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Periostin in tumor microenvironment is associated with poor prognosis and platinum resistance in epithelial ovarian carcinoma.

ABSTRACT: The interplay between tumor microenvironment and cancer that causes chemoresistance remains unclear. By analyzing public available microarray datasets, we identified that periostin (POSTN) was overexpressed in cancer stroma in epithelial ovarian cancer (EOC) patients. Immunohistochemistry analysis showed overexpression of stromal POSTN is a powerful independent poor prognostic predictor for EOC patients. Furthermore, patients with high levels of stromal POSTN tend to have higher percentage of cisplatin resistance compared to those with low levels of stromal POSTN. Moreover, we found POSTN treatment can induce cisplatin resistant and activate AKT pathway in A2780 cells in vitro. Inhibition of AKT activity by AKT inhibitor MK-2206 abolished POSTN-induced AKT activation and cisplatin resistance in vitro. Taken together, we found high POSTN expression in cancer microenvironment is correlated with poor prognosis in EOC patients and associated with platinum resistance. The effect of POSTN in cancer stroma cells may activate AKT pathway in tumor and AKT inhibitor can be beneficial to augment the efficacy of existing cancer therapeutics.

SUBMITTER: Sung PL

PROVIDER: S-EPMC4826188 | biostudies-literature | 2016 Jan

REPOSITORIES: biostudies-literature

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Periostin in tumor microenvironment is associated with poor prognosis and platinum resistance in epithelial ovarian carcinoma.

Sung Pi-Lin PL Jan Yi-Hua YH Lin Shih-Chieh SC Huang Chao-Cheng CC Lin Hao H Wen Kuo-Chang KC Chao Kuan-Chong KC Lai Chiung-Ru CR Wang Peng-Hui PH Chuang Chi-Mu CM Wu Hua-Hsi HH Twu Nae-Fang NF Yen Ming-Shyen MS Hsiao Michael M Huang Chi-Ying F CY

Oncotarget 20160101 4

The interplay between tumor microenvironment and cancer that causes chemoresistance remains unclear. By analyzing public available microarray datasets, we identified that periostin (POSTN) was overexpressed in cancer stroma in epithelial ovarian cancer (EOC) patients. Immunohistochemistry analysis showed overexpression of stromal POSTN is a powerful independent poor prognostic predictor for EOC patients. Furthermore, patients with high levels of stromal POSTN tend to have higher percentage of ci ...[more]

PMID: 26716408

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Project description:BackgroundAcetyl-CoA acetyltransferase 2 (ACAT2) is a lipid metabolism enzyme and rarely was researched in epithelial ovarian cancer (EOC).MethodsACAT2 expressions were confirmed in two pairs of cell lines (A2780 and A2780/DDP, OVCAR8 and OVCAR8/DDP) from Gene Expression Omnibus database by bioinformatics analysis, and in A2780 and A2780/DDP cell lines by quantitative real-time polymerase chain reaction and western blotting. Tissue samples were stained by immunohistochemistry and scored for ACAT2 expression. The relationships between ACAT2 expression and clinicopathological characteristics were analyzed by χ2 test. The prognosis of ACAT2 was analyzed by the log-rank tests and Cox regression models.ResultsACAT2 was remarkably upregulated in the above drug-resistant cell lines by mRNA (all P < 0.05) and protein expression (P = 0.026) than those in sensitive ones. Patients were classified as ACAT2-high (n = 51) and ACAT2-low (n = 26) according to immunohistochemical score. ACAT2 expression had a significantly inverse correlation with FIGO stage (P = 0.030) and chemo-response (P = 0.041). A marginal statistical significance existed in ACAT2 expression and ascites volume (P = 0.092). Univariate analysis suggested that high-expressed ACAT2 was associated with decreased platinum-free interval (PFI) (8.57 vs. 14.13 months, P = 0.044), progression-free survival (PFS) (14.12 vs. 19.79 months, P = 0.039) and overall survival (OS) (36.89 vs. 52.40 months, P = 0.044). Multivariate analysis demonstrated that ACAT2 expression (hazard ratio = 2.18, 95% confidence interval: 1.15-4.11, P = 0.017) affected OS independently, rather than PFI and PFS.ConclusionThe expression of ACAT2 in A2780/DDP and OVCAR8/DDP was higher than the corresponding A2780 and OVCAR8. High-expressed ACAT2 was associated with advanced FIGO stage, chemo-resistance, and decreased PFI, PFS and OS. It was an independent prognostic factor of OS in EOC.

Project description:Invasion and metastasis are direct causes of mortality in patients with breast cancer and require reciprocal interactions between cancer cells and the extracellular matrix (ECM). Periostin, a fasciclin-containing adhesive ECM glycoprotein, is frequently overexpressed in various types of human cancer, and its overexpression in cancer-associated stroma and/or cancer cells is usually associated with poor clinical outcomes. However, the expression of periostin in the successive steps of breast tumorigenesis and its association with outcome variables have not been well established in breast carcinoma. The present study aimed to assess the role of periostin alteration in breast tumorigenesis and evaluate the putative prognostic value of periostin as a function of its compartmentalization. Immunohistochemical staining with anti-periostin antibody was performed in a total of 300 patients (26 patients with normal breast tissues, 76 patients with ductal carcinoma in situ [DCIS], and 198 patients with invasive breast carcinoma [IBC]) using tissue microarray. Periostin immunoreactivity was assessed in both epithelial tissue and the surrounding stromal compartment. The mRNA and protein expression of periostin were analyzed in 10 paired normal/invasive cancer frozen specimens by quantitative real time-polymerase chain reaction and western blot analysis, respectively. In cancer tissues, periostin mRNA and protein expression were increased compared with adjacent normal tissues. Both epithelial and stromal periostin staining scores significantly increased in a stepwise manner with disease progression from normal breast tissue to DCIS and IBC (P = 0.000 and 0.000, respectively). High epithelial and stromal periostin expression was observed in 109/189 (57.7%) and 158/189 (83.6%) cases of IBC, respectively. High epithelial periostin expression was more frequently observed in the distant metastatic relapse-positive group than in the distant metastatic relapse-negative group (41/51 [80.4%] vs. 68/138 [49.3%] cases [P = 0.000]). Furthermore, high epithelial periostin expression was associated with reduced disease-free survival and overall survival in univariate and multivariate analysis. Periostin may play an important role in the progression of breast tumor, and epithelial periostin expression may serve as a new parameter for prediction of prognosis in patients with IBC. Further studies examining periostin expression and its potential as a target of IBC therapy are warranted.

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Periostin in tumor microenvironment is associated with poor prognosis and platinum resistance in epithelial ovarian carcinoma.

Publications

Periostin in tumor microenvironment is associated with poor prognosis and platinum resistance in epithelial ovarian carcinoma.

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