10631

POSTN

periostin, osteoblast specific factor;POSTN;periostin, osteoblast specific factor

osteoblast specific factor 2 (fasciclin I-like)|periodontal ligament-specific periostin|periostin

13q13.3

protein-coding

Although the outgrowth of micrometastases into macrometastases is the rate-limiting step in metastatic progression and the main determinant of cancer fatality, the molecular mechanisms involved have been little studied. Here, we compared the gene expression profiles of melanoma lymph node micro- and macrometastases and unexpectedly found no common up-regulation of any single growth factor/cytokine, except for the cytokine-like SPP1. Importantly, metastatic outgrowth was found to be consistently associated with activation of the transforming growth factor-beta signaling pathway (confirmed by phospho-SMAD2 staining) and concerted up-regulation of POSTN, FN1, COL-I, and VCAN genes-all inducible by transforming growth factor-beta. The encoded extracellular matrix proteins were found to together form intricate fibrillar networks around tumor cell nests in melanoma and breast cancer metastases from various organs. Functional analyses suggested that these newly synthesized protein networks regulate adhesion, migration, and growth of tumor cells, fibroblasts, and endothelial cells. POSTN acted as an anti-adhesive molecule counteracting the adhesive functions of FN1 and COL-I. Further, cellular FN and POSTN were specifically overexpressed in the newly forming/formed tumor blood vessels. Transforming growth factor-beta receptors and the metastasis-related matrix proteins, POSTN and FN1, in particular, may thus provide attractive targets for development of new therapies against disseminated melanoma, breast cancer, and possibly other tumors, by affecting key processes of metastasis: tumor/stromal cell migration, growth, and angiogenesis.

Molecular mechanisms associated with tumor metastasis remain poorly understood. Here we report that acquired expression of periostin by colon cancer cells greatly promoted metastatic development of colon tumors. Periostin is overexpressed in more than 80% of human colon cancers examined with highest expression in metastatic tumors. Periostin expression dramatically enhanced metastatic growth of colon cancer by both preventing stress-induced apoptosis in the cancer cells and augmenting endothelial cell survival to promote angiogenesis. At the molecular level, periostin activated the Akt/PKB signaling pathway through the alpha(v)beta(3) integrins to increase cellular survival. These data demonstrated that the survival-promoting function is crucial for periostin to promote tumor metastasis of colon cancer.

AIM: To investigate the expression and localization of periostin in gastric cancer and its clinical relevance. METHODS: Reverse transcriptase polymerase chain reaction was used to measure periostin mRNA expression. Western blotting was carried out to detect periostin protein expression. Immunohistochemistry was performed to localize and quantify the expression of periostin in benign gastric diseases and gastric cancer, and immunostaining results were correlated with gastric cancer pathological stages. RESULTS: Periostin expression was low at both mRNA and protein levels in normal gastric tissues, but was overexpressed in gastric cancer tissues. Immunohistochemical staining revealed that periostin was overexpressed in primary gastric cancer, as well as in metastatic lymph nodes, but only faint staining was found in benign gastric ulcers. By quantitative analysis of the immunostaining results, periostin expression was increased 2.5-4-fold in gastric cancer, compared to that in benign gastric disease, and there was a trend toward increasing periostin expression with tumor stage. CONCLUSION: This observation demonstrated that periostin was overexpressed in gastric cancer and lymph node metastasis, which suggests that periostin plays an important role in the progression and metastasis of gastric cancer.

We have previously reported that expression of periostin mRNA is markedly reduced in a variety of human cancer cell lines, suggesting that downregulation of periostin mRNA expression is correlated with the development of human cancers. In our study, to clarify the role of the periostin in human bladder carcinogenesis, we examined the expression of periostin mRNA in normal bladder tissues, bladder cancer tissues and bladder cancer cell lines by Northern blot analysis and RT-PCR analysis. Although the expression of periostin mRNA was detected in 100% (5/5) of normal bladder tissues, it was not detected in 3 human bladder cancer cell lines examined. It was also detected in 81.8% (9/11) of grade 1, 40.0% (4/10) of grade 2 and 33.3% (4/12) of grade 3 bladder cancer tissues, indicating that downregulation of periostin mRNA is significantly related to higher grade bladder cancer (p<0.05). To assess the tumor suppressor function of periostin, we investigated the ability of periostin gene to suppress malignant phenotypes of a bladder cancer cell line, SBT31A. Ectopic expression of periostin gene by a retrovirus vector suppressed in vitro cell invasiveness of the bladder cancer cells without affecting cell proliferation and tumor growth in nude mice. Periostin also suppressed in vivo lung metastasis of the mouse melanoma cell line, B16-F10. mutational analysis revealed that the C-terminal region of periostin was sufficient to suppress cell invasiveness and metastasis of the cancer cells. Periostin may play a role as a suppressor of invasion and metastasis in the progression of human bladder cancers.

