Prostate cancer risk–associated variants have been reported in populations of European descent, African-Americans and Japanese using genome-wide association studies (GWAS). To systematically investigate prostate cancer risk–associated variants in Chinese men, we performed the first GWAS in Han Chinese. In addition to confirming several associations reported in other ancestry groups, this study identified two new risk-associated loci for prostate cancer on chromosomes 9q31.2 (rs817826, P = 5.45 × 10−14) and 19q13.4 (rs103294, P = 5.34 × 10−16) in 4,484 prostate cancer cases and 8,934 controls. The rs103294 marker at 19q13.4 is in strong linkage equilibrium with a 6.7-kb germline deletion that removes the first six of seven exons in LILRA3, a gene regulating inflammatory response, and was significantly associated with the mRNA expression of LILRA3 in T cells (P < 1 × 10−4). These findings may advance the understanding of genetic susceptibility to prostate cancer.

Proviral integration site for Moloney murine leukemia virus-1 (Pim-1) is a serine/threonine kinase that regulates multiple cellular functions such as cell cycle, cell survival, drug resistance. Aberrant elevation of Pim-1 kinase is associated with numerous types of cancer. Two distinct isoforms of Pim-1 (Pim-1S and Pim-1L) show distinct cellular functions. Pim-1S predominately localizes to the nucleus and Pim-1L localizes to plasma membrane for drug resistance. Recent studies show that mitochondrial Pim-1 maintains mitochondrial integrity. Pim-1 is emerging as a cancer drug target, particularly in prostate cancer. Recently the potent new functions of Pim-1 in immunotherapy, senescence bypass, metastasis and epigenetic dynamics have been found. The aim of the present updated review is to provide brief information regarding networks of Pim-1 kinase and focus on its recent advances as a novel drug target.

Androgen-deprivation therapy (ADT) with newly developed antiandrogen enzalutamide (Enz) may increase the castration-resistant prostate cancer (CRPC) patients survival an extra 4.8 months. Yet eventually most patients may fail with development of Enz resistance. While recent clinical studies indicated that the increased expression of the androgen receptor (AR) splicing variant ARv7 might have key roles for the development of Enz resistance in CRPC, its detailed mechanism, especially its linkage to the circular RNAs (circRNAs), a form of non-coding RNA, however, remains unclear. Here we found from human clinical sample survey that circRNA17 (hsa_circ_0001427) has a lower expression in higher Gleason score PCa, and results from in vitro cell lines studies also revealed the lower expression in CRPC C4–2 Enz-resistant (EnzR-C4–2) cells compared to their parental Enz-sensitive (EnzS-C4–2) cells. Mechanism dissection indicated that suppressing circRNA17 in EnzS-C4–2 cells increased ARv7 expression that might then lead to increase the Enz resistance and cell invasion. Mechanism dissection demonstrated that Enz could suppress the circRNA17 expression at the transcriptional level via suppressing transcription of its host gene PDLIM5, and circRNA17 could regulate ARv7 expression via altering the expression of miR-181c-5p that involved the direct binding of miR-181c-5p to the 3′UTR of ARv7. Preclinical study using in vivo mouse model with xenografted EnzR-CWR22Rv1 cells revealed that adding circRNA17 or miRNA-181c-5p could suppress the EnzR-CWR22Rv1 cells growth. Together, results from these preclinical studies suggest that circRNA17 may function as suppressor to alter the Enz sensitivity and cell invasion in CRPC cells via altering the miR-181c-5p/ARv7 signaling and targeting this newly identified signaling may help in the development of a better therapy to further suppress the EnzR cell growth.

BACKGROUND A rare mutation G84E in HOXB13 was recently identified to be associated with prostate cancer (PCa) in Caucasians. The goal of this study is to test association between HOXB13 genetic variants and PCa risk in Chinese men. METHODS All study subjects were part of the Chinese Consortium for Prostate Cancer Genetics (China PCa). In the first stage, we screened for mutations by sequencing the HOXB13 coding region in 96 unrelated PCa patients. In stage 2, G84E and novel mutations found in stage 1 were genotyped in 671 PCa patients and 1,536 controls. In stage 3, mutation status in 751 additional PCa patients was imputed via haplotype. RESULTS The G84E mutation was not detected in this study. However, a novel mutation, G135E, was identified among 96 patients in stage 1. It was also observed twice in 575 additional PCa patients but not in 1,536 control subjects of stage 2. The frequency of G135E was significantly different between cases and controls, with a P-value of 0.027, based on Fisher’s exact test. Haplotype estimation showed that G135E mutation carriers shared a unique haplotype that was not observed in other subjects. In stage 3, two more PCa patients were predicted to carry the G135E mutation. CONCLUSIONS We identified a novel rare mutation in the HOXB13 gene, G135E, which appears to be a founder mutation. This mutation is associated with increased PCa risk in Chinese men. Consistent with a previous report, our findings provide further evidence that rare mutations in HOXB13 contribute to PCa risk. Prostate 73: 169–175, 2013.