Coexpression of aPKCλ/ι and IL-6 in prostate cancer tissue correlates with biochemical recurrence.

Atypical protein kinase C λ/ι (aPKCλ/ι) and interleukin-6 (IL-6) have been implicated in prostate cancer progression, the mechanisms of which have been demonstrated both in vitro and in vivo. However, the clinical significance of the correlation between the expressions of these factors remains to be clarified. In the present study, we report a significant correlation between aPKCλ/ι and IL-6 proteins in prostate cancer tissue by immunohistochemical staining. We evaluated the association of both proteins by analyzing clinicopathological parameters using chi-square test, Kaplan-Meier with log-rank test, and a Cox proportional hazard regression model in univariate and multivariate analyses. The results again showed that the expression of aPKCλ/ι and IL-6 correlates in prostate cancer tissue (P < 0.001). Atypical protein kinase C λ/ι was also found to correlate with the Gleason score (P < 0.001) and with biochemical recurrence after prostatectomy (P = 0.02). Furthermore, aPKCλ/ι correlated with biochemical recurrence in a Kaplan-Meier and log-rank test (P = 0.01) and Cox analysis (P = 0.02 in the univariate analysis, P = 0.02 in the multivariate analysis). The coexpression of aPKCλ/ι and IL-6 also correlated with biochemical recurrence by Kaplan-Meier and log-rank test (P = 0.005) and Cox analysis (P = 0.01 in the univariate analysis, P = 0.03 in the multivariate analysis). These results indicate a strong correlation between aPKCλ/ι and IL-6 in prostate tumors, and that the aPKCλ/ι-IL-6 axis is a reliable prognostic factor for the biochemical recurrence of this cancer.

ETS family-associated gene fusions in Japanese prostate cancer: analysis of 194 radical prostatectomy samples.

The incidence and clinical significance of the TMPRSS2:ERG gene fusion in prostate cancer has been investigated with contradictory results. It is now common knowledge that significant variability in gene alterations exists according to ethnic background in various kinds of cancer. In this study, we evaluated gene fusions involving the ETS gene family in Japanese prostate cancer. Total RNA from 194 formalin-fixed and paraffin-embedded prostate cancer samples obtained by radical prostatectomy was subjected to reverse-transcriptase polymerase chain reaction to detect the common TMPRSS2:ERG T1-E4 and T1-E5 fusion transcripts and five other non-TMPRSS2:ERG fusion transcripts. We identified 54 TMPRSS2:ERG-positive cases (54/194, 28%) and two HNRPA2B1:ETV1-positive cases (2/194, 1%). The SLC45A3-ELK4 transcript, a fusion transcript without structural gene rearrangement, was detectable in five cases (5/194, 3%). The frequencies of both TMPRSS2:ERG- and non-TMPRSS2:ERG-positive cases were lower than those reported for European, North American or Brazilian patients. Internodular heterogeneity of TMPRSS2:ERG was observed in 5 out of 11 multifocal cases (45%); a frequency similar to that found in European and North American cases. We found a positive correlation between the TMPRSS2:ERG fusion and a Gleason score of ≤7 and patient age, but found no relationship with pT stage or plasma prostate-specific antigen concentration. To exclude the possibility that Japanese prostate cancer displays novel TMPRSS2:ERG transcript variants or has unique 5' fusion partners for the ETS genes, we performed 5' RACE using fresh-frozen prostate cancer samples. We identified only the normal 5' cDNA ends for ERG, ETV1 and ETV5 in fusion-negative cases. Because we identified a relatively low frequency of TMPRSS2:ERG and other fusions, further evaluation is required before this promising molecular marker should be introduced into the management of Japanese prostate cancer patients.

Aberrant nuclear localization and gene mutation of beta-catenin in low-grade adenocarcinoma of fetal lung type: up-regulation of the Wnt signaling pathway may be a common denominator for the development of tumors that form morules.

The salient histopathologic features of low-grade adenocarcinoma of the fetal lung type (L-FLAC)/well-differentiated fetal adenocarcinoma (WDFA) include complex glandular structures and morules with biotin-rich optically clear nuclei. Interestingly, these characteristic features are shared by the cribriform-morular variant of papillary thyroid carcinoma, whose morphology is identical to that of familial adenomatous polyposis (FAP)-associated thyroid carcinoma. Furthermore, the single reported case of lung cancer associated with FAP was L-FLAC/WDFA. These observations lead us to hypothesize that up-regulation of the Wnt signaling pathway underlies the development of L-FLAC/WDFA. To verify this hypothesis, 11 cases of L-FLAC/WDFA, including the one FAP-associated case, eight cases of high-grade adenocarcinoma of the fetal lung type (H-FLAC), 24 cases of conventional pulmonary adenocarcinoma (CAC), and 13 fetal lungs were immunostained for beta-catenin. All cases of L-FLAC/WDFA showed predominantly aberrant nuclear/cytoplasmic expression, especially in budding glands and morules, whereas six of eight cases (75%) of H-FLAC and all but one case (96%) of CAC showed predominantly membranous expression. Fetal lungs showed nuclear/cytoplasmic expression restricted to the distal branching airway epithelium. Mutational analysis of exon 3 of the beta-catenin gene in five sporadic cases of L-FLAC/WDFA showed a point mutation at codon 34 and codon 37 in two cases, respectively. The present study indicates that up-regulating disturbances in the Wnt signaling pathway, including mutation of the beta-catenin gene, underlie tumorigenesis of L-FLAC/WDFA. The expression pattern of beta-catenin in L-FLAC/WDFA resembles that of the developing fetal lung airway. With the expression pattern of beta-catenin as a marker, most cases of H-FLAC as well as CAC appear to have different oncogenic pathways from cases of L-FLAC/WDFA. The present study together with other available data also suggests that abnormal up-regulation of the Wnt signaling pathway may be a common denominator for the development of tumors with morular formation from a variety of anatomic sites.