The recognition of functional roles for transcribed long non-coding RNA (lncRNA) has provided a new dimension to our understanding of cellular physiology and disease pathogenesis. LncRNAs are a large group of structurally complex RNA genes that can interact with DNA, RNA or protein molecules to modulate gene expression and to exert cellular effects through diverse mechanisms. The emerging knowledge regarding their functional roles and their aberrant expression in disease states emphasizes the potential for lncRNA to serve as targets for therapeutic intervention. In this concise review, we outline the mechanisms of action of lncRNAs, their functional cellular roles, and their involvement in disease. Using liver cancer as an example, we provide an overview of the emerging opportunities and potential approaches to target lncRNA dependent mechanisms for therapeutic purposes.

There is growing interest in the epigenetic mechanisms that impact human health and disease, including the role of microRNAs (miRNAs). These small (18–25 nucleotide), evolutionarily conserved, non-coding RNA molecules regulate gene expression in a post-transcriptional manner. Several well-orchestered regulatory mechanisms involving miRNAs have been identified, with the potential to target multiple signaling pathways dysregulated in cancer. Since the initial discovery of miRNAs, there has been progress towards therapeutic applications, and several natural and synthetic chemopreventive agents also have been evaluated as modulators of miRNA expression in different cancer types. This review summarizes the most up-to-date information related to miRNA biogenesis, and critically evaluates proposed miRNA regulatory mechanisms in relation to cancer signaling pathways, as well as other epigenetic modifications (DNA methylation patterns, histone marks) and their involvement in drug resistance. We also discuss the mechanisms by which dietary factors regulate miRNA expression, in the context of chemoprevention versus therapy.

Purpose In clear cell renal cell carcinoma BAP1 and PBRM1 are 2 of the most commonly mutated genes (10% to 15% and 40% to 50%, respectively). We sought to determine the prognostic significance of PBRM1 and BAP1 expression in clear cell renal cell carcinoma. Materials and Methods We used immunohistochemistry to assess PBRM1 protein expression in 1,479 primary clear cell renal cell carcinoma tumors that were previously stained for BAP1. A centralized pathologist reviewed all cases and categorized tumors as positive or deficient for PBRM1 and BAP1. Kaplan-Meier and Cox regression models were used to evaluate association of PBRM1 and BAP1 expression with the risk of death from renal cell carcinoma and the risk of metastasis after adjustment for age and the Mayo Clinic SSIGN (stage, size, grade and necrosis) score. Results PBRM1 and BAP1 expression was PBRM1+ BAP1+ in 40.1% of tumors, PBRM1− BAP1+ in 48.6%, PBRM1+ BAP1− in 8.7% and PBRM1− BAP1− in 1.8%. The incidence of PBRM1 and BAP1 loss in the same tumor was significantly lower than expected (actual 1.8% vs expected 5.3%, p <0.0001). Compared to patients with PBRM1+ BAP1+ tumors those with PBRM1− BAP1+ lesions were more likely to die of renal cell carcinoma (HR 1.39, p = 0.035), followed by those with PBRM1+ BAP1− and PBRM1− BAP1− tumors (HR 3.25 and 5.2, respectively, each p <0.001). PBRM1 and BAP1 expression did not add independent prognostic information to the SSIGN score. Conclusions PBRM1 and BAP1 expression identified 4 clinical subgroups of patients with clear cell renal cell carcinoma who had divergent clinical outcomes. The clinical value of these biomarkers will be fully realized when therapies targeting pathways downstream of PBRM1 and BAP1 are developed.

Purpose The majority of patients diagnosed with clear cell renal cell carcinoma (ccRCC) have low-risk disease with a <10% chance of ccRCC-specific death. DNA sequencing revealed that mutations in BAP1 occur in 5–15% of ccRCC and are associated with poor outcomes. The vast majority of BAP1 mutations abolish protein expression. We developed a highly sensitive immunohistochemistry (IHC) assay to assess BAP1 expression. Herein, we utilize our IHC assay to test whether BAP1 expression is an independent marker of ccRCC specific survival particularly in patients classified as low-risk. Patients and Methods We assessed BAP1 expression using IHC in 1,439 patients who underwent nephrectomy to treat clinically localized ccRCC. A centralized pathologist dichotomized patients as either BAP1 positive or negative. We employed Kaplan-Meier and Cox regression models to associate BAP1 expression with cancer-specific survival. Results 10.3% of tumors were BAP1 negative, 84.5% of tumors were BAP1 positive, and 4.6% of tumors had ambiguous staining for BAP1. Patients with BAP1 negative tumors have an increased risk of ccRCC related death (HR 3.06; 95% CI 2.28 – 4.10; p=6.77×10−14). BAP1 expression remained an independent marker of prognosis after adjusting for the UCLA integrated staging system (UISS) (HR 1.67; CI 1.24–2.25; p<0.001). Finally, BAP1 was an independent prognostic marker in low-risk patients with a Mayo Clinic stage, size, grade, and necrosis (SSIGN) score of ≤3 (HR 3.24; 95% CI 1.26–8.33; p=0.015). Conclusion Using a large patient cohort, we demonstrate that BAP1 expression is an independent marker of prognosis in patients with low-risk (SSIGN≤3) ccRCC.

Hepatic ischemia-reperfusion injury (IRI) and associated inflammation contributes to liver dysfunction and complications after liver surgery and transplantation. Mesenchymal stem cells (MSC) have been reported to reduce hepatic IRI because of their reparative immunomodulatory effects in injured tissues. Recent studies have highlighted beneficial effects of extracellular vesicles from MSCs (MSC-EV) on tissue injury. The effects of systemically administered mouse bone marrow derived MSC-EV were evaluated in an experimental murine model of hepatic IRI induced by cross clamping the hepatic artery and portal vein for 90 minutes followed by reperfusion for periods of upto 6 hours. Compared with controls, intravenous administration of MSC-EV 30 minutes prior to IRI dramatically reduced the extent of tissue necrosis, decreased caspase-3 positive and apoptotic cells, and reduced serum aminotransferase levels. MSC-EV increased hepatic mRNA expression of NACHT, LRR and PYD domains-containing protein 12 (Nlrp12), and the chemokine (C-X-C motif) ligand 1 (CXCL1), and reduced mRNA expression of several inflammatory cytokines such as IL-6 during IRI. MSC-EV increased cell viability and suppressed both oxidative injury and NF-κB activity in AML12 murine hepatocytes in vitro. In conclusion, the administration of EV derived from bone marrow derived MSCs may ameliorate hepatic IRI by reducing hepatic injury through modulation of the inflammatory response.