-2. expressions were scored and studied statistically. Invasiveness was studied with Transwell assay. Silencing or Med19 in BCa cells induced altered expressions of BMPs. Increased expressions of BMP-1, BMP-4, BMP-6, BMP-7, and BMP-15 and decreased expressions of BMP-2, BMP-5, and BMP-9 were noticed, but only BMP-2 reached statistical significance. expressions of Med19 and BMP-2 were significantly higher in cases with bone metastasis and were positively correlated in cases with bone metastasis and muscle invasion. Med19 is a critical factor involved in the invasiveness and promotion of bone metastasis of BCa, possibly via BMP-2.

AIM: To analyze the expression of bone morphogenetic proteins (BMPs) in prostate and breast cancers with established metastasis in bone, where prostate cancer causes osteoblastic metastases, and breast cancer osteolytic metastases. METHODS: Primary tumor specimens from 20 patients with prostate cancer and 15 with breast cancer were studied for BMP-2/4, -3, -5, -6 and -7 immunohistochemistry. All patients had multiple bone metastases proven by bone scan. We also examined BMPs expression in normal prostate and breast tissues. BMPs expression was compared with clinicopathological and biochemical parameters. RESULTS: Cytoplasmic BMPs immunostaining was observed in both prostate cancer and normal prostate tissue. expression of BMP-2/4, -5, -6, and -7 proteins was detected in all normal prostate samples, with the predominance of BMP-2/4 (87.8-/+11.4% positive cells) and BMP-7 (94.6-/+0.9% positive cells). In prostate cancer tissues, we found variable expression of all BMPs. BMP-2/4 (83-/+11.6% positive cells) was predominantly expressed in prostate carcinoma, whereas the expression of BMP-7 (24.3-/+19.2% positive cells) was significantly lower than in the normal prostate. In all breast cancers tissues, we found nuclear staining only for BMP-7. In normal breast tissue, the BMP expression was not detectable. The percent of BMP-7 positive cells in breast cancer (86.4-/+7.3%) was higher than in prostatic cancer. Comparing BMP expression levels and clinicopathological parameters, we did not find statistical difference, except for serum alkaline phosphatase, which was significantly higher in patients with prostate cancer. CONCLUSION: The expression of BMPs differs between prostate and breast cancer cells. Identifying the BMP proteins in cancers may be useful for monitoring the tumor status with reference to metastases.

Bone morphogenetic proteins (BMPs) have been implicated in tumorigenesis and metastatic progression in various types of cancer cells, but the role and cellular mechanism in the invasive phenotype of gastric cancer cells is not known. Herein, we determined the roles of phosphoinositide 3-kinase (PI3K)/AKT, extracellular signal-regulated protein kinase (ERK), nuclear factor (NF)-kappaB, and matrix metalloproteinase (MMP) expression in BMP-2-mediated metastatic function in gastric cancer. We found that stimulation of BMP-2 in gastric cancer cells enhanced the phosphorylation of AKT and ERK. Accompanying activation of AKT and ERK kinase, BMP-2 also enhanced phosphorylation/degradation of IkappaBalpha and the nuclear translocation/activation of NF-kappaB. Interestingly, blockade of PI3K/AKT and ERK signaling using LY294002 and PD98059, respectively, significantly inhibited BMP-2-induced motility and invasiveness in association with the activation of NF-kappaB. Furthermore, BMP-2-induced MMP-9 expression and enzymatic activity was also significantly blocked by treatment with PI3K/AKT, ERK, or NF-kappaB inhibitors. Immunohistochemistry staining of 178 gastric tumor biopsies indicated that expression of BMP-2 and MMP-9 had a significant positive correlation with lymph node metastasis and a poor prognosis. These results indicate that the BMP-2 signaling pathway enhances tumor metastasis in gastric cancer by sequential activation of the PI3K/AKT or MAPK pathway followed by the induction of NF-kappaB and MMP-9 activity, indicating that BMP-2 has the potential to be a therapeutic molecular target to decrease metastasis.

AIM: To analyze the expression of bone morphogenetic proteins (BMPs) in prostate and breast cancers with established metastasis in bone, where prostate cancer causes osteoblastic metastases, and breast cancer osteolytic metastases. METHODS: Primary tumor specimens from 20 patients with prostate cancer and 15 with breast cancer were studied for BMP-2/4, -3, -5, -6 and -7 immunohistochemistry. All patients had multiple bone metastases proven by bone scan. We also examined BMPs expression in normal prostate and breast tissues. BMPs expression was compared with clinicopathological and biochemical parameters. RESULTS: Cytoplasmic BMPs immunostaining was observed in both prostate cancer and normal prostate tissue. expression of BMP-2/4, -5, -6, and -7 proteins was detected in all normal prostate samples, with the predominance of BMP-2/4 (87.8-/+11.4% positive cells) and BMP-7 (94.6-/+0.9% positive cells). In prostate cancer tissues, we found variable expression of all BMPs. BMP-2/4 (83-/+11.6% positive cells) was predominantly expressed in prostate carcinoma, whereas the expression of BMP-7 (24.3-/+19.2% positive cells) was significantly lower than in the normal prostate. In all breast cancers tissues, we found nuclear staining only for BMP-7. In normal breast tissue, the BMP expression was not detectable. The percent of BMP-7 positive cells in breast cancer (86.4-/+7.3%) was higher than in prostatic cancer. Comparing BMP expression levels and clinicopathological parameters, we did not find statistical difference, except for serum alkaline phosphatase, which was significantly higher in patients with prostate cancer. CONCLUSION: The expression of BMPs differs between prostate and breast cancer cells. Identifying the BMP proteins in cancers may be useful for monitoring the tumor status with reference to metastases.