BACKGROUND: Recently, periostin (POSTN), a gene encoding a protein with similarity to the fasciclin family and involved in cell survival and angiogenesis, has emerged as a promising marker for tumor progression in various types of human cancers. There is some controversy regarding both POSTN expression levels and the nature of periostin-producing cells within tumors. In this study, we used quantitative RT-PCR to assess periostin gene expression in normal tissues, primary cell cultures, tumor tissues and tumor cell lines. RESULTS: Periostin expression levels are highly variable in both normal tissues and tumors and strong POSTN overexpression is mostly detected in tumors from pancreas and liver. POSTN is not expressed in blood cancers. In melanoma samples, average periostin expression is not increased in primary tumors whereas POSTN overexpression was detected in about 60% of melanoma metastatic tumors in the liver or lymph nodes. Identification of the cellular source of periostin production in melanoma metastases -cancer cells or stroma- was assessed by comparing periostin expression in 23 newly-established melanoma cell lines and matched tumors. In contrast to the reduction by more than 99% of COL6A3 stromal marker mRNA in all cell lines, significant POSTN transcription was maintained in some melanoma cell lines, suggesting that both stromal cells and melanoma cells express periostin. The high level of periostin expression in primary cultures of skin fibroblasts suggests that fibroblasts may contribute for a large part to periostin production in melanoma-associated stroma. On the other hand, periostin expression in melanoma cells is probably acquired during the tumorigenic process as 1) normal melanocytes do not express POSTN and 2) melanoma cells from distinct metastases of the same patient were associated with very different levels of periostin expression. CONCLUSION: Our comparative analysis suggests that, although periostin overexpression is clearly detected in some cancers, it is not a general feature of tumors. In melanoma, our study identifies both stromal and melanoma cells as sources of periostin production and correlates POSTN expression levels with increased primary tumor thickness and metastatic process development.

Although the outgrowth of micrometastases into macrometastases is the rate-limiting step in metastatic progression and the main determinant of cancer fatality, the molecular mechanisms involved have been little studied. Here, we compared the gene expression profiles of melanoma lymph node micro- and macrometastases and unexpectedly found no common up-regulation of any single growth factor/cytokine, except for the cytokine-like SPP1. Importantly, metastatic outgrowth was found to be consistently associated with activation of the transforming growth factor-beta signaling pathway (confirmed by phospho-SMAD2 staining) and concerted up-regulation of POSTN, FN1, COL-I, and VCAN genes-all inducible by transforming growth factor-beta. The encoded extracellular matrix proteins were found to together form intricate fibrillar networks around tumor cell nests in melanoma and breast cancer metastases from various organs. Functional analyses suggested that these newly synthesized protein networks regulate adhesion, migration, and growth of tumor cells, fibroblasts, and endothelial cells. POSTN acted as an anti-adhesive molecule counteracting the adhesive functions of FN1 and COL-I. Further, cellular FN and POSTN were specifically overexpressed in the newly forming/formed tumor blood vessels. Transforming growth factor-beta receptors and the metastasis-related matrix proteins, POSTN and FN1, in particular, may thus provide attractive targets for development of new therapies against disseminated melanoma, breast cancer, and possibly other tumors, by affecting key processes of metastasis: tumor/stromal cell migration, growth, and angiogenesis.

tumor metastasis is a multistep pathological process involved in the final phase of tumor development. During this process, epithelium-derived tumor cells undergo fibroblast-like transformation, referred to as epithelial-mesenchymal transition (EMT), which contributes to aggressive behavior of tumors. We identify periostin, a mesenchyme-specific gene product, as a contributor to EMT and metastatic potential. Stable expression of a periostin transgene in tumorigenic but non-metastatic 293T cells caused cells to undergo fibroblast-like transformation accompanied by increased expressions of vimentin, epidermal growth factor receptor (EGFR), and matrix metalloproteinase-9. The cells expressing ectopic periostin increased cell migration, invasion, and adhesion by 2-9-fold. Invasive characteristics required signaling through integrin alpha(v)beta5 and EGFR. In addition, periostin-engineered 293T cells formed metastases in immunodeficient mice following either cardiac inoculation or injection into mammary fat pad. These data demonstrate an active role for periostin in EMT and metastasis that requires cross-talk between integrin and EGFR signaling pathways.

Although the outgrowth of micrometastases into macrometastases is the rate-limiting step in metastatic progression and the main determinant of cancer fatality, the molecular mechanisms involved have been little studied. Here, we compared the gene expression profiles of melanoma lymph node micro- and macrometastases and unexpectedly found no common up-regulation of any single growth factor/cytokine, except for the cytokine-like SPP1. Importantly, metastatic outgrowth was found to be consistently associated with activation of the transforming growth factor-beta signaling pathway (confirmed by phospho-SMAD2 staining) and concerted up-regulation of POSTN, FN1, COL-I, and VCAN genes-all inducible by transforming growth factor-beta. The encoded extracellular matrix proteins were found to together form intricate fibrillar networks around tumor cell nests in melanoma and breast cancer metastases from various organs. Functional analyses suggested that these newly synthesized protein networks regulate adhesion, migration, and growth of tumor cells, fibroblasts, and endothelial cells. POSTN acted as an anti-adhesive molecule counteracting the adhesive functions of FN1 and COL-I. Further, cellular FN and POSTN were specifically overexpressed in the newly forming/formed tumor blood vessels. Transforming growth factor-beta receptors and the metastasis-related matrix proteins, POSTN and FN1, in particular, may thus provide attractive targets for development of new therapies against disseminated melanoma, breast cancer, and possibly other tumors, by affecting key processes of metastasis: tumor/stromal cell migration, growth, and angiogenesis.

