Role of galectin-1 in urinary bladder urothelial carcinoma cell invasion through the JNK pathway.

Human galectin-1 is a member of the galectin family, proteins with conserved carbohydrate-recognition domains that bind galactoside. Galectin-1 is highly expressed in various tumors and participates in various oncogenic processes. However, detailed descriptions of the function of galectin-1 in urinary bladder urothelial carcinoma have not been reported. Our previous cohort investigation showed that galectin-1 is associated with tumor invasiveness and is a possible independent prognostic marker of urinary bladder urothelial carcinoma. The present study aimed to clarify the relevance of galectin-1 expression level to tumor progression and invasion. In order to decipher a mechanism for the contribution of galectin-1 to the malignant behavior of urinary bladder urothelial carcinoma, two bladder cancer cell lines (T24 and J82) were established with knockdown of galectin-1 expression by shRNA. Bladder cancer cells with LGALS1 gene silencing showed reduced cell proliferation, lower invasive capability, and lower clonogenicity. Extensive signaling pathway studies indicated that galectin-1 participated in bladder cancer cell invasion by mediating the activity of MMP9 through the Ras-Rac1-MEKK4-JNK-AP1 signaling pathway. Our functional analyses of galectin-1 in urinary bladder urothelial carcinoma provided novel insights into the critical role of galectin-1 in tumor progression and invasion. These results revealed that silencing the galectin-1-mediated MAPK signaling pathway presented a novel strategy for bladder cancer therapy.

Galectin-1 dysregulation independently predicts disease specific survival in bladder urothelial carcinoma.

PURPOSE: Galectin-1 is highly expressed in various tumors and participates in various oncogenic processes. Our previous proteomics investigation demonstrated that galectin-1 is up-regulated in high compared to nonhigh grade lesions. Thus, in the current cohort study we clarified the correlation of galectin-1 over expression with various clinicopathological features and prognosis. MATERIALS AND METHODS: We selected 185 cases of consecutively treated primary localized bladder urothelial carcinoma for study. Transurethral resection of bladder tumor was performed in all patients followed by radical cystectomy in those with T2 to T4 tumors. Pathological slides were examined to determine cytoplasmic galectin-1 immuno-expression and correlate galectin-1 dysregulation with various clinicopathological factors and disease specific survival. RESULTS: Positive galectin-1 immuno-expression in tumors was significantly linked to pT status (p = 0.0295), histological grade (p = 0.037), vascular invasion (p = 0.0287) and nodal status (p = 0.0012). Galectin-1 over expression in tumors significantly predicted disease specific survival at the univariate (p = 0.0002) and multivariate levels (p = 0.03, HR 2.438, 95% CI 1.090-5.451). In situ hybridization indicated that the LGALS1 gene was amplified in 43 specimens in an independent cohort of 56 snap frozen tumor specimens. Association analysis showed that an increased LGALS1 mRNA level was linked to bladder urothelial carcinoma invasiveness (p = 0.016) and LGALS1 gene amplification was significantly associated the amount of GAL-1 protein in tumors (p <0.0001). On the univariate level gene amplification was also closely linked to disease specific survival (p = 0.0006). CONCLUSIONS: These results reveal that galectin-1 over expression is a possible independent factor for bladder cancer prognosis.

HuR cytoplasmic expression is associated with increased cyclin A expression and poor outcome with upper urinary tract urothelial carcinoma.

BACKGROUND: HuR is an RNA-binding protein that post-transcriptionally modulates the expressions of various target genes implicated in carcinogenesis, such as CCNA2 encoding cyclin A. No prior study attempted to evaluate the significance of HuR expression in a large cohort with upper urinary tract urothelial carcinomas (UTUCs). METHODS: In total, 340 cases of primary localized UTUC without previous or concordant bladder carcinoma were selected. All of these patients received ureterectomy or radical nephroureterectomy with curative intents. Pathological slides were reviewed, and clinical findings were collected. Immunostaining for HuR and cyclin A was performed and evaluated by using H-score. The results of cytoplasmic HuR and nuclear cyclin A expressions were correlated with disease-specific survival (DSS), metastasis-free survival (MeFS), urinary bladder recurrence-free survival (UBRFS), and various clinicopathological factors. RESULTS: HuR cytoplasmic expression was significantly related to the pT status, lymph node metastasis, a higher histological grade, the pattern of invasion, vascular and perineurial invasion, and cyclin A expression (p = 0.005). Importantly, HuR cytoplasmic expression was strongly associated with a worse DSS (p < 0.0001), MeFS (p < 0.0001), and UBRFS (p = 0.0370) in the univariate analysis, and the first two results remained independently predictive of adverse outcomes (p = 0.038, relative risk [RR] = 1.996 for DSS; p = 0.027, RR = 1.880 for MeFS). Cyclin A nuclear expression was associated with a poor DSS (p = 0.0035) and MeFS (p = 0.0015) in the univariate analysis but was not prognosticatory in the multivariate analyses. High-risk patients (pT3 or pT4 with/without nodal metastasis) with high HuR cytoplasmic expression had better DSS if adjuvant chemotherapy was performed (p = 0.015). CONCLUSIONS: HuR cytoplasmic expression was correlated with adverse phenotypes and cyclin A overexpression and also independently predictive of worse DSS and MeFS, suggesting its roles in tumorigenesis or carcinogenesis and potentiality as a prognostic marker of UTUC. High HuR cytoplasmic expression might identify patients more likely to be beneficial for adjuvant chemotherapy.

