PSA time to nadir as a prognostic factor of first-line docetaxel treatment in castration-resistant prostate cancer: Evidence from patients in Northwestern China / 亚洲男科学杂志(英文版)

Docetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) in China; however, the prognostic factors associated with effects in these patients are still controversial. In this study, we retrospectively reviewed the data from 71 eligible Chinese patients who received docetaxel chemotherapy from 2009 to 2016 in our hospital and experienced a reduction of prostate-specific antigen (PSA) level ≥50% during the treatment and investigated the potential role of time to nadir (TTN) of PSA. TTN was defined as the time from start of chemotherapy to the nadir of PSA level during the treatment. Multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS). In these patients, the median of TTN was 17 weeks. Patients with TTN ≥17 weeks had a longer response time to chemotherapy compared to TTN 50% PSA remission.

PSA time to nadir as a prognostic factor of first-line docetaxel treatment in castration-resistant prostate cancer: evidence from patients in Northwestern China / 亚洲男科学杂志(英文版)

Docetaxel-based chemotherapy remains the first-line treatment for patients with metastatic castration-resistant prostate cancer (mCRPC) in China; however, the prognostic factors associated with effects in these patients are still controversial. In this study, we retrospectively reviewed the data from 71 eligible Chinese patients who received docetaxel chemotherapy from 2009 to 2016 in our hospital and experienced a reduction of prostate-specific antigen (PSA) level ≥50% during the treatment and investigated the potential role of time to nadir (TTN) of PSA. TTN was defined as the time from start of chemotherapy to the nadir of PSA level during the treatment. Multivariable Cox regression models and Kaplan-Meier analysis were used to predict overall survival (OS). In these patients, the median of TTN was 17 weeks. Patients with TTN ≥17 weeks had a longer response time to chemotherapy compared to TTN <17 weeks (42.83 vs 21.50 weeks, P < 0.001). The time to PSA progression in patients with TTN ≥17 weeks was 11.44 weeks compared to 5.63 weeks when TTN was <17 weeks. We found several factors to be associated with OS, including TTN (hazard ratio [HR]: 3.937, 95% confidence interval [CI]: 1.502-10.309, P = 0.005), PSA level at the diagnosis of cancer (HR: 4.337, 95% CI: 1.616-11.645, P = 0.004), duration of initial androgen deprivation therapy (HR: 2.982, 95% CI: 1.104-8.045, P = 0.031), neutrophil-to-lymphocyte ratio (HR: 3.963, 95% CI: 1.380-11.384, P = 0.011), and total PSA response (Class 1 [<0 response] compared to Class 2 [0-50% response], HR: 3.978, 95% CI: 1.278-12.387, P = 0.017). In conclusion, TTN of PSA remains an important prognostic marker in predicting therapeutic outcome in Chinese population who receive chemotherapy for mCRPC and have >50% PSA remission.

Regulatory effect of Skp2 on the expression and transactivation of the androgen receptor in the progression of castration-resistant prostate cancer / 中华男科学杂志

<p><b>OBJECTIVE</b>To determine the expression of Skp2 in different prostate cancer (PCa) cell lines and tissues, and explore its influence on the androgen receptor (AR) signaling pathway and development of castration-resistant prostate cancer (CRPC).</p><p><b>METHODS</b>The expression levels of Skp2 and AR in different PCa cell lines were detected by Western blot. After knockdown of Skp2 in the C4-2 and 22RV1 cells transfected with shRNA, the expressions of AR and P27 were determined and the activity of ARR3-Luc measured by dual-luciferase reporter gene assay following treatment with dihydrotestosterone (DHT). The expressions of AR and Skp2 in human naïve PCa or CRPC specimens were detected by immunohistochemical staining followed by analysis of their differences and correlation.</p><p><b>RESULTS</b>The Skp2 protein expression level was significantly higher in the C4-2 or 22RV1 cells than in the LNCaP cells. DHT treatment increased the expression of Skp2 in the C4-2 cells, but knock-down of Skp2 significantly up-regulated the expression of the well-known downstream protein P27 and down-regulated that of AR. Consistently, DHT treatment increased the activity of ARR3-Luc, while knockdown of Skp2 remarkably decreased it in the C4-2 and 22RV1 cells (P < 0.05). In addition, significantly higher expressions of Skp2 and AR were observed in the CRPC than in the naïve specimens (P < 0.05), with a positive correlation between the two proteins (r = 0.658 1, P < 0.05).</p><p><b>CONCLUSION</b>Skp2 can enhance the expression and transcription activity of the AR protein in CRPC cells or tissues and is promising to be a critical molecular therapeutic target.</p>

