Subcellular Compartmentalization of Survivin is Associated with Biological Aggressiveness and Prognosis in Prostate Cancer

Abstract

the role of subcellular survivin compartmentalization in the biology and prognosis of prostate cancer is unclear. We therefore investigated subcellular localization of survivin in more than 3000 prostate cancer patients by quantitative immunohistochemistry and performed transcriptomics of 250 prostate cancer patients and healthy donors using publicly available datasets. Survivin (BIRC5) gene expression was increased in primary prostate cancers and metastases, but did not differ in recurrent vs non-recurrent prostate cancers. Survivin immunohistochemistry (IHC) staining was limited exclusively to the nucleus in 900 prostate cancers (40.0%), and accompanied by various levels of cytoplasmic positivity in 1338 tumors (59.4%). 0.5% of prostate cancers did not express survivin. Nuclear and cytoplasmic survivin staining intensities were strongly associated with each other, pT category, and higher Gleason scores. cytoplasmic but not nuclear survivin staining correlated with high tumor cell proliferation in prostate cancers. Strong cytoplasmic survivin staining, but not nuclear staining predicted an unfavorable outcome in univariate analyses. Multivariate Cox regression analysis showed that survivin is not an independent prognostic marker. In conclusion, we provide evidence that survivin expression is increased in prostate cancers, especially in metastatic disease, resulting in higher aggressiveness and tumor progression. In addition, subcellular compartmentalization is an important aspect of survivin cancer biology, as only cytoplasmic, but not nuclear survivin accumulation is linked to biological aggressiveness and prognosis of prostate cancers.

BIRC3 and BIRC5: multi‐faceted inhibitors in cancer

“…Higher expression in HGG [ 3 , 12 , 56 ] Breast cancer Pro-oncogenic: antiapoptotic, chemoresistance [ 57 – 62 ] Breast cancer Oncosuppressive: high expression correlates to drug sensitivity [ 2 ] BIRC5 Lung, pancreatic, breast, ovarian, brain, colon cancer Pro-oncogenic [ 63 – 65 ] B-cell acute lymphoblastic leukemia, B-cell lymphoma and T-cell leukemia/lymphoma Pro-oncogenic [ 66 – 68 ] Hepatocellular carcinoma (HCC) Pro-oncogenic: high expression correlates to lower survival [ 70 ] Gastrointestinal stromal tumors (GIST) Pro-oncogenic: high expression correlates to lower survival [ 71 ] Prostate cancer Pro-oncogenic: high expression correlates to p53 mutations and metastases. Cytoplasmic localization associates to an aggressive disease [ 72 , 74 ] Gioma, astrocytoma, glioblastoma, medulloblastoma Pro-oncogenic: anti-apoptotic function. High expression correlates to lower short-term and long-term survival.…”

“…A significant subset of prostate cancer patients display mutated p53 and is characterized by tumor aggressiveness and significantly increased risk of progression after radical prostatectomy [ 73 ]. Recent data obtained on a very large number of prostate cancer samples demonstrate that BIRC5 mRNA increased in prostate cancer and prostate cancer metastases compared to tissues from healthy donors or from adjacent normal prostate tissues combined [ 74 ]. Interestingly, from the same study emerges that cytoplasmic localization is associated to an aggressive disease (higher Gleason score), higher pathological tumor stage and higher Ki67 proliferative index.…”

“…The resulting heterodimers facilitate anti-proteasomal stability and inhibition of caspase-mediated apoptosis, thereby promoting tumor growth and survival (Fig. 4 ) [ 74 ].…”

“…Higher expression in HGG Gastrointestinal stromal tumors (GIST) Pro-oncogenic: high expression correlates to lower survival [71] Prostate cancer Pro-oncogenic: high expression correlates to p53 mutations and metastases. Cytoplasmic localization associates to an aggressive disease [72,74] Gioma, astrocytoma, glioblastoma, medulloblastoma Pro-oncogenic: anti-apoptotic function. High expression correlates to lower short-term and long-term survival.…”

Comprehensive analyses reveal three-gene signatures in ovarian cancer

“…Survivin is highly expressed in a variety of cancer tissues compared to normal tissues. It was reported that expression level of survivin (BIRC5) gene is signi cantly increased in primary prostate cancers and metastases, but there is no difference between recurrent and non-recurrent prostate cancer [7]. The chemokine ligand 13 (CXCL13) and its chemokine receptor 5 (CXCR5) play fundamental roles in in ammatory, infectious and immune responses.…”