Actinin-4 expression in ovarian cancer: a novel prognostic indicator independent of clinical stage and histological type

Abstract

Actinin-4 is an isoform of non-muscular a-actinin and actin-bundling protein. By enhancing cell motility, actinin-4 shows different biological properties from another isoform of non-muscular actinin 'actinin-1' and variable clinicopathological implications of actinin-4 have been demonstrated in some human malignancies such as breast cancers, lung cancers, and colorectal cancers. We herein described the clinicopathological and prognostic significance of actinin-4 expression in ovarian cancers. Actinin-4 expression was analyzed immunohistochemically in 265 primary ovarian carcinomas: 116 serous, 71 clear cell, 43 endometrioid, and 35 mucinous adenocarcinomas. With reference to endothelial immunoreactivity, cytoplasmic expression of actinin-4 was classified as either low (including negative) or high. Then, various parameters such as patients' characteristics, histopathological findings including E-cadherin and b-catenin immunoreactivity, and clinical outcome, were compared between groups showing differences in the intensity or intracellular distribution of actinin-4 immunoreactivity. High expression of actinin-4 was demonstrated in 137 (57%) cases and was associated with serous histology (P ¼ 0.0075), high histological grade (Po0.0001), an advanced disease stage (P ¼ 0.036), a high degree of residual disease after initial surgery (P ¼ 0.0047), poor patient outcome (5-year survival: 52.4% in the high-expression group vs 71.9% in the low expression group, P ¼ 0.0043 by log-rank test), and also with reduced E-cadherin and preserved b-catenin expressions (P ¼ 0.0097 and 0.017, respectively). Nuclear immunoreactivity for actinin-4 was detected in 20 (7.5%) cases and was associated with low histological grade (P ¼ 0.0079) but not with other variables. Multivariate analysis showed that high actinin-4 expression was an independent prognostic factor for overall survival, as well as a high degree of residual disease and clear-cell histology. Accumulation of actinin-4 in the cytoplasm may be related to a higher propensity for tumor invasiveness and metastasis, probably by enhancing cell motility, and could be a novel prognostic indicator for patients with ovarian carcinomas.

SOX10 is a novel marker of acinus and intercalated duct differentiation in salivary gland tumors: a clue to the histogenesis for tumor diagnosis

“…Two core specimens, 2.0 mm in diameter, for each case were taken from these blocks and transferred to recipient blocks using a TMA Master tissue microarray (3DHistech, Budapest, Hungary). 8 …”

Actinin-4 gene amplification in ovarian cancer: a candidate oncogene associated with poor patient prognosis and tumor chemoresistance

“…5,11,12 Previously, using immunohistochemistry, we detected high actinin-4 protein expression in the cytoplasm in 52% (137 of 265 cases) of ovarian cancers, and this was significantly associated with a clinically advanced tumor stage, a serous adenocarcinoma histology, high-grade tumor histology, a high degree of residual tumor after initial surgery, and a poor patient outcome. 13 Multivariate analysis indicated that high actinin-4 expression can be a prognostic indicator that is independent of clinical stage and histologic subtype. 13 Therefore, as is the case in other solid cancers, the cytoplasmic accumulation of actinin-4 protein in ovarian cancer cells is suggested to be associated with tumor cell motility, invasiveness, and metastatic potential.…”

“…13 Multivariate analysis indicated that high actinin-4 expression can be a prognostic indicator that is independent of clinical stage and histologic subtype. 13 Therefore, as is the case in other solid cancers, the cytoplasmic accumulation of actinin-4 protein in ovarian cancer cells is suggested to be associated with tumor cell motility, invasiveness, and metastatic potential.…”

“…10,13 Immunohistochemistry was performed as described previously. 13 Endothelium contained in the tissue microarray cores was used as an internal control for the actinin-4 immunoreaction (Figure 2a and b). As negative controls, the primary antibodies were omitted from each reaction process, and absence of immunoreactivity was confirmed.…”

“…19 Histological grading, with reference to the grading system proposed by Shimizu et al 20 and Silverberg,21 was performed as described previously. 13 The staging of tumors was assigned according to the International Federation of Gynecology and Obstetrics (FIGO) system. The chemotherapeutic regimens comprised cyclophosphamide, doxorubicin, and cisplatin in 80 patients, paclitaxel and carboplatin in 30, irinotecan and cisplatin in 8, etoposide and cisplatin in 7, docetaxel and carboplatin in 6, cyclophosphamide and cisplatin in 3, irinotecan and carboplatin in 1, and cyclophosphamide and carboplatin in 1.…”