Maspin Modulates Malignant Phenotypes Depending on Subcellular Localization in Pancreatic Ductal Adenocarcinoma Cell...

Background/Objectives: Mammary serine protease inhibitor (maspin) was originally identified as a tumor suppressor gene, as loss of its expression in breast cancer cell lines promotes invasiveness and tumorigenicity. In contrast, normal pancreatic ductal epithelium does not express the maspin protein, and its expression frequency increases as pancreatic intraepithelial neoplasia (PanIN) progresses to pancreatic ductal adenocarcinoma (PDAC). We have previously reported that cytoplasmic-only localization of maspin (cytMaspin) is an independent indicator of poor prognosis in patients with PDAC. However, the functional role of maspin in PDAC remains unclear. Methods: We investigated the subcellular localization and biological function of maspin in PDAC cell lines using Western blotting, immunofluorescence, RNA-seq, wound-healing assays, and invasion assays. Results: Endogenous maspin was detected in most PDAC cell lines, and RNA-seq was performed in S2-007 (panMaspin; nuclear and cytoplasmic localization of maspin) and S2-028 (cytMaspin), which were derived from the same parental cell line (SUIT-2). The invasive capability of S2-028 cells (cytMaspin) was higher than that of S2-007 cells (panMaspin), showing upregulation of the ErbB family and axon-guidance pathways. Furthermore, maspin overexpression in PANC-1 and S2-020 cells resulted in panMaspin and cytMaspin, respectively. PANC-1 cells overexpressing maspin showed decreased invasive capability via suppression of HER2 expression and Akt activation. Conclusions: Although maspin expression has generally been considered an unfavorable prognostic indicator in patients with PDAC, our findings suggest that its biological effects may differ depending on its subcellular localization. Specifically, nuclear localization is linked to less aggressive phenotypes, whereas cytoplasmic localization is associated with more malignant behavior.