The emerging roles of bone morphogenetic proteins (BMPs) in the initiation and progression of multiple cancers have drawn great attention in cancer research. We hypothesized that BMP2 promotes cancer metastasis by modulating MMP-2 secretion and activity through intracellular ROS regulation and ERK activation in human pancreatic cancer. Our data show that stimulation of PANC-1 cells with BMP2 induced MMP-2 secretion and activation, associated with decreased E-cadherin expression, resulting in epithelial-to-mesenchymal transformation (EMT) and cell invasion. Blockade of ROS by the ROS scavenger, 2-MPG, abolished cell invasion, inhibited the EMT process and decreased MMP-2 expression, suggesting ROS accumulation caused an increase in MMP-2 expression in BMP2-stimulated PANC-1 cell invasion. Furthermore, treatment of PANC-1 cells with 2-MPG or ERK inhibitor PD98059 reduced the phosphorylation of ERK, resulting in attenuation of BMP2-induced cell invasion and MMP-2 activation. Taken together, these results suggest that BMP2 induces the cell invasion of PANC-1 cells by enhancing MMP-2 secretion and acting through ROS accumulation and ERK activation.

AIM: To analyze the expression of bone morphogenetic proteins (BMPs) in prostate and breast cancers with established metastasis in bone, where prostate cancer causes osteoblastic metastases, and breast cancer osteolytic metastases. METHODS: Primary tumor specimens from 20 patients with prostate cancer and 15 with breast cancer were studied for BMP-2/4, -3, -5, -6 and -7 immunohistochemistry. All patients had multiple bone metastases proven by bone scan. We also examined BMPs expression in normal prostate and breast tissues. BMPs expression was compared with clinicopathological and biochemical parameters. RESULTS: Cytoplasmic BMPs immunostaining was observed in both prostate cancer and normal prostate tissue. expression of BMP-2/4, -5, -6, and -7 proteins was detected in all normal prostate samples, with the predominance of BMP-2/4 (87.8-/+11.4% positive cells) and BMP-7 (94.6-/+0.9% positive cells). In prostate cancer tissues, we found variable expression of all BMPs. BMP-2/4 (83-/+11.6% positive cells) was predominantly expressed in prostate carcinoma, whereas the expression of BMP-7 (24.3-/+19.2% positive cells) was significantly lower than in the normal prostate. In all breast cancers tissues, we found nuclear staining only for BMP-7. In normal breast tissue, the BMP expression was not detectable. The percent of BMP-7 positive cells in breast cancer (86.4-/+7.3%) was higher than in prostatic cancer. Comparing BMP expression levels and clinicopathological parameters, we did not find statistical difference, except for serum alkaline phosphatase, which was significantly higher in patients with prostate cancer. CONCLUSION: The expression of BMPs differs between prostate and breast cancer cells. Identifying the BMP proteins in cancers may be useful for monitoring the tumor status with reference to metastases.

The molecular mechanisms involved in prostate cancer (PC) metastasis and bone remodeling are poorly understood. We recently reported that phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) mediates transcriptional regulation and activation of bone morphogenetic protein (BMP)-2 signaling by nuclear factor (NF)-kappaB in bone metastatic prostate cancer cells. In the present study, we demonstrate that NF-kappaB, whether activated by recombinant human tumor necrosis factor (TNF)-alpha or by ectopic expression of the p65 subunit, is involved in extracellular matrix adhesion and invasion of osteotropic PC-3 and C4-2B, but not LNCaP, cells. The enhanced metastatic potential was associated with transcriptional upregulation of osteopontin, osteocalcin, and collagen IA1 in osteotropic PC cells, suggesting their role in osteomimicry of PC cells. Unlike BMP-4, BMP-2 protein enhanced the invasive properties of C4-2B cells, but not in LNCaP cells. Also, this effect was nullified by Noggin. In addition, BMP-2 mediates TNF-alpha-induced invasion of C4-2B cells in a NF-kappaB-dependent fashion. TNF-alpha or conditioned media (CM) of TNF-alpha-stimulated C4-2B cells upregulated BMP-2 and BMP-dependent Smad transcripts and inhibited receptor activator of NF-kappaB ligand transcripts in RAW 264.7 preosteoclast cells, respectively, implying that this factor may contribute to suppression of osteoclastogenesis via direct and paracrine mechanisms. In contrast, CM of TNF-alpha-stimulate or BMP2-stimulated C4-2B cells induced in vitro mineralization of MC3T3-E1 osteoblast cells in a BMP-2-dependent and NF-kappaB-dependent manner, respectively. Taken together, the results suggest that mutual interactions between these factors may be pivotal not only in enhancing the osteomimicry and metastatic potential of PC cells, but also in bone remodeling and in shifting the balance from osteoclastogenesis towards osteoblastogenesis.