Research

MicroRNAs (miRNAs) are short non-coding RNAs that post-transcriptionally regulate protein expression. The human genome encodes more than 2,500 miRNAs, with each being able to modulate several targets, act along a variety of cellular pathways, and affect various tissues. They are frequently dysregulated in cancers and, via their protein targets, act as oncogenes or tumor-suppressors. As such, their effects are pervasive—miRNAs have been implicated in various biological processes including apoptosis, epithelial-to-mesenchymal transition, and angiogenesis. In this context, miRNA involved in metastasis have been termed “metastamiRs”. This chapter focuses on the role of miRNAs in the metastatic processes of prostate cancer. Our primary aims are to detail specific biological processes and molecular targets through which miRNAs act and that may serve as therapeutic targets. Secondly, we discuss the potential of miRNAs to serve as biomarkers of tumor aggression and thus potentially guide personalized therapy.

Bladder cancer is among the most common cancers globally, with significant mortality associated with more advanced disease. Early detection and diagnostic accuracy are thus fundamental to the clinical pathway for managing bladder cancer. MicroRNA (miRNA) are small, non-coding segments of RNA that regulate gene expression and have been implicated in the process of carcinogenesis. Dysregulation and aberrant expression of miRNAs have been shown to have both oncogenic and tumor suppressive effects. A vast number of miRNA, across the entire field of cancer biology, have already been identified and characterized, and many of these have been associated with bladder cancer. These miRNAs have furthered our understanding of the genetic profile of bladder cancer, and ultimately, may be utilized in the detection, prognosis, and treatment of this disease. This chapter focuses on the role of miRNA in the pathogenesis of metastatic bladder cancer and overviews many of the miRNA thought to be associated with bladder cancer.  Additionally, this chapter explores the clinical utilities of miRNAs in bladder cancer to serve as biomarkers and guide individualized treatment.

MicroRNAs are short noncoding RNAs that regulate post-transcriptional protein expression. Aberrant microRNA expression has been widely implicated in cancer biology with various effects depending on the affected downstream target(s). In renal cell carcinoma, microRNAs have been shown to influence metastasis by targeting oncogenes or tumor suppressors in complex regulatory networks­­ - leading them to be coined “metastamiRs.” This chapter aims to identify the microRNAs responsible for metastasis in renal cell carcinoma, review their molecular function and oncologic outcome, and discuss their potential roles for diagnosis, prognosis, and therapy.

Using an established rat peripheral-nerve regeneration model, the authors have demonstrated enhancement of regeneration following subcutaneous priming of bioresorbable poly(lactic-co-glycolic)acid (PLGA) guides in vivo. Four weeks after nerve reconstruction, regeneration of the peripheral nerve through the cell-infiltrated guides displayed a significant increase in the total axon number and myelination status recorded in primed over unprimed guides, demonstrating the importance of cell-mediated events in the regeneration process. To define the different components enhancing nerve regeneration in this model, they have focused on identifying factors capable of eliciting Schwann-cell migration, since this has been identified as an early and necessary event in nerve regeneration. Using an in vitro migration assay, screening of a limited number of cellular and extracellular factors has demonstrated differential promotion of Schwann-cell migration. Of interest, combining fibronectin and bFGF resulted in a two-fold enhancement in Schwann-cell migration over that recorded with either alone. These results describe a rapid screening process for identifying various molecules and combinations thereof, with potential involvement in Schwann-cell migration. Coupling these findings to the use of the PLGA guide as an in vivo delivery system provides a rationale for the selection of exogenous factors to test for the enhancement of peripheral-nerve regeneration.

BACKGROUND: Mutations in fibroblast growth factor 3 receptor (FGFR3) are frequent events in low-grade bladder tumors. To assess the potential utility of the detection of FGFR3 mutations in a screening modality, the authors analyzed urine sediment DNA samples from 192 patients in a retrospective study.

METHODS: Urine sediment DNA samples from 192 patients were prepared. Seventy-two patients had undergone transurethral resection (TURBT group) of mainly Ta lesions and 120 patients had undergone cystectomy (cystectomy group). The majority of patients in the cystectomy group had more advanced tumors compared with patients in the TURBT group. DNA preparations were screened for FGFR3 mutations in exons 7, 10, and 15 using single-strand conformation polymorphism (SSCP) and DNA sequencing.

RESULTS: Using SSCP, 67% of patients in the TURBT group and 28% in the cystectomy group displayed FGFR3 mutations. Comparative analysis of cytology results and FGFR3 mutational analysis were performed in 122 cases. Within the TURBT group, FGFR3 mutation analysis outperformed cytology. FGFR3 mutation analysis identified change in 68% of urine sediment DNA samples whereas cytology recorded the presence of tumor cells in 32% of the DNA samples. In the cystectomy group, cytology outperformed FGFR3 mutation analysis. Cytology recorded tumor detection in 90% of patients, while SSCP identified mutational change in 24%.

CONCLUSIONS: Combining FGFR3 mutation results with cytology in both groups correctly identified tumor presence in 105 of 122 (86%) of patients. The greater sensitivity of FGFR3 mutation detection over cytology in identifying the presence of low-grade, superficial bladder tumors represents a potential new tool to complement standard cytology in screening patients for bladder tumors and recurrent disease.

Mechanisms that inhibit cell cycle progression and establish growth arrest are fundamental to tumor suppression and to normal cell differentiation. A complete understanding of these mechanisms should provide new diagnostic and therapeutic targets for future clinical applications related to cancer-specific pathways. This review will focus on the HMG-box protein 1 (HBP1) transcriptional repressor and its roles in cell cycle progression and tumor suppression. The work of several labs now suggests a new pathway for inhibiting G1 progression with exciting possible implications for tumor suppression. Our recent work suggests that the two previously unassociated proteins-the HBP1 transcription factor and the p38 MAP kinase pathway-may now participate together in a G1 regulatory network. Several recent papers collectively highlight an unexpected role and connection of the p38 MAP kinase-signaling pathway in cell cycle control, senescence, and tumor suppression. Together, these initially divergent observations may provide clues into a new tumor suppressive network and spur further investigations that may contribute to new diagnostic and therapeutic targets for cancer.