Abstract 5143: MHC class I polypeptide-related sequence A (MICA) as a factor of aggressive prostate cancer
Authors: Sakiyama Marcelo J. , Garcia Angel , Espinoza Ingrid , Lewin Jack , Zhang Xu , Tarsi Elizabeth , Craft Tara , Fair Logan , Monico Jesus , Sullivan Lisa , Pound Charles R. , Vijayakumar Srinivasan , Gomez Christian R. 
Published: July 2016

Abstract
Prostate cancer (PCa) remains the second most common cancer in American men, with higher incidence and death rates in African American men (AAM) relative to Caucasian American men (CAM). MHC class I polypeptide-related sequence A (MICA) is a transmembrane protein responsible for activation of immunocytes, by binding the NKG2D receptor. The expression of MICA under normal conditions is low. However under stress conditions such as those found in neoplasms, MICA expression is increased. The soluble form of MICA (sMICA) is released by tumor cells and promotes immune evasion by binding and downregulating the NKG2D receptor in immune surveillance cells. Increased levels of sMICA have been found in patient sera of several types of cancer, including PCa. We hypothesized that low oxygen levels, a condition of the microenvironment present in aggressive tumors, would modify the levels of sMICA in PCa cell lines. Likewise we speculated that when compared to CAM, MICA would be differentially expressed in tumors from AAM, known to suffer a more aggressive disease. To address those questions, LNCaP cells were cultured under 20% O2 (normoxia) and 2% O2 (hypoxia) at various time points, supernatants were collected and the presence of sMICA in culture supernatant and patient sera was detected by ELISA. After 48 hours, the cells grown in hypoxia expressed about 5-fold more sMICA than cells grown in normoxia. When assessed in patient plasma, PCa patients had 2-fold more sMICA compared to healthy controls. In additional experiments cells growing under different oxygen levels were lysed and used in Western blot analysis to detect cellular MICA. Normal oxygen levels increased MICA protein by 3.5-fold. Hypoxia reduced MICA expression by 11%. A tissue microarray (TMA) was stained with MICA polyclonal antibody. The TMA was composed of 34 tumor samples and 30 controls. The samples came from 32 CAM and 32 AAM. The staining intensity was scored as 0, 1, 2 or 3 and scores 2 and 3 were defined as high intensity. Association of the staining result to presence of tumor was evaluated using the Fisher's exact test. A higher proportion of high intensity in tumor site (50%) was found when compared to non-tumor site (20%, p = 0.019). Interestingly, stronger association was expressed in CAM (p = 0.036) than in AAM (p = 0.265). The results found in the cell line suggest that different oxygen levels affect the expression of sMICA. Higher expression of MICA in prostate tumor tissue and sMICA in patient sera are consistent with data previously reported in other cancers. Lower intensity in MICA staining in AAM patients may be related to better capacity of the tumor to evade the immune system. Overall our findings suggest the involvement of MICA on aggressive PCa. More studies are needed to decipher the biological mechanisms of MICA's immune evasion in prostate tumors and to establish its contributing role to aggressive disease in minorities.
Funding sources: PCRP W81XWH-14-1-0151, UMMC Office of Research
Citation Format: Marcelo J. Sakiyama, Angel Garcia, Ingrid Espinoza, Jack Lewin, Xu Zhang, Elizabeth Tarsi, Tara Craft, Logan Fair, Jesus Monico, Lisa Sullivan, Charles R. Pound, Srinivasan Vijayakumar, Christian R. Gomez. MHC class I polypeptide-related sequence A (MICA) as a factor of aggressive prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5143.