Changes of intracellular cholesterol metabolism in neuroendocrine differentiation of prostate cancer and their significance / 中华男科学杂志

<p><b>OBJECTIVE</b>To explore the roles of intracellular cholesterol metabolism in neuroendocrine (NE) differentiation of prostate cancer based on an androgen-independent prostate cancer NE cell model induced by androgen deprivation.</p><p><b>METHODS</b>LNCaP cells were cultured in androgen-depleted medium, and NE phenotypes were identified by observing the changes in cell morphology, molecular markers (SgIII, NSE and CgA) and cell proliferation. The expression and distribution of cholesterol and Sg III were determined by immunofluorescence staining. The expressions of the key genes LDL-R, SREBP-1 and SREBP-2 involved in cholesterol synthesis and uptake were detected by semi-quantitative RT-PCR.</p><p><b>RESULTS</b>The LNCaP cells showed shrinking bodies and extending axons after androgen deprivation, and all the molecular markers, such as Sg III, NSE and CgA, significantly increased in a time-dependent manner, while the cell proliferation was obviously inhibited (P < 0.05). The cholesterol distribution in the LNCaP cells after NE differentiation presented remarkable aggregation at the axon terminals. However, there were no significant differences in the expression of cholesterol between the two types of cells, nor in the changes of the expressions of key genes LDL-R, SREBP-1 and SREBP-2 involved in cholesterol synthesis and uptake (P > 0.05).</p><p><b>CONCLUSION</b>Transient androgen depletion could successfully induce NE differentiation of LNCaP cells, and the intracellular cholesterol could re-distribute into axon terminals to enhance the formation of neurosecretory granules.</p>

Advances in the studies of androgen metabolism and de novo androgen synthesis in castration resistant prostate cancer / 中华男科学杂志

Prostate cancer generally relapses into castration resistant prostate cancer (CRPC) after androgen deprivation therapy, which may be associated with androgen metabolism, particularly de novo androgen synthesis apart from the amplification and mutation of androgen receptor and the activation of its signaling pathways. This article focuses on the advances in the studies of the changes in androgen metabolism and de novo androgen synthesis in CRPC as well as their possible mechanisms and clinical significance.

Epithelial-mesenchymal transition and human fetal prostate development / 中华男科学杂志

<p><b>OBJECTIVE</b>To investigate the role and significance of epithelial-mesenchymal transition (EMT) and its transcriptional regulator Twist1 in the development of the human fetal prostate.</p><p><b>METHODS</b>Twenty-five human fetal prostate specimens at various developmental stages (16-39 weeks) were included in this study. EMT markers, such as E-Cadherin, N-Cadherin and Vimentin, and EMT transcriptional regulator Twist1 were determined by immunohistochemistry, and their relationship with the development of the human fetal prostate was analyzed.</p><p><b>RESULTS</b>E-Cadherin was expressed in the fetal prostate epithelium only, while Vimentin, N-Cadherin and Twist1 in both the epithelium and the stroma. The expression of E-Cadherin gradually increased, but those of Vimentin, N-Cadherin and Twist1 gradually decreased with the gestation stages. No significant changes were observed in the staining patterns of Vimentin, N-Cadherin and Twist1 in the stroma during the whole developmental process.</p><p><b>CONCLUSION</b>EMT is involved in the development of the human fetal prostate, which may promote epithelial cell motility to form prostatic bud tubules in early gestation stages and boost the differentiation of prostate epithelia in later stages.</p>

Comparison of transcription factors repressing epithelial phenotype in two different prostate cancer EMT models and its significance / 中华男科学杂志

