Shou Chew

Chuandong Geng, B. He, Limei Xu, C. Barbieri, V. Eedunuri, Sue Anne Chew, M. Zimmermann, Richard Bond, John Shou, Chao Li, Mirjam Blattner, D. Lonard, F. Demichelis, C. Coarfa, M. Rubin, Peng-fei Zhou, B. O’Malley, N. Mitsiades

Chuandong Geng, K. Rajapakshe, Shrijal S Shah, John Shou, V. Eedunuri, Christopher Foley, W. Fiskus, M. Rajendran, Sue Anne Chew, M. Zimmermann, Richard Bond, B. He, C. Coarfa, N. Mitsiades

Somatic missense mutations in the substrate-binding pocket of the E3 ubiquitin ligase adaptor SPOP are present in up to 15% of human prostate adenocarcinomas (PC), but are rare in other malignancies suggesting a prostate-specific mechanism of action. SPOP promotes ubiquitination and degradation of several protein substrates, including the androgen receptor (AR) coactivator factor SRC-3. However, the relative contributions that SPOP substrates may contribute to the pathophysiology of SPOP-mutant (mt) PC is unknown. Using an unbiased bioinformatics approach, we determined that the gene expression profile of PC cells engineered to express mt-SPOP overlaps greatly with the gene signature of both SRC-3 and AR transcriptional output, with a stronger effect on AR than SRC-3. This finding suggests that in addition to its SRC-3-mediated effects, SPOP also exerts SRC-3-independent effects that are AR mediated. Indeed, we found that wild-type (wt) but not PC-associated mutants of SPOP promoted AR ubiquitination and degradation, acting directly through a SPOP-binding motif in the hinge region of AR. In support of these results, tumor xenografts composed of PC cells expressing mt-SPOP expressed higher AR protein levels and grew faster than tumors composed of PC cells expressing wt-SPOP. Further, genetic ablation of SPOP was sufficient to increase AR protein levels in mouse prostate. Examination of public human PC datasets confirmed a strong link between transcriptomic profiles of mt-SPOP and AR. Overall, our studies highlight the AR axis as the key transcriptional output of SPOP in PC, and they provide an explanation for the prostate-specific tumor suppressor role of wt-SPOP.

B. He, R. Lanz, W. Fiskus, Chuandong Geng, P. Yi, Sean M. Hartig, K. Rajapakshe, John Shou, Liping Wei, Shrijal S Shah, Christopher Foley, Sue Anne Chew, V. Eedunuri, D. Bedoya, Qin Feng, T. Minami, C. Mitsiades, A. Frolov, N. Weigel, S. Hilsenbeck, D. Rosen, T. Palzkill, M. Ittmann, Yongcheng Song, C. Coarfa, B. O’Malley, N. Mitsiades

Shou-Lun Lee, G. Chau, C. Yao, Chew‐Wun Wu, S. Yin

Chew‐Wun Wu, Jeng-Min Chiou, Feng-shou Ko, S. Lo, J. Chen, Wing-Yiu Lui, Jacqueline Whang-Peng

Quality of life (QOL) was studied in gastric cancer patients treated on a randomised, controlled trial comparing D1 (level 1) with D3 (levels 1, 2 and 3) lymphadenectomy. A total of 221 patients were randomly assigned to D1 (n=110) and D3 (n=111) surgery. Quality-of-life assessments included functional outcomes (a 14-item survey about treatment-specific symptoms) and health perception (Spitzer QOL Index) was performed before and after surgery at disease-free status. Patients suffered from irrelative events such as loss of partners was excluded thereafter. Main analyses were done by intention-to-treat. Thus, 214 D1 (106/110=96.4%) and D3 (108/111=97.3%) R0 patients were assessed. Longitudinal analysis showed that functional outcomes decreased at 6 months after surgery and increased over time thereafter, while health perceptions increased over time in general. On the basis of linear mixed model analyses, patients having total gastrectomy, advanced cancer and hemipancreaticosplenectomy, but not complications had poorer QOL than those without. D1 and D3 patients showed no significant difference in QOL. The results suggest that changes of QOL were largely due to scope of gastric resection, disease status and distal pancreaticosplenectomy, rather than the extent of lymph node dissection. This indicates that nodal dissection can be performed for a potentially curable gastric cancer.