Oncostatin M, a member of the interleukin-6 family of cytokines, has been implicated in tumorigenesis of human prostate cancer. In the current study, we demonstrate that oncostatin M promotes human adipose tissue-derived mesenchymal stem cell-stimulated tumor growth in an in vivo xenograft transplantation model of the human prostate cancer cell line PC-3M-luc-C6, a PC3M cell line expressing the luciferase gene. Conditioned medium derived from oncostatin M-treated mesenchymal stem cells stimulated adhesion of PC-3M-luc-C6 cells. We identified TGFBI and periostin, extracellular matrix proteins implicated in tumorigenesis and metastasis, as oncostatin M-induced secreted proteins in mesenchymal stem cells. Treatment with oncostatin M stimulated secretion of periostin and TGFBI from mesenchymal stem cells in a time-dependent manner. Immunodepletion of TGFBI and periostin from conditioned medium derived from oncostatin M-treated mesenchymal stem cells resulted in abrogation of adhesion of PC-3M-luc-C6 cells stimulated by oncostatin M-conditioned medium. In addition, small interfering RNA-mediated silencing of TGFBI and periostin resulted in abrogation of cell adhesion stimulated by oncostatin M-conditioned medium. These results suggest that mesenchymal stem cell-derived TGFBI and periostin play a key role in tumorigenesis by stimulating adhesion of prostate cancer cells.

Recently, the tumor microenvironment is increasingly recognized as playing an important role in cancer proliferation, invasion, and metastasis. To screen stroma-associated proteins involved in nasopharyngeal carcinoma (NPC) carcinogenesis, laser capture microdissection (LCM) and quantitative proteomic analysis were employed to assess different protein expression of the stroma between NPC and normal nasopharyngeal mucosa (NNM). In this study, periostin was identified to be significantly up-regulated in NPC stroma compared with NNM stroma and the result was further confirmed by Western blotting. Immunohistochemistry showed that over-expression of periostin was frequently observed in the stroma of NPC and matched lymph node metastases (LNM) compared with the stroma of NNM. Statistical analysis showed over-expression of periostin was significantly associated with advanced clinical stage (P < 0.001) and lymph node metastasis (P < 0.001) and decreased overall survival (P < 0.001) in NPC. Cox regression analysis indicated over-expression of periostin was an independent prognostic factor. Furthermore, ectopic expression of periostin was used to examine its effect on invasiveness of NPC cell in vitro and the result showed that periostin was able to promote invasiveness of NPC cell. In conclusion, periostin expression is correlated with tumor stage, lymph node metastasis, and patient survival. Periostin is a potential biomarker for the differentiation and prognosis of NPC, and it might play an important role in the progression of NPC.

OBJECTIVE: Perostin (PN) has been found to be overexpressed in a variety of human malignancies including ovarian cancer. In the present study, we investigated PN expression status in a large cohort of ovarian tumors with the focus on biological influence of PN related on ovarian tumor angiogenesis and metastasis. METHODS: PN expression was determined by cDNA microarray, PN northern blot and PN IHC tissue array analyses. Exogenous PN expression in ovarian cancer cells OVCAR-3 and OV2008 were achieved through retroviral transfection and confirmed by PN western blot and ELISA. The effects of exogenous PN expression on tumor angiogenesis and metastatic growth were accessed in orthotopic mouse models. The in vitro cell adhesion, migration and invasion assays were performed to investigate the potential mechanisms involved in PNs in vivo effects. RESULTS: PN was frequently overexpressed in ovarian tumors. Higher PN levels significantly correlated with clinical late stages (III/IV) and cancer recurrence. PN was produced by engineered PN-overexpressing cells at levels comparable to that of A2780 cells, an ovarian carcinoma cell line with endogenous PN expression. PN overexpression did not change cell growth rates in vitro; however it significantly promoted intraperitoneal tumor metastatic growth in immunodeficient mice, which was associated with increased tumor angiogenesis and decreased tumor cell apoptosis. In vitro purified PN promoted cell adhesion, migration, and invasion of both human umbilical endothelial cells (HUVECs) and/or ovarian cancer cells. CONCLUSIONS: Our data indicate PN plays a critical role in both ovarian tumor angiogenesis and metastasis. Thus PN may represent a clinically effective new target for therapy of ovarian cancer.