<p><b>OBJECTIVE</b>To screen and compare the specific transcription factors that repress the epithelial phenotype in epithelial-mesenchymal transition (EMT) in two different human prostate cancer models LNCaP/HIF1alpha and ARCaP.</p><p><b>METHODS</b>We established two different prostate cancer EMT models, LNCaP/HIF1alpha and ARCaP, cultured LNCaP, LNCaP/HIF1alpha, IF11 and IA8 cells in vitro, and detected the five transcription factors Snail, Slug, ZEB1, SIP1 and Twist1 in these cells by RT-PCR.</p><p><b>RESULTS</b>Different levels of Snail, Slug, ZEB1, SIP1 and Twist1 were detected in both LNCaP and LNCaP/HIF1alpha cells, with significant differences only in the expressions of Slug and Twist1 between the two cells. The expression of Slug was increased, but that of Twist1 decreased in the LNCaP/HIF1alpha cells. All the five transcription factors but Twist1 were expressed in both the IF11 and IA8 cells, but only the express- sions of ZEB1 and Slug were increased significantly in the IA8 cells.</p><p><b>CONCLUSION</b>There are different mechanisms underlying transcriptional regulation in different prostate cancer EMT models. Slug may be one of the key transcription factors involved in the HIF1alpha-induced EMT of LNCaP cells, while ZEB1 and Slug may play an important role in repressing the epithelial phenotype of the ARCaP model.</p>

Expression of Smad4 in prostate cancer LNCaP and ARCaP cell lines with different metastatic potentials and its significance / 中华男科学杂志

<p><b>OBJECTIVE</b>To observe the expression of Smad4, the core of TGF-beta/Smads signal transduction pathway in different prostate cancer cell lines, and explore their molecular mechanism of bone metastatic potential.</p><p><b>METHODS</b>The Millicell polycarbonate filter coated with matrigel was used to confirm the invasive potency of LNCaP and ARCaP cell lines (IF11 and IA8). The expressions of the Smad4 protein and mRNA in these prostate cancer cells with different metastatic potentials were detected by Western blotting and RT-PCR, respectively.</p><p><b>RESULTS</b>ARCaP cell lines (IF11 and IA8) exhibited a stronger potency of invasion than LNCaP (P < 0.01). The Smad4 protein and mRNA highly expressed in the LNCaP cell line that was well-known with a low metastatic potential, but not in the ARCaP (IF11 or IA8) cells with high metastatic potentials (P < 0.01).</p><p><b>CONCLUSION</b>Smad4 expresses differently in LNCaP and ARCaP cell lines with different metastatic potentials and, as a tumor suppressive gene, its deficient expression may play an important role in the invasion and metastasis of advanced prostate cancer.</p>

Identification of TGF-beta/Smads pathway in human prostate cancer cell lines and its significance / 中华男科学杂志

<p><b>OBJECTIVE</b>To determine the TGF-beta/Smads signal pathway in different human prostate cancer cell lines, and to explore the role of the TGF-beta/Smads pathway in the progression and metastasis of prostate cancer and its possible mechanisms.</p><p><b>METHODS</b>We detected the expressions of the key proteins involved in the TGF-beta/Smads pathway, TbetaR II, Smad2/3, p-Smad2 and Smad4, in prostate cancer cell lines LNCaP, PC-3, DU145, IF11 and IA8 with different metastatic potentials by Western blotting.</p><p><b>RESULTS</b>TbetaR II was expressed highly in PC-3, DU145, IF11 and IA8, but extremely lowly in LNCaP. Smad2/3 was highly expressed in all the cell lines with different intensity, while p-Smad2 only in PC-3 and DU145. The expression of Smad4 was detected in LNCaP, PC-3 and DU145, but not in IF11 and IA8.</p><p><b>CONCLUSION</b>The status of the TGF-beta/Smads pathway differs in the cell lines with different metastatic potentials, only active in PC-3 and DU145. The TGF-beta/Smads pathway may be involved in the invasion and metastasis of prostate cancer through altering the expressions of the key proteins in it.</p>

Transforming growth factor beta upregulates the expression of invasion and metastasis associated proteins in prostate cancer LNCaP cell lines in vitro / 中华男科学杂志

<p><b>OBJECTIVE</b>To determine the effect of the transforming growth factor beta (TGF-beta) on the expression of invasion and metastasis associated proteins in the prostate cancer LNCaP cell line in vitro.</p><p><b>METHODS</b>The prostate cancer cell line LNCaP was treated with TGF-beta in vitro. Western blotting was used to detect the expression of the "invasion and metastasis" associated proteins E-Cadherin, N-Cadherin and Vimentin.</p><p><b>RESULTS</b>The expression of N-Cadherin and Vimentin of the LNCaP cells treated with TGF-beta for 12 hours was significantly upregulated, but not that of E-Cadherin.</p><p><b>CONCLUSION</b>TGF-beta may induce epithelial-mesenchymal transition (EMT) of LNCaP cells which might be of importance in promoting prostate cancer cells invading to ambient tissues and metastasizing to distant organs.</p>