A Role for De Novo Purine Metabolic Enzyme PAICS in Bladder Cancer Progression.

Genomic and transcriptome sequencing of bladder cancer (BLCA) has identified multiple molecular alterations during cancer progression. Many of these identified genetic and epigenetic changes play a role in the progression of this disease. Studies have identified molecular subtypes in muscle-invasive bladder cancer (MIBC) with different sensitivities to frontline therapy suggesting the heterogeneity in these tumors and the importance of molecular characterization of MIBC to provide effective treatment. Specifically, it has become increasingly evident, as demonstrated by The Cancer Genome Atlas project, that metabolic enzymes are commonly dysregulated in BLCA. Elevated expression of multiple metabolic enzymes is due to the increased demand from rapidly proliferating BLCA cells requiring extensive nucleotide synthesis. Cancer cells utilize the de novo purine and pyrimidine biosynthetic pathway as a source of their nucleotide needs. In this study, we show that phosphoribosyl aminoimidazole succinocarboxamide synthetase (PAICS), an enzyme involved in de novo purine biosynthetic pathway, is significantly overexpressed in BLCA. Immunohistochemical staining of paraffin-embedded tissue sections showed that PAICS is overexpressed in MIBC. Furthermore, we found that tumor suppressor miR-128 negatively regulated PAICS expression by binding to its 3'-untranslated region. We also found that PAICS induces EMT by positively regulating SNAI1 and by a reduction in E-cadherin expression. Additionally, our in vitro functional studies and in vivo chicken chorioallantoic membrane assay show that PAICS plays a critical role in BLCA cell proliferation, invasion, and tumor growth. Collectively, our data suggest that targeting PAICS may provide a therapeutic option in BLCA.

MicroRNA expression profiling of Xp11 renal cell carcinoma.

Renal cell carcinomas (RCCs) with Xp11 translocation (Xp11 RCC) constitute a distinctive molecular subtype characterized by chromosomal translocations involving the Xp11.2 locus, resulting in gene fusions between the TFE3 transcription factor with a second gene (usually ASPSCR1, PRCC, NONO, or SFPQ). RCCs with Xp11 translocations comprise up to 1% to 4% of adult cases, frequently displaying papillary architecture with epithelioid clear cells. To better understand the biology of this molecularly distinct tumor subtype, we analyze the microRNA (miRNA) expression profiles of Xp11 RCC compared with normal renal parenchyma using microarray and quantitative reverse-transcription polymerase chain reaction. We further compare Xp11 RCC with other RCC histologic subtypes using publically available data sets, identifying common and distinctive miRNA signatures along with the associated signaling pathways and biological processes. Overall, Xp11 RCC more closely resembles clear cell rather than papillary RCC. Furthermore, among the most differentially expressed miRNAs specific for Xp11 RCC, we identify miR-148a-3p, miR-221-3p, miR-185-5p, miR-196b-5p, and miR-642a-5p to be up-regulated, whereas miR-133b and miR-658 were down-regulated. Finally, Xp11 RCC is most strongly associated with miRNA expression profiles modulating DNA damage responses, cell cycle progression and apoptosis, and the Hedgehog signaling pathway. In summary, we describe here for the first time the miRNA expression profiles of a molecularly distinct type of renal cancer associated with Xp11.2 translocations involving the TFE3 gene. Our results might help understanding the molecular underpinning of Xp11 RCC, assisting in developing targeted treatments for this disease.

An integrated genome-wide approach to discover deregulated microRNAs in non-small cell lung cancer: Clinical significance of miR-23b-3p deregulation.

In spite of significant technical advances, genesis and progression of non-small cell lung cancer (NSCLC) remain poorly understood. We undertook an integrated genetic approach to discover novel microRNAs that were deregulated in NSCLCs. A total 119 primary NSCLCs with matched normal were analyzed for genome-wide copy number changes. We also tested a subset of matched samples by microRNA expression array, and integrated them to identify microRNAs positioned in allelic imbalance area. Our findings support that most of the identified deregulated microRNAs (miR-21, miR-23b, miR-31, miR-126, miR-150, and miR-205) were positioned in allelic imbalance areas. Among microRNAs tested in independent 114 NSCLCs, overexpression of miR-23b was revealed to be a significantly poor prognostic factor of recurrence free survival (HR = 2.40, P = 0.005, 95%CI: 1.32-4.29) and overall survival (HR = 2.35, P = 0.005, 95%CI: 1.30-4.19) in multivariable analysis. In addition, overexpression of miR-23b in H1838 cell line significantly increased cell proliferation, while inhibition of miR-23b in H1437 and H1944 cell lines significantly decreased cell doubling time. In summary, integration of genomic analysis and microRNA expression profiling could identify novel cancer-related microRNAs, and miR-23b could be a potential prognostic marker for early stage NSCLCs. Further biological studies of miR-23b are warranted for the potential development of targeted therapy.