ANRIL Deregulation in Breast Cancer
Meseure et al. Page 623
Increasingly, long non-coding RNA (lncRNA) functions are being attributed to many critical biological processes in cancer. This study demonstrates a complex pattern of interactions between lncRNA ANRIL (Antisense Non-coding RNA in the INK4 Locus),several miRs, PRC2/PRC1 subunits and p15/CDKN2Bp16/CDKN2A-p14/ARF locus in a large cohort of invasive breast carcinomas. Significant overexpression of ANRIL and EZH2 and under-expression of CBX7 was observed. Correlations were identified between these genes, their expression patterns and clinicopathological parameters, molecular subtypes and patient outcomes. Multivariate analysis revealed that combined EZH2/CBX7 status is an independent prognostic factor. These data suggest that global expression patterns should be accounted for when defining functionality of repressive Polycomb complexes and therapeutic targeting potential.
HuR Mediates TRAIL Resistance
Romeo et al. Page 599
In this issue, new evidence suggests a mechanism for cancer's resistance to TRAIL-based therapies. For years, the thought has been death receptor activation using a synthetic mimic of TRAIL would selectively kill cancer. However, like most targeted agents used to fight pancreatic cancer, TRAIL-targeted therapies performed poorly in trials. Here, HuR (Hu antigen R) was demonstrated to be a key regulator of TRAIL resistance, which becomes especially active when pancreatic cancer cells are treated with TRAIL. Treated cells activate HuR, which reduces the expression of a death receptor available for TRAIL-induced apoptosis. Small molecule or siRNA inhibition of HuR, sensitized pancreatic cancer cells to TRAIL-drug combinations as compared to TRAIL alone. Upon further validation, this approach could help resurrect a disappointing anti-pancreatic cancer agent.
DNA Repair Inhibition by Oxidative Stress
McAdam et al. Page 612
McAdam and colleagues highlight the importance of damage to the DNA repair proteome by demonstrating that DNA repair is impaired in oxidatively stressed cultured human cells. In particular, they show that oxidative stress caused by UVA radiation or by interventions that deplete cellular antioxidants damages nucleotide excision repair (NER) proteins and inhibits the removal of the sunlight-induced DNA lesions that are implicated in skin cancer development. Because UVA comprises around 95% of incident ultraviolet radiation, oxidative inactivation of NER has implications for skin carcinogenesis. DNA repair also attenuates the effectiveness of anticancer drugs and its inhibition by protein oxidation may increase therapeutic efficacy.
Non-canonical WNT5A-ROR2 Axis in Esophageal Adenocarcinoma
Lyros et al. Page 647
This novel study introduces for the first time the embryological WNT5a/ROR2 signaling pathway in the pathogenesis of Barrett's-associated esophageal adenocarcinoma. By analyzing human esophageal specimens and esophageal cells, Lyros and colleagues present evidence that early loss of WNT5a expression along with upregulation of ROR2-receptor contribute to tumor growth of esophageal adenocarcinoma.These findings highlight the significance of the WNT5a/ROR2 signaling pathway in the development and malignant transformation of Barrett'esophagus into esophageal adenocarcinoma and suggest a number of novel therapeutic opportunities at all stages of the metaplasia-dysplasia-adenocarcinoma sequence.