Colorectal cancer (CRC) is one of the most frequently occurring cancers with high morbidity and mortality worldwide. Amphiregulin (AREG), a member of the epidermal growth factor family and a rational target for CRC therapy, is essential for the three-dimensional structure of tumor formation. To clone the genes associated with increased AREG expression, we performed a cDNA microarray analysis in two CRC cell lines undergoing two-dimensional (2DC) and three-dimensional culture (3DC). Upregulated (>2.0-fold) and downregulated (<0.5-fold) genes in 3DC compared with 2DC were selected. Pathway analysis using DAVID based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway databases revealed a number of genes involved in glycolysis. In CRC cells, glucose elevated the expression of GLUT1 and AREG as well as the activity of the hypoxia-inducible factor 1 (HIF-1) luciferase reporter promoter. The suppression of AREG expression reduced the uptake of glucose and production of lactate. Luciferase assay identified a critical regulatory region for AREG expression between −130 and −180 bp upstream of the start site, which contained a carbohydrate response element (ChoRE). Max-like protein X (MLX) bound to ChoRE and enhanced the expression of AREG. Together these data suggest that AREG plays a pivotal role in the development of CRC through activation of the Warburg effect.

Ovarian cancer is the most lethal gynecologic malignancy. Recently, several molecularly targeted anticancer agents have been developed for ovarian cancer; however, its prognosis remains extremely poor. The development of molecularly targeted therapy, as well as companion diagnostics, is required to improve outcomes for patients with ovarian cancer. In this study, to identify microRNAs (miRNAs) involved in the progression of ovarian cancer we analyzed serum miRNAs in patients with ovarian cancer using miRNA array and quantitative RT‐PCR and examined the anticancer properties of miRNA expression in ovarian cancer cells. In patients with ovarian cancer, high amount of miR‐135a‐3p in serum samples was significantly associated with favorable clinical prognosis. The amount of miR‐135a‐3p was significantly decreased in patients with ovarian cancer compared with patients with ovarian cysts or normal ovaries. In SKOV‐3 and ES‐2 human ovarian cancer cells, enhanced expression of miR‐135a‐3p induced drug sensitivity to cisplatin and paclitaxel and suppressed cell proliferation and xenograft tumor growth. These findings suggest that miR‐135a‐3p may be considered as a biomarker and a therapeutic agent in ovarian cancer.

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BackgroundBK-UM (CRM197) is a mutant form of diphtheria toxin and a specific inhibitor of heparin-binding epidermal growth factor-like growth factor (HB-EGF). We assessed the safety, pharmacokinetics, recommended dose, and efficacy of BK-UM in patients with recurrent ovarian cancer (OC) or peritoneal cancer (PC), and measured HB-EGF levels in serum and abdominal fluid after BK-UM administration.MethodsEleven patients with advanced or recurrent OC or PC were enrolled and treated with BK-UM via the intraperitoneal route. The dose was escalated (1.0, 2.0, 3.3, and 5.0 mg/m2) using a 3 + 3 design.ResultsEight of 11 patients completed treatment. No dose-limiting toxicity (DLT) was experienced at dose levels 1 (1.0 mg/m2) and 2 (2.0 mg/m2). Grade 3 transient hypotension as an adverse event (defined as a DLT in the present study) was observed in two of four patients at dose level 3 (3.3 mg/m2). Treatment with BK-UM was associated with decreases in HB-EGF levels in serum and abdominal fluid in seven of 11 patients and five of eight patients, respectively. Clinical outcomes included a partial response in one patient, stable disease in five patients, and progressive disease in five patients.ConclusionsBK-UM was well tolerated at doses of 1.0 and 2.0 mg/m2, with evidence for clinical efficacy in patients with recurrent OC or PC. A dose of 2.0 mg/m2 BK-UM is recommended for subsequent clinical trials.Trial registrationThis trial was prospectively performed as an investigator-initiated clinical trial. The trial numbers are UMIN000001002 and UMIN000001001, with registration dates of 1/30/2008 and 2/4/2008, respectively. UMIN000001001 was registered as a trial for the continuous administration of BK-UM after UMIN000001002.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3071-5) contains supplementary material, which is available to authorized users.

Abstract.Lung cancer is the most common cancer and remains the leading cause of cancer-related deaths worldwide. In total, 85% of lung cancer cases are non-small cell lung cancer, (NSCLC) and 15% are small cell lung cancers (SCLC). More than half of patients who were diagnosed with NSCLC at an advanced stage have an extremely poor prognosis; median overall survival is less than 12 months and 5-year survival is less than 1% despite advances in chemotherapy (1, 2).NSCLC encompasses the pathologically distinct adenocarcinoma, squamous cell carcinoma, and large cell carcinoma sub-types. Approximately 45% and 40% of patients with NSCLC are positive for epidermal growth factor receptor (EGFR) exon 19 deletions and exon 21 L858R mutations, respectively (3, 4). These mutations are predictive of treatment benefit from small molecule EGFR tyrosine kinase inhibitors (TKIs) such as erlotinib, gefitinib, and afatinib. In addition, such sensitizing EGFR mutations occur in approximately 10% of Caucasian patients and more than 50% of Asian patients with NSCLC (5). However, most patients develop resistance to these small-molecule EGFR TKIs after the first 8 to 16 months (6). T790M in EGFR is an acquired resistance mutation in 60-70% of patients who initially respond to prior treatment with small-molecule EGFR TKIs (6). On the basis of these lines of evidence, the development of molecularlytargeted therapies is required to ameliorate the clinical prognosis in NSCLC with T790M mutation.Heparin-binding EGF-like growth factor (HB-EGF) is an EGFR ligand (7-9), and is initially synthesized as a transmembrane protein, similarly to other members of the EGF family of growth factors (7-9) Previously, we reported that RNA interference of proHB-EGF (HBEGF) gene, or the addition of cross-reacting material 197 (CRM197), a specific HB-EGF inhibitor, resulted in significant apoptosis of cancer cells harboring HB-EGF expression, indicating that HB-EGF could be a valid target for cancer therapy in ovarian, breast, bladder, and gastric cancer, among others 3825