K-homology splicing regulatory protein (KSRP) promotes post-transcriptional destabilization of Spry4 transcripts in non-small cell lung cancer.

AU-rich element-binding proteins (ARE-BPs) offer post-transcriptional regulation of gene expression via physical interaction and recruitment of RNA decay machinery to the AU-rich elements within the 3'-UTR of the target transcripts. However, the role of ARE-BPs in lung cancer remains poorly understood. In this study, we have identified that K-homology splicing regulatory protein (KSRP), an ARE-BP, is robustly up-regulated in human lung cancer. Importantly, Kaplan-Meier survival analysis indicated that elevated KSRP expression was correlated with poor overall survival of lung cancer patients. Furthermore, cigarette smoke, a leading risk factor for lung cancer, was also identified to be an important contributor to increased KSRP expression. Remarkably, silencing of KSRP decreased cell proliferation, reversed anchorage-independent growth, and reduced migration/invasion, suggesting an oncogenic role for KSRP in lung cancer. Finally, we provide mechanistic evidence that KSRP promotes the down-regulation of Spry4 by a previously unidentified mechanism, i.e. post-transcriptional mRNA regulation.

Expression of the Novel Costimulatory Molecule B7-H5 in Pancreatic Cancer.

BACKGROUND: This study investigated how the B7-H5 protein, a new member of the B7 family, is expressed in normal human pancreas tissues and examined its expression changes in pancreatic cancer. METHODS: In this analysis, B7-H5 expression was examined by immunohistochemical staining of frozen specimens from patients undergoing pancreatic resection. RESULTS: Membranous B7-H5 protein was expressed on normal ductal epithelium within the pancreas. Other cell types from the normal pancreas, such as acinar cells and islet cells, did not express B7-H5. In adenocarcinoma, B7-H5 staining was decreased or absent. Interestingly, B7-H5 expression in intraductal papillary mucinous neoplasms varied with grade. No B7-H5 expression was found with other cancer types such as neuroendocrine tumors, but normal ducts adjacent to tumors were highly positive. CONCLUSIONS: The findings showed that B7-H5 expression was restricted to ductal cells in the normal pancreas and the expression was downregulated in pancreatic adenocarcinomas. In addition, the findings showed that B7-H5 expression changes within different stages of dysplasia. The study suggests that loss of the B7-H5 signal may contribute to immune evasion of pancreatic adenocarcinoma. However future studies are needed.

Methylation of Wnt7a is modulated by DNMT1 and cigarette smoke condensate in non-small cell lung cancer.

Wnt7a is known to be a tumor suppressor that is lost in NSCLC, but no mechanism of loss has been established. Methylation of promoter regions has been established as a common mechanism of loss of tumor suppressor expression in NSCLC. We previously demonstrated that loss of Wnt7a in non-transformed lung epithelial cell lines led to increased cell growth, altered 3-D culture growth, and increased migration. The Wnt7a promoter has a higher percentage of methylation in NSCLC tumor tissue compared to matched normal lung tissue and methylation of the promoter region leads to decreased activity. We treated H157 and H1299 NSCLC cell lines with 5-Aza-2'-deoxycytidine and detected loss of Wnt7a promoter methylation, increased Wnt7a expression, and increased activity of the Wnt7a lung signaling pathway. When DNMT1 expression was knocked down by shRNA, expression of Wnt7a increased and methylation decreased. Together these data suggest that in NSCLC, Wnt7a is lost by methylation in a subset of tumors and that this methylation is maintained by DNMT1. Restoration of Wnt7a expression through demethylation could be an important therapeutic approach in the treatment of NSCLC.

Stromal cell-derived factor 1α mediates resistance to mTOR-directed therapy in pancreatic cancer.

PURPOSE: The factors preventing the translation of preclinical findings supporting the clinical development mTOR-targeted therapy in pancreatic cancer therapy remain undetermined. Stromal cell.derived factor 1α (SDF-1α)-CXCR4 signaling was examined as a representative microenvironmental factor able to promote mTOR-targeted therapy resistance in pancreatic cancer. EXPERIMENTAL DESIGN: Primary pancreas explant xenografts and in vitro experiments were used to perform pharmacodynamic analyses of SDF-1α-CXCR4 regulation of the mTOR pathway. Combinatorial effects of CXCR4, EGFR, and mTOR pharmacologic inhibition were evaluated in temsirolimus-resistant and -sensitive xenografts. Intratumoral gene and protein expressions of mTOR pathway effectors cyclin D1, c-Myc, and VEGF were evaluated. RESULTS: Baseline intratumoral SDF-1α gene expression correlated with temsirolimus resistance in explant models. SDF-1α stimulation of pancreatic cells resulted in CXCR4-mediated PI3-kinase-dependent S6-RP phosphorylation (pS6-RP) on exposure to temsirolimus. Combinatorial therapy with AMD3465 (CXCR4 small-molecule inhibitor) and temsirolimus resulted in effective tumor growth inhibition to overcome temsirolimus resistance. In contrast, SDF-1α exposure induced a temsirolimus-resistant phenotype in temsirolimus-sensitive explants. AMD3465 inhibited CXCR4-mediated intratumoral S6-RP phosphorylation and cyclin D and c-myc gene expression. Next, CXCR4 promoted intratumoral EGFR expression in association with temsirolimus resistance. Treatment with AMD3465, temsirolimus- and erlotinib-mediated tumor growth inhibition to overcome temsirolimus resistance in the explant model. Lastly, SDF-1α-CXCR4 signaling increased intratumoral VEGF gene and protein expression. CONCLUSIONS: SDF-1α-CXCR4 signaling represents a microenvironmental factor that can maintain mTOR pathway fidelity to promote resistance to mTOR-targeted therapy in pancreatic cancer by a variety of mechanisms such as recruitment of EGFR signaling and angiogenesis.

Successes and challenges in translational research: the development of targeted therapy for gastrointestinal stromal tumours.

Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms that most commonly affect the stomach or small intestine, but that can occur anywhere within the gastrointestinal tract. The annual incidence of GISTs is estimated to be 10 to 20 cases per million. Traditionally, the only effective treatment was surgical resection, and recurrences were common even with complete removal of tumor. Systemic therapy with standard cytotoxic chemotherapeutic agents was completely ineffective. A series of exciting laboratory developments led to the discovery that the small molecule tyrosine kinase inhibitor STI571 (imatinib mesylate) has significant clinical activity in GISTs, representing one of the first therapeutic uses of a targeted agent directed against a solid tumor. In this article we will describe the key steps that led to the initial clinical trials of imatinib in GISTs, and we will also discuss the process of incorporating this novel therapy into mainstream oncologic practice.