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ACTN4

alpha-Actinin-4 (ACTN4) is frequently amplified and overexpressed in various cancers. Although ACTN4 functions in cancer cell migration and invasion, the roles of ACTN4 during the epithelial-to-mesenchymal transition (EMT) and cervical cancer tumorigenesis are unknown. In this study, we investigated the function of ACTN4 in the progression of cervical cancer and the mechanisms of EMT and tumorigenesis induced by ACTN4. We found that ACTN4 induced EMT by upregulating Snail, which was dependent on the Akt signaling pathway in cervical cancer. ACTN4 induced cell migration and invasion through Snail-mediated matrix metalloproteinase-9 expression. ACTN4 expression level was correlated with stabilization of beta-catenin. Accumulatioin of beta-catenin owing to ACTN4 induced tumorigenesis via upregulation of genes involved in cell proliferation, including cyclin D1 and c-myc. ACTN4 knockdown reduced cervical cancer cell proliferation and tumor formation in vivo. The expression level of ACTN4 is highly elevated in human cervical tumors, compared with that in normal cervical tissues. ACTN4-overexpressing MDCK cells induced tumor formation and metastatic nodules in nude mice. Our findings indicate that ACTN4 promotes EMT and tumorigenesis by regulating Snail expression and the Akt pathway in cervical cancer. We propose a novel mechanism for EMT and tumorigenesis in cervical cancer.

Acquired radioresistance accompanied with increased metastatic potential is a major hurdle in effective radiotherapy of breast cancers. However, the nature of their inter-dependence and the underlying mechanism remains largely intangible. By employing radioresistant (RR) cell lines, we herein demonstrate that MCF-7 RR cells display phenotypic and molecular alterations evocative of epithelial to mesenchymal transition (EMT) with increased traction forces and membrane ruffling culminating in boosted invasiveness. We then show that these changes can be attributed to overexpression of alpha-actinin-4 (ACTN4), with ACTN4 knockdown near-completely abrogating both radioresistance and EMT-associated changes. We further found that in MCF-7 RR cells, ACTN4 mediates the observed effects by activating AKT, and downstream AKT/GSK3beta signalling. Though ACTN4 plays a similar role in mediating radioresistance and invasiveness in MDA-MB-231 RR cells, co-immunoprecipitation studies reveal that these changes are effected through increased association with AKT and not by overexpression of AKT. Taken together, our study identifies ACTN4/AKT/GSK3beta as a novel pathway regulating radioresistance coupled invasion which can be further explored to improve the radiotherapeutic gain.CI - Copyright (c) 2017 Elsevier B.V. All rights reserved.