The involvement of microRNAs in autocrine hGH-mediated oncogenesis

Abstract

MicroRNAs (miRNAs) are short 17-25 nucleotide RNAs which are ubiquitous regulators of gene expression. Regulation of miRNA expression has recently been highlighted as a key aspect affecting the pathogenesis of many types of malignancies, including breast and colon cancer. Furthermore, regulation of the enzymes involved in miRNA processing has also been implicated in the development and progression of several cancers, including breast cancer. The human growth hormone (hGH)/insulin-like growth factor-1 (IGF-1) axis has emerged as an important mediator of tumour development. Tumoral hGH expression positively correlates with lymph node metastasis, tumour stage, HER-2 status and poor outcome in breast cancer patients. Recent reports suggest that the hGH/IGF-1 axis may influence the expression of miRNAs and this study investigates whether miRNA expression, and the expression of key proteins involved in miRNA processing, are affected by autocrine hGH in breast and colon cancer cells. The study also assessed the functional implications of autocrine hGH expression in colon carcinoma cells. Our initial findings demonstrate that forced expression of hGH in colon carcinoma cells increases total cell number by increasing cell proliferation and survival, and stimulates anchorage-independent cell growth and motility. Conversely, functional inhibition of endogenously expressed hGH decreases total cell number, due to reduced proliferation and survival, and inhibits anchorage-independent cell growth and motility. Autocrine hGH modulates miRNA expression profiles in both breast and colon cancer cells, increasing expression of several oncogenic miRNAs and reducing expression of tumour-suppressive miRNAs. One consequence of such deregulation is increased Nuclear Factor-KappaB (NFkB) activity in hGH-expressing breast cancer cells. Furthermore, autocrine hGH decreases the expression of components of the miRNA biogenesis pathway, Drosha and Dicer, and modulates the expression of Ago1 and Ago2 in mammary carcinoma cells. Our findings demonstrate that autocrine hGH enhances the oncogenicity of colon carcinoma cells. In addition, autocrine hGH regulates the expression of a subset of miRNAs in breast and colon carcinoma cells and regulates the expression of key proteins involved in miRNA processing in breast cancer cells. Thus deregulation of miRNA physiology may be one mechanism whereby autocrine hGH contributes to tumour progression.