SHCBP1 promotes tumor cell proliferation, migration, and invasion, and is associated with poor prostate cancer prognosis.

OBJECTIVE: Prostate cancer (PCa) is an aggressive tumor. SHC SH2-domain-binding protein 1 (SHCBP1) has been identified frequently upregulated in various cancers, in addition to PCa. The aims of this study were to determine the relationships between SHCBP1 and clinicopathological characteristics of PCa and to explore the role of SHCBP1 in PCa proliferation and progression. METHODS: Tissue microarray and immunohistochemistry were used to determine the prognostic significance of SHCBP1. The relationship between clinicopathological characteristics of PCa and SHCBP1 was then analyzed using Cox regression analyses. To investigate SHCBP1 functions in vitro and in vivo, we knocked down SHCBP1 in PCa cell lines and established xenograft mice models. A series of cytological function assays were utilized to determine the role of SHCBP1 in cell proliferation, migration, invasion, and apoptosis. RESULTS: SHCBP1 was significantly upregulated in PCa tissues compared with BPH tissues. Patients with a higher expression of SHCBP1 were associated with poor survival outcomes than those with a lower expression of SHCBP1. Lentivirus-mediated shRNA knockdown of SHCBP1 in prostate cancer cell lines diminished cell growth, migration, and invasion dramatically both in vitro and in vivo, accompanied by an enhanced expression of large tumor suppressor 1 (LATS1) and tumor protein P53 (TP53) and inhibition of MDM2 proto-oncogene (MDM2), which suggested that SHCBP1 may promote proliferation and invasion in vitro via the LATS1-MDM2-TP53 pathway. The results of cycloheximide (CHX) and MG-132 assays indicated that SHCBP1 knockdown could attenuate the degradation of TP53 by the proteasome, prolong the half-life of TP53, and enhance the stabilization of TP53. CONCLUSION: These findings suggest that SHCBP1 overexpression contributes to PCa progression and that targeting SHCBP1 might be therapeutically beneficial to patients with PCa.

Bladder cancer cell­secreted exosomal miR­21 activates the PI3K/AKT pathway in macrophages to promote cancer progression.

Tumour­associated macrophages (TAMs) compose a major component of the tumour microenvironment and form in this microenvironment prior to cancer metastasis. However, the detailed mechanisms of TAM remodelling in the context of bladder cancer have not been clearly defined. The present study collected exosomes from the conditioned medium of human bladder T24 cancer cells. The effects of macrophages treated with exosomes derived from T24 cells on bladder cancer cell migration and invasion were analysed by Transwell assays. The expression levels of endogenous and exosomal microRNA­21 (miR­21) were examined by reverse transcription­quantitative PCR, while the expression level of the target protein was analysed by western blot analysis. Luciferase reporter plasmids and mutants were used to confirm direct targeting. The effects of miR­21 on bladder cancer cell migration and invasion were analysed by Transwell and Matrigel assays following miR­21 transfection. It was identified that exosomes derived from bladder cancer cells polarized THP­1 cell­derived macrophages into the M2 phenotype, and TAM­mediated pro­migratory and pro­invasive activity was determined. Moreover, it was found that miR­21 was highly expressed in exosomes derived from bladder cancer cells as well as in macrophages treated with exosomes. In addition, macrophages transfected with miR­21 exhibited M2 polarization and promoted T24 cell migratory and invasive ability. Mechanistically, exosomal miR­21 derived from bladder cancer cells inhibited phosphatase and tensin homolog activation of the PI3K/AKT signalling pathway in macrophages and enhanced STAT3 expression to promote M2 phenotypic polarization. The present results suggest that exosomal miR­21 can promote cancer progression by polarizing TAMs.

Molecular network-based identification of competing endogenous RNAs and mRNA signatures that predict survival in prostate cancer.

BACKGROUND: The aim of the study is described the regulatory mechanisms and prognostic values of differentially expressed RNAs in prostate cancer and construct an mRNA signature that predicts survival. METHODS: The RNA profiles of 499 prostate cancer tissues and 52 non-prostate cancer tissues from TCGA were analyzed. The differential expression of RNAs was examined using the edgeR package. Survival was analyzed by Kaplan-Meier method. microRNA (miRNA), messenger RNA (mRNA), and long non-coding RNA (lncRNA) networks from the miRcode database were constructed, based on the differentially expressed RNAs between non-prostate and prostate cancer tissues. RESULTS: A total of 773 lncRNAs, 1417 mRNAs, and 58 miRNAs were differentially expressed between non-prostate and prostate cancer samples. The newly constructed ceRNA network comprised 63 prostate cancer-specific lncRNAs, 13 miRNAs, and 18 mRNAs. Three of 63 differentially expressed lncRNAs and 1 of 18 differentially expressed mRNAs were significantly associated with overall survival in prostate cancer (P value < 0.05). After the univariate and multivariate Cox regression analyses, 4 mRNAs (HOXB5, GPC2, PGA5, and AMBN) were screened and used to establish a predictive model for the overall survival of patients. Our ROC curve analysis revealed that the 4-mRNA signature performed well. CONCLUSION: These ceRNAs may play a critical role in the progression and metastasis of prostate cancer and are thus candidate therapeutic targets and potential prognostic biomarkers. A novel model that incorporated these candidates was established and might provide more powerful prognostic information in predicting survival in prostate cancer.

Activation of a c-Jun N-terminal kinase-mediated autophagy pathway attenuates the anticancer activity of gemcitabine in human bladder cancer cells.

The role of autophagy in the anticancer activity of gemcitabine (GEM) in bladder cancer is unclear. The aim of this study is to determine whether GEM activates autophagy, the role of autophagy in the anticancer activity of GEM, and the underlying mechanism by which GEM induces autophagy. Human bladder cancer cell lines T24 and BIU87 were treated with GEM in vitro. Cell viability was measured using the Cell Counting Kit-8 assay. Apoptosis was detected by annexin V assay and western blot. Autophagy was measured by western blot and transmission electron microscopy. c-Jun N-terminal kinase (JNK) activation was detected by western blot. Chemical inhibitors were used for intervention of JNK and autophagy. GEM killed bladder cancer cells, which was associated with apoptosis induction. Autophagy was effectively activated by GEM. Suppressing autophagy in GEM-treated cells significantly decreased cell viability, which was associated with increased apoptosis. GEM-induced JNK activation and suppressed B-cell lymphoma 2 expression. The JNK inhibitor SP600125 inhibited GEM-induced autophagy activation and increased GEM's cytotoxicity. GEM kills bladder cancer cells through apoptosis. Meanwhile, JNK-mediated autophagy was activated, which protects the cells against apoptosis. Therefore, inhibition of autophagy could be exploited to enhance the anticancer efficacy of GEM for treating bladder cancer.