Lower Levels of Human MOB3B Are Associated with Prostate Cancer Susceptibility and Aggressive Clinicopathological Characteristics

Mps one binder (MOB) proteins are integral components of signaling pathways that control important cellular processes, such as mitotic exit, centrosome duplication, apoptosis, and cell proliferation. However, the biochemical and cellular functions of the human MOB (hMOB) protein family remain largely unknown. The present study investigated the association between hMOB3B expression and clinicopathological characteristics of prostate cancer (PCa).Study subjects included 137 PCa patients and 137 age-matched benign prostatic hyperplasia (BPH) patients. hMOB3B expression was estimated using real-time PCR and compared with clinicopathological parameters of PCa. hMOB3B mRNA expression was significantly lower in PCa tissues than in BPH control tissues (P<0.001). According to receiver operating characteristics curve analysis, the sensitivity of hMOB3B expression for PCa diagnosis was 84.7%, with a specificity of 86% (AUC=0.910; 95% CI=0.869-0.941; P<0.001). hMOB3B expression was significantly lower in patients with elevated prostate specific antigen (PSA) levels (≥10 ng/mL), a Gleason score≥8, and metastatic disease (any T, N+/M+) than in those with low PSA levels, a low Gleason score, and non-metastatic disease (each P<0.05). In conclusion, low levels of hMOB3B are closely associated with aggressive clinicopathologic features in patients with PCa. Our results suggest that hMOB3B may act as a tumor suppressor in human PCa. Graphical Abstract Keywords: Prostatic Neoplasms, Gene Expression, Genes, Tumor Suppressor, hMOB3B INTRODUCTION Prostate cancer (PCa) is the second most frequently diagnosed cancer and the sixth leading cause of cancer death in men worldwide with an approximately 14% (903,500) of total new cancer cases and 6% (258,400) of the total cancer deaths in males in 2008 (1). In Korea, PCa is the fifth most common cancer in men, and its incidence is the most rapidly increasing of all cancers (2). PCa shows an extremely heterogeneous clinical course, ranging from indolent to aggressive, metastatic lethal disease (3). Consequently, there is a great need to accurately estimate the tumor characteristics of PCa so that appropriate treatment options can be considered. Currently, histopathological analysis (including tumor stage and grade) and serum prostate specific antigen (PSA) levels are key determinants of therapeutic decision-making. However, none of the histological criteria or bio-markers reported to date show sufficient sensitivity and specificity for detecting, monitoring, or determining the prognosis of PCa (4, 5). Thus, there is a critical need for methods capable of predicting oncologic outcomes and responses to therapy in PCa patients. The abnormal expression of certain genes in cancer cells is closely related to distinct aspects of tumor progression, including tumor growth, invasion, and metastasis. Proper cell division requires the precise coordination and execution of several events in the cell cycle, including centrosome duplication, DNA replication, mitotic spindle assembly, chromosome segregation, and cytokinesis (6). A failure in the execution or proper timing of any of these events could lead to chromosome segregation defects, resulting in aneuploidy or polyploidy (7, 8, 9). Mps one binder (MOB) was originally identified in yeast as a regulator of mitotic exit and cytokinesis, and was later identified as a tumor suppressor (10). hMOB1 can bind to and activate mammalian large tumor suppressor (LATS) and nuclear Dbf2-related (NDR) kinases (LATS1, LATS2, NDR1, and 2) by targeting and activating these kinases at the plasma membrane (11, 12). Increased expression of LATS1 or LATS2 inhibits tumor cell growth by inducing cell cycle arrest or apoptosis (10, 11, 13, 14, 15). Recent studies show that hMOB1 is downregulated in colorectal and non-small cell lung cancers (9, 12). hMOB2 binds to the same domain on NDR1/2, but does not bind to LATS1/2; binding of hMOB2 to NDR1/2 kinases inhibits the phosphorylation of NDR and thereby blocks kinase activation (16). hMOB2 is classified as an inhibitor of NDR signaling, whereas hMOB1 is classified as a co-activator of the NDR/LATS signaling cascades (17, 18). The human MOB protein family consists of six members: hMOB1A, 1B, 2, 3A, 3B, and 3C (18). Unfortunately, although hMOB1 and 2 have been extensively studied, the biological roles and binding partners of hMOB3A/B/C are unknown (18). Recent studies revealed that all six hMOB3B are abundantly expressed in human prostate tissue (10), and that methylation-induced gene silencing of hMOB3B occurs in PCa (19). Based on previous research, we hypothesized that hMOB3B acts as a tumor suppressor, and that its loss of function contributes to the carcinogenesis and aggressiveness of human PCa. Here, we compared the expression levels of hMOB3B in normal and prostate cancer tissues to examine the contribution of this gene to prostate carcinogenesis. Also, and more importantly, we investigated the effect of hMOB3B on the clinicopathological characteristics of PCa in Korean men.