Primary urothelial carcinoma of the upper tract: important clinicopathological factors predicting bladder recurrence after surgical resection.

The aim of the present study was to further characterize potential clinicopathological predictors for urinary bladder recurrence-free survival (UBRFS) in patients with primary urothelial carcinoma of the upper urinary tract (UUT-UC). The present series included 385 cases of surgically treated primary localized UUT-UC without previous or concurrent urothelial carcinoma of the urinary bladder. Among the 374 patients with follow-up information, clinicopathological features and therapeutic information including whether they received a laparoscopy-assisted nephroureterectomy (LNU) and adjuvant chemotherapy were correlated with UBRFS. After a median follow up of 69 months, 86 patients (23%) developed urinary bladder recurrence. The median time to develop urinary bladder recurrence was 12 months. At the univariate level, an increment in histological grade (P= 0.0321), a prominent papillary configuration (P= 0.0004), LNU (P= 0.0397) and male gender (P= 0.0401) significantly predicted an inferior UBRFS. At the multivariate level, increase of histological grade (P < 0.0001, relative risk (RR) = 3.776), prominent papillary configuration (P < 0.0001, RR = 3.244), and male gender (P= 0.0463, RR = 1.444) independently predicted UBRFS. In conclusion, male patients and those with high-grade and papillary UUT-UC, and who received LNU had higher risks of urinary bladder recurrence. Accordingly, for these patients, more intensive follow up coupled with postoperative intravesical adjuvant therapy to prevent urinary bladder recurrence should also be considered.

Malignant Peripheral Nerve Sheath Tumor of Prostate: A Rare Case Report and Literature Review.

A mid-aged male presented with progressive lower urinary tract symptoms (LUTS) for years. Huge prostate with low serum prostate-specific antigen (PSA) level was detected. The specimen from transurethral resection revealed surprising pathology finding as malignant peripheral nerve sheath tumor (MPNST). Considering its huge size (more than 300 gm) and location, we prescribed neoadjuvant chemotherapy firstly. The tumor became regressive and then radical surgical resection was achieved. Adjuvant multimodality treatment including concurrent chemoradiotherapy (CCRT) and target therapy was given. However, he expired about one year later. MPNST originating from prostate is very rare and seldom reported before. We here present this extremely rare disease and share our treatment experience.

Laparoscopy-assisted transvaginal total exenteration for locally advanced cervical cancer with bladder invasion after radiotherapy.

When invasive cervical cancer involves the urinary bladder or rectum, exenteration can be curative treatment. However, this operation, particularly by an open approach, carries significant morbidity, both physically and psychologically. Laparoscopic surgery has been documented to be a reasonable alternative to the open counterpart for a variety of pelvic operative procedures, including such advanced procedures as laparoscopy-assisted vaginal hysterectomy, total laparoscopic hysterectomy, and laparoscopy radical hysterectomy. With improving surgical technology and increasing surgical experience, exenteration is a logical extension of current laparoscopic practice. However, it raises skepticism regarding the feasibility and justification for the complicated surgery. We herein describe our experience in a patient undergoing total exenteration assisted by laparoscopic technology for advanced recurrent cervical cancer after extensive radiotherapy. Transperitoneal laparoscopic total exenteration with ureterosigmoidstomy and end-sigmoidostomy was accomplished in 6 hours. The whole specimen was removed en bloc transvaginally. The patient tolerated the procedure well. The only complication was a wound infection 50 days postoperatively that was controlled with debridement and antibiotics. No episodes of pyelonephritis occurred. After 1 year of follow-up, the patient is free of cancer by imaging studies and lives without associated morbidity of this extensive palliative operation except the care of the sigmoid colostomy.

IGFBP-5 overexpression as a poor prognostic factor in patients with urothelial carcinomas of upper urinary tracts and urinary bladder.

