Abstract 5246: A paradox: Expression of the myelin and lymphocyte protein 2 (MAL2) is down-regulated in human hepatocholangio and renal carcinomas in contrast to its up-regulation in other cancers

Recent work has found that Myelin and Lymphocyte Protein 2 (MAL2), a protein that functions in polarized protein sorting, is frequently overexpressed in many epithelial-derived human cancers, and has been linked to poor prognosis in patients with colorectal and pancreatic cancers. Yet, its role in tumorigenesis is unknown. Our recent overexpression/knockdown studies in polarized hepatic WIF-B cells, Hep3B hepatocellular carcinoma cells and hepatoma-derived Clone9 cells all indicate that MAL2 is a tumor suppressor. How can MAL2’s function as a tumor suppressor be reconciled with its upregulated expression and link to bad prognosis in human cancers? MAL2 resides on chromosome region 8q24, a region frequently amplified in multiple epithelial-derived human cancers along with c-Myc, a well-known oncogenic driver whose overexpression dysregulates gene expression leading to downstream decreased expression of MAL2 via inactivation of the Miz1 transcription factor. Our prediction is that lower grade lesions from human epithelial-derived cancers display high MAL2 expression that will diminish as cancers progress into higher grade lesions and metastases with a concomitant increase in c-Myc expression. We tested this hypothesis with a cohort, of 23 cholangiocarcinoma (CC), 18 hepatocellular (HCC) and 20 renal cell (RCC) human carcinoma cases whose formalin fixed paraffin embedded tissue sections containing benign and later-stage tumor lesions were immunostained using the Dako Autostainers Link 48 along with Mal2 rabbit polyclonal (ABCAM), Miz-1 monoclonal ZBTB17(NOVUS), c-Myc monoclonal Y69 (ABCAM) and Ki-67 monoclonal Mib-1(Dako) antibodies. Nuclear and/or cytoplasmic immunoreactivity was scored based on the intensity and percentage of positive cells in both the benign epithelium and adjacent tumor component in each case. In all three carcinoma types, both MAL2 and Miz-1 expression was high in the benign tissue. In the tumor component MAL2 and Miz-1 expression was respectively lost in 15/23(65%) and 22/23(96%) CC, 13/18(72%) and 17/18(94%) HCC, 13/20(65%) and 16/20(80%) RCC cases. In contrast only 2/20 (10%) and 1/20(5%) RCC cases showed an upregulated expression of MAL2 and Miz-1 respectively compared to the benign component, with all three remaining carcinoma cases showing no up-or-down regulation in protein expression. However, no enhanced c-Myc expression was detected in the tumor lesions despite the higher proliferative index as indicated by Ki-67 labeling. These results indicate a concordant down-regulation of both MAL2 and Miz-1 in CC, HCC, and RCC supporting a tumor suppressor role in these cancers. We are currently extending these studies to other epithelial-derived cancer tissue types and also are more closely examining MAL2, Miz1 and c-Myc expression across graded lesions to better test our hypothesis. Note: This abstract was not presented at the meeting. Citation Format: Alfonso Lopez-Coral, Joeffrey J. Chahine, Bhaskar V. Kallakury, Pamela L. Tuma. A paradox: Expression of the myelin and lymphocyte protein 2 (MAL2) is down-regulated in human hepatocholangio and renal carcinomas in contrast to its up-regulation in other cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5246.