Abstract 5721: c-Myc expression coupled with loss of cytoplasmic Miz-1 expression and its re-localization to a nuclear expression in high grade cholangio and hepatocholangio carcinomas

Abstract

Abstract Miz-1 (Myc-interacting zinc finger) activates target genes through transcription factors that are regulated by specific antimitogenic signals. Association with Myc converts Miz-1 from being a transcriptional activator to a repressor. This binding and the formation of Myc/Miz-1 complex induces a change in the biophysical properties of the Miz-1 protein, rendering the complex insoluble and causing to relocalize inside the nucleus. In addition, this association stabilizes Myc and as a result represses transcription. With uncontrolled tumor progress, metastatic tumor expansion can occur through epithelial-to-mesenchymal transition (EMT) and the induction of ZEB-1 (Zinc Finger E-Box Binding Homeobox-1). Zeb-1 expression is highly associated with aggressive behavior tumor types. A cohort of 98 human cholangiocarcinoma carcinoma (CC) including 14 with mixed (CC)/(HCC) resected cases whose formalin fixed paraffin embedded (FFPE) tissue sections containing adjacent benign and malignant tumor lesions were examined by immunohistochemistry (IHC) using Miz-1 (ZBTB17), ZEB-1 (OT13G6), c-Myc (Y69), and Ki-67 (Mib-1) monoclonal antibodies. The clinicopathologic variables, including viral hepatitis, cirrhosis, tumor size, grade and number, vascular invasion, tumor-node-metastasis (TNM) stage, were obtained from each patient’s medical records. The variables were assessed for correlation with the immunohistochemical results. Compared to the adjacent benign liver section, reduction of Miz-1 expression was observed in 98/98 (100%) (P<0.0001) cases, while positive expression of c-Myc, Ki-67 (> 5%), and ZEB-1 was observed in 18/98 (18.36%) (P<0.0001), 27/98 (27.55%) (P=0.000003), and 15/98 (15.30%) (P<0.00001) cases respectively. Of note, complete loss of Miz-1 expression was noted in 20/36 (55.55%) (P=0.106) high grade tumors (III/IV) associated with positive c-Myc, Ki-67 (>5%), ZEB-1, and nuclear Miz-1 expression in 12/20 (60%) (P=0.12) cases (4 CC and 8 mixed (CC)/(HCC) cases). All 12 cases with positive ZEB-1 had confirmed positive lymph node involvement. These results support the role of Miz-1 as one of the intermediary checkpoints required for the induction of cell cycle arrest and apoptosis. Positive c-Myc/ZEB-1 coupled with Miz-1 reduced cytoplasmic and its re-localization to a nuclear expression confirms the transcriptional repressor role of the Myc/Miz-1 complex and the activation of the ZEB-1 gene as a predictor of increased metastatic expansion, therapy resistance, and poor survival in high grade CC, and CC/HCC cases. These findings correlate with a cohort of an adequate number of differently graded lesions from 147 HCC cases that showed similar expression pattern of Miz-1, c-Myc and Zeb-1 to better confirm our hypothesis in epithelial derived human malignancies with frequently amplified 8q24 chromosome. Citation Format: Joeffrey J. Chahine, Sumeyye Culfaci, DongHyang Kwon, Pamela Tuma, Bhaskar V.S. Kallakury. c-Myc expression coupled with loss of cytoplasmic Miz-1 expression and its re-localization to a nuclear expression in high grade cholangio and hepatocholangio carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5721.