Investigator
Shimane University
NAC1/ACOX2 Axis as a Novel Therapeutic Target for Endometriosis-Related Ovarian Neoplasms
NAC1, a transcription regulator protein associated with cancer, is highly expressed in several tumor types, including ovarian cancer. However, it remains unclear how NAC1 is involved in carcinogenesis. Our previous studies demonstrated that the knockdown of NAC1 in ovarian clear cell carcinoma (OCCC) cell lines induces apoptosis and restores their sensitivity to chemotherapy, suggesting NAC1 as a potential therapeutic target. The present study aimed to identify molecular pathways through which NAC1 is involved in the development of endometriosis-related ovarian neoplasms (ERONs). Immunohistochemistry was performed to clarify the relationship between NAC1 and the potential target protein ACOX2 in surgical specimens of ERONs. Reporter assays were conducted to determine the interaction of NAC1 with the specific cis-element on the ACOX2 promoter. Subsequently, a ChIP assay was performed to investigate the in vivo interaction of NAC1 with the ACOX2 promoter. There was an inverse relationship between NAC1 and ACOX2 expressions in the tumor specimens of ERONs. High NAC1/low ACOX2 expression was found to be a worse prognostic marker for patient survival. Reporter assays demonstrated that NAC1 negatively regulated the ACOX2 promoter via the proximal CATG site. ChIP assays confirmed in vivo binding of NAC1 to the promoter. The present study implicated that NAC1 may contribute to the development of ERONs as a transcriptional repressor by regulating ACOX2 expression via specific binding sites on the promoter, providing a novel insight into the NAC1/ACOX2 axis as a potential therapeutic target of this tumor type.
A Comparative Analysis of Usual- and Gastric-Type Cervical Adenocarcinoma in a Japanese Population Reveals Distinct Clinicopathological and Molecular Features with Prognostic and Therapeutic Insights
Gastric-type cervical adenocarcinoma (GCA) is a rare and aggressive subtype of cervical adenocarcinoma. Despite its clinical significance, its molecular carcinogenesis and therapeutic targets remain poorly understood. This study aimed to compare the clinicopathological, immunohistochemical, and molecular profiles of GCA and usual-type cervical adenocarcinoma (UCA), exploring prognostic and therapeutic biomarkers in a Japanese population. A total of 110 cervical adenocarcinoma cases, including 16 GCA and 94 UCA cases, were retrospectively analyzed for clinicopathological features, and a panel of immunohistochemical markers was assessed. Sanger sequences were performed for the KRAS, PIK3CA, and BRAF genes, and survival and clinicopathological correlations were assessed using Kaplan–Meier and Cox regression analyses. GCA was significantly associated with more aggressive features than UCA, including lymph node involvement, advanced FIGO stages, increasing recurrence rate, and poor survival status. High ARID1B expression was observed in a subset of GCA cases and correlated with worse progression-free and overall survival. Additionally, PD-L1 expression was more frequent in GCA than UCA and was associated with unfavorable prognostic factors. Conversely, UCA cases showed strong p16 expression, supporting their HPV-driven pathogenesis. Molecular profiling revealed KRAS and PIK3CA mutations in both subtypes, while BRAF mutations were identified exclusively in GCA. These findings reveal distinct clinical and molecular profiles for both tumor types and underscore ARID1B and PD-L1 as predictive prognostic and therapeutic biomarkers in GCA, implicating the use of subtype-specific treatment strategies.
Establishment of a Novel In Vitro and In Vivo Model to Understand Molecular Carcinogenesis of Endometriosis-Related Ovarian Neoplasms
The molecular mechanisms through which endometriosis-related ovarian neoplasms (ERONs) develop from benign endometrioma remain unclear. It is especially a long-standing mystery why ovarian endometrioma has the potential to develop into two representative histological subtypes: endometrioid ovarian carcinoma or clear cell ovarian carcinoma. This study aimed to investigate the molecular carcinogenesis of ERONs using newly developed in vitro and in vivo carcinogenesis models. Epithelial cells were isolated and purified from surgically removed benign endometrioma samples, followed by immortalization by overexpressing cyclinD1/CDK4 in combination with the human TERT gene. Immortalized cells were subjected to various molecular manipulations by combining knockout or overexpression of several candidate drivers, including ARID1A, KRAS, PIK3CA, AKT, and MYC, based on previous comprehensive genome-wide studies of ERONs. These cells were then inoculated into immunocompromised mice and evaluated for malignant transformation. Inoculated cells harboring a combination of three genetic alterations successfully developed tumors with malignant features in mice, whereas those with two genetic manipulations failed to do so. Especially, ARID1A gene knockout, combined with overexpressing the KRAS oncogenic mutant allele (or overexpressing AKT) and c-Myc overexpression led to efficient tumor formation. Of note, these three combinations of genetic alterations produced tumors that histologically represented typical clear cell carcinoma in SCID mice, while the same combination led to tumors with endometrioid histology in nude mice. A combination of ARID1A mutation, KRAS mutation or AKT activation, and c-Myc overexpression were confirmed to be the main candidate drivers for the development of ERONs, as suggested by comprehensive genetic analyses of ERONs. A tumor immune microenvironment involving B-cell signaling may contribute to the diverse histological phenotypes. The present model may help to clarify the molecular mechanisms of ERON carcinogenesis and understand their histological diversity and novel molecular targets.
