Urothelial carcinoma with trophoblastic differentiation: Reappraisal of the clinical implication and immunohistochemically features.

PURPOSE: To investigate the clinical implications of identifying urothelial carcinoma (UC) with trophoblastic differentiation (UCTD). MATERIALS AND METHODS: A prospective cohort study was performed from 2010 to 2016 to examine the incidence of UCTD in urinary tract cancer and association with clinicopathological indicators and patient outcome. RESULTS: UCTD was detected in 47 of 859 (5.5%) cases of UC of the bladder and 65 of 635 (10.2%) cases in the upper urinary tract. UCTD of the bladder was significantly associated with non-papillary, multiple, larger size ( > 3 cm), muscle invasion, and nodal metastasis (P ≤ 0.0001, respectively). A higher risk of recurrence (P = 0.005), progression (P < 0.0001), and patient death (P < 0.0001) was observed for UCTD than those with traditional, high-grade UC of the bladder. Among four patterns of expression, focal expression of ß-human chorionic gonadotropin was frequently detected in papillary tumor (P < 0.005) and UCs of smaller than 3 cm (P = 0.03). Significant indicators in predicting poor disease-specific overall survival in multivariate statistical model were tumor staging (P = 0.001), followed by non-focal ß-hCG expression (P = 0.049). CONCLUSION: UCTD is more often identified in the upper urinary tract than in the bladder. UCTD of the bladder was significantly associated with higher risk of recurrence, progression, and patient death. Expression of ß-hCG in non-focal patterns predicts a worse prognosis for patients with UCTD and deserves an individualized treatment planning.

EMP1, EMP 2, and EMP3 as novel therapeutic targets in human cancer.

The epithelial membrane protein genes 1, 2, and 3 (EMP1, EMP2, and EMP3) belong to the peripheral myelin protein 22-kDa (PMP22) gene family, which consists of at least seven members: PMP22, EMP1, EMP2, EMP3, PERP, brain cell membrane protein 1, and MP20. This review addresses the structural and functional features of EMPs, detailing their tissue distribution and functions in the human body, their expression pattern in a variety of tumors, and highlighting the underlying mechanisms involved in carcinogenesis. The implications in cancer biology, patient prognosis prediction, and potential application in disease therapy are discussed. For example, EMP1 was reported to be a biomarker of gefitinib resistance in lung cancer and contributes to prednisolone resistance in acute lymphoblastic leukemia patients. EMP2 functions as an oncogene in human endometrial and ovarian cancers; however, characteristics of EMP2 in urothelial cancer fulfill the criteria of a suppressor gene. Of particular interest, EMP3 overexpression in breast cancer is significantly related to strong HER-2 expression. Co-expression of HER-2 and EMP3 is the most important indicator of progression-free and metastasis-free survival for patients with urothelial carcinoma of the upper urinary tract. Altogether, discovery of pharmacological inhibitors and/or regulators of EMP protein activity could open novel strategies for enhanced therapy against EMP-mediated human diseases.

SH3BGRL3 Protein as a Potential Prognostic Biomarker for Urothelial Carcinoma: A Novel Binding Partner of Epidermal Growth Factor Receptor.

PURPOSE: Mass spectrometry-based biomarker discovery has clinical benefit. To identify novel biomarkers for urothelial carcinoma, we performed quantitative proteomics on pooled urine pairs from patients with and without urothelial carcinoma. EXPERIMENTAL DESIGN: Shot-gun proteomics using liquid chromatography-tandem mass spectrometry and stable isotope dimethyl labeling identified 219 candidate proteins. The potential implication of SH3 domain binding glutamic acid-rich protein like 3 (SH3BGRL3) was examined by immunoblotting of the urine (n = 13) and urothelial tumors (n = 32). Additional immunohistochemistry was performed on bladder cancer array (n = 1145) and correlated with tumor aggressiveness. Then, biologic functions and signaling pathways of SH3BGRL3 were explored using stable cell lines. RESULTS: The detectable urine SH3BGRL3 in patients with urothelial carcinoma was positively associated with higher histologic grading and muscle invasiveness of urothelial carcinoma. SH3BGRL3 is expressed in 13.9% (159/1145) of bladder cancer cohort and is positively associated with muscle invasion (P = 0.0028). SH3BGRL3 expression is associated with increased risk of progression in patients with nonmuscle-invasive bladder cancer (P = 0.032). SH3BGRL3 expression is significantly associated with a high level of epidermal growth factor receptor (EGFR) in bladder cancer (P < 0.0001). SH3BGRL3 promotes the epithelial-mesenchymal transition, cell migration, and proliferation of urothelial carcinoma in vitro. SH3BGRL3 interacts with phosphor-EGFR at Y1068, Y1086, and Y1173 through Grb2 by its proline-rich motif, and activates the Akt-associated signaling pathway. CONCLUSIONS: Evaluation of SH3BGRL3 expression status or urine content may identify a subset of patients with bladder cancer who may require more intensive treatment. SH3BGRL3 deserves further investigation as a cotargeting candidate for designing EGFR-based cancer therapies. Clin Cancer Res; 21(24); 5601-11. ©2015 AACR.

Hypoxia promotes nuclear translocation and transcriptional function in the oncogenic tyrosine kinase RON.

Tumor hypoxia drives metastatic progression, drug resistance, and posttreatment relapses, but how cancer cells adapt and evolve in response to hypoxic stress is not well understood. In this study, we address this question with the discovery that the receptor tyrosine kinase RON translocates into the nucleus of hypoxic cancer cells. In response to hypoxia, nuclear RON interacts with the hypoxia-inducible factor HIF-1α in a manner that relies on RON tyrosine kinase activity, binding to the c-JUN promoter and activating it. Mechanistic investigations revealed unexpectedly that nuclear RON played a more important role in activation of the c-JUN promoter than HIF-1α, leading to increased cell proliferation, survival adaptation, in vitro migration, and tumorigenicity under hypoxic conditions. Taken together, our results pointed to a novel function for RON as a transcriptional regulator that promotes the survival of cancer cells subjected to hypoxia. These results suggest novel implications for the use of small-molecule inhibitors or monoclonal antibodies targeting the RON kinase in the prevention or treatment of advanced cancer.

[Detection and identification of human metapneumovirus by real time reverse transcription PCR].

OBJECTIVE: To develop a rapid, sensitive and specific real time reverse transcription PCR for detecting and identifying human metapneumovirus. METHODS: The Hmpv-L gene of human metapneumovirus was chosen as target gene, the primers and TaqMan probe were designed, and the PCR reaction was optimized systematically. The total RNA was extracted from respiratory specimens, and reverse transcription was performed through random primer. The cDNA was detected by using real time PCR. The specificity, sensitivity and reproducibility of real time PCR were estimated. The real time PCR was applied to detect 180 clinical respiratory specimens. RESULTS: The human metapneumovirus can be detected using real time reverse transcription PCR accurately and quickly, and the sensitivity was 1 copy/microl. The coefficient of variation of intra-assay and inter-assay was less than 5%. Among those 180 specimens, 28 (15.56%) were positive for human metapneumovirus, the clinical diagnoses for these 28 patients were pneumonia (15.60%, 17/109) and bronchiolitis (15.49%, 11/71). 21 positive specimens were from patients under 2 years of age, and 6 positive specimens were from patients between 2 and 5 years of age, only 1 positive specimens was from patients over 5 years. CONCLUSION: It is demonstrated that real time reverse transcription PCR is a reliable, accurate and feasible assay for human metapneumovirus, which has become one of the most important pathogens induced acute respiratory infections in pediatric patients.