The potential role of PHF6 as an oncogene: a genotranscriptomic/proteomic meta-analysis.

Epigenetic complexes control various pathways within the cells. Their abnormalities can be involved in the initiation and the progression of different types of cancer. Nucleosome remodeling and deacetylase (NuRD) is an epigenetic complex that comprises several subunits such as PHF6. Although PHF6 is reported as a tumor suppressor in some of the hematopoietic malignancies, its function is still challenging in other cancers. Our study aimed at investigating the role of PHF6 in different types of cancer. We conducted a meta-analysis of PHF6 in human cancers at genomic, transcriptomic, and proteomic levels. For this purpose, we acquired the data from several databases, and tried to statistically integrate and analyze the data in order to find the potential role of PHF6 in different tumors. The results demonstrated that although PHF6 has been previously known as a tumor suppressor gene, it was remarkably overexpressed in many cancer types such as breast and colorectal cancers. Notably, PHF6 was under-expressed in a few types of cancer, including esophageal tumors. Moreover, the results indicated that although the mutation rate of PHF6 is relatively low, it is mutated in some tumor types.  In addition, our data for 40 epigenetic genes showed that missense and nonsense mutations were associated with overexpression and under-expression, respectively. Our results suggest that PHF6 may function as an oncogenic factor in several types of cancer. We also hypothesize that PHF6 may also play its role in a tissue-specific manner. Our findings suggest further investigations regarding the exact role of PHF6 in tumor types.

STAT3-mediated IGF-2 secretion in the tumour microenvironment elicits innate resistance to anti-IGF-1R antibody.

Drug resistance is a major impediment in medical oncology. Recent studies have emphasized the importance of the tumour microenvironment (TME) to innate resistance, to molecularly targeted therapies. In this study, we investigate the role of TME in resistance to cixutumumab, an anti-IGF-1R monoclonal antibody that has shown limited clinical efficacy. We show that treatment with cixutumumab accelerates tumour infiltration of stromal cells and metastatic tumour growth, and decreases overall survival of mice. Cixutumumab treatment stimulates STAT3-dependent transcriptional upregulation of IGF-2 in cancer cells and recruitment of macrophages and fibroblasts via paracrine IGF-2/IGF-2R activation, resulting in the stroma-derived CXCL8 production, and thus angiogenic and metastatic environment. Silencing IGF-2 or STAT3 expression in cancer cells or IGF-2R or CXCL8 expression in stromal cells significantly inhibits the cancer-stroma communication and vascular endothelial cells' angiogenic activities. These findings suggest that blocking the STAT3/IGF-2/IGF-2R intercellular signalling loop may overcome the adverse consequences of anti-IGF-1R monoclonal antibody-based therapies.