BACKGROUND: Urothelial carcinoma (UC) is prevalent worldwide. Dysregulation of cell growth is a critical event of tumorigenesis and has not been assessed systemically in UC. We thus assessed the published transcriptome of urinary bladder urothelial carcinoma (UBUC) and identified insulin-like growth factor-binding protein-5 (IGFBP-5) as the most significantly upregulated gene associated with the regulation of cell growth. Moreover, validated by using public domain data set, IGFBP-5 expression also significantly predicted worse outcome. IGFBP-5 is one of the binding proteins that regulate insulin-like growth factors (IGFs) and its significance has not been comprehensively evaluated in UCs. METHODS: Using immunohistochemistry, we evaluated the IGFBP-5 expression status and its associations with clinicopathological features and survival in 340 cases of upper urinary tract urothelial carcinoma (UTUC) and 295 cases of UBUC. Western blot analysis was used to evaluate IGFBP-5 protein expression in human urothelial cell (HUC) lines. RESULTS: IGFBP-5 overexpression was significantly associated with advanced pT stage (p<0.001), high histological grade (UTUC, p<0.001; UBUC, p=0.035), lymph node metastasis (UTUC, p=0.006; UBUC, p=0.004), vascular invasion (UTUC, p<0.001; UBUC, p=0.003), perineural invasion (UTUC, p=0.034; UBUC, p=0.021) and frequent mitosis (UTUC, p<0.001; UBUC, p=0.023). IGFBP-5 overexpression also independently predicted poor disease-specific survival and metastasis-free survival in both groups of patients. Western blot analysis showed IGFBP-5 protein as overexpressed in human urothelial cancer cell lines and not in normal urothelial cancer cells. CONCLUSIONS: IGFBP-5 plays an important role in tumour progression in UC. Its overexpression is associated with advanced tumour stage and conferred poorer clinical outcome.

Rsf-1/HBXAP overexpression is independent of gene amplification and is associated with poor outcome in patients with urinary bladder urothelial carcinoma.

BACKGROUNDS: Urothelial carcinoma of the urinary bladder (UCUB) is prevalent in developed countries. It often shows genetic instability and is associated with amplification (or gain) of various oncogenic genes or suppressive genes. Rsf-1, a subunit of ATP-dependent chromatin-remodelling complexes that mediates ATPase-dependent chromatin remodelling, confers tumour aggressiveness in certain carcinomas. The authors evaluate the Rsf-1 gene and expression status and its associations with clinicopathological features and survival in their UCUB collection. METHODS: Immunohistochemistry was used to assess the Rsf-1 expression profile in 295 UCUB specimens, and was found to correlate with clinicopathological data. Real-time RT-PCR and fluorescence in situ hybridisation were used to detect RSF-1 mRNA expression and gene dosage in 20 independent cases. Western blot analysis was used to evaluate Rsf-1 protein expression in human urothelial cell lines. RESULTS: Rsf-1 overexpression was demonstrated in 101 cases (34.2%), and was significantly associated with advanced primary tumour (p<0.001), nodal metastasis (p=0.004), higher histological grades (p=0.001) and frequent mitoses (p<0.001). Moreover, it was predictive in disease-specific survival and metastasis-free survival in both univariate and multivariate analyses (p<0.0001 for both). Although RSF-1 gene amplification can be barely detected, its mRNA expression is significantly enhanced in tumours with higher primary tumour (p=0.041) and positive nodal statuses (p=0.010), respectively. Rsf-1 protein was abundant in invasive urothelial carcinoma cells but was not benign. CONCLUSIONS: Overexpression of Rsf-1 is associated with higher tumour stage and poorer clinical outcome. The current study by the authors suggests gene amplification-independent mechanisms driving Rsf-1 overexpression during UCUB tumour progression.

Loss of lactate dehydrogenase B subunit expression is correlated with tumour progression and independently predicts inferior disease-specific survival in urinary bladder urothelial carcinoma.

AIMS: In our previous studies, comparative proteomics demonstrated that lactate dehydrogenase B subunit (LDH-B) is down-regulated in high grade compared to non-high grade urinary bladder urothelial carcinoma (UBUC). However, this finding has not been validated by clinical cohort investigation. Therefore, in the present study, 269 primary localised UBUC specimens were examined for LDH-B expression to clarify the relevance of LDH-B expression level to UBUC progression. METHODS: Immunohistochemistry (IHC) was implemented to investigate LDH-B protein expression in 269 primary localised UBUC specimens and to evaluate the association with tumour progression and prognosis. RESULTS: Our data demonstrated that dwindled LDH-B expression level was strongly associated with increment of primary tumour status (p < 0.0001), higher histological grade (p = 0.0024), and the presence of vascular (p = 0.0118) as well as perineurial (p = 0.0094) invasion, suggesting that LDH-B might be related to tumour progression. At the univariate level, low LDH-B expression is one of many parameters which significantly predicted both disease-specific survival (DSS) (p = 0.0001) and metastasis-free survival (MeFS) (p = 0.0024). In Cox multivariate regression model, higher pT status was the strongest independent prognosticator for both DSS (p = 0.0006) and MeFS (p = 0.0067) while low LDH-B expression remained prognostically significant for DSS (p = 0.0401). CONCLUSION: The above results confirmed the prognostic roles of LDH-B in UBUC.