Malignant mesothelioma (MM) is a fatal tumor, and the absence of a specific diagnostic marker and/or a pathogenic molecule-targeting drug is a major issue for its pathological diagnosis and for targeting therapy. The molecular target of MM has not been elucidated because of unknown survival, death, and cytotoxic signals in MM. HEG homolog 1 (HEG1) is a mucin-like membrane protein that contains epidermal growth factor-like domains, and it plays an important role in cancers through aberrant signaling, including that during cell adhesion, as well as through protection from invasion of tumor cells. HEG1 expression supports the survival and proliferation of MM cells. In this study, functional analysis of HEG1 and microRNAs using MM cell lines (H226, MESO4, H2052) was performed. The MTS assay revealed that cell proliferation was significantly reduced upon transient transfection with microRNA-23b (miR-23b) inhibitor and/or HEG1 siRNA. The Annexin V assay revealed that apoptosis was induced upon suppression of miR-23b and/or HEG1. Western blotting showed that the autophagy-related protein LC3-II was induced upon suppression of miR-23b and/or HEG1. These results revealed that miR-23b contributes to HEG1-dependent cell proliferation through evasion of cytotoxicity induced by apoptosis and auto-phagy in MM cells. HEG1-dependent/mediated miR-23b signaling may therefore be a potential target for MM diagnosis and therapy. (C) 2020 Elsevier Inc. All rights reserved.