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A screen of microRNA (miRNA) expression following differentiation in human foreskin keratinocytes (HFKs) identified changes in several miRNAs, including miRNA 203 (miR-203), which has previously been shown to play an important role in epithelial cell biology by regulating p63 levels. We investigated how expression of human papillomavirus type 16 (HPV16) oncoproteins E6 and E7 affected miR-203 expression during proliferation and differentiation of HFKs. We demonstrated that miR-203 expression is reduced in HFKs where p53 function is compromised, either by the viral oncoprotein E6 or by knockout of p53 using short hairpin RNAs (p53i). We show that the induction of miR-203 observed during calcium-induced differentiation of HFKs is significantly reduced in HFKs expressing E6 and in p53i HFKs. Induction of miR-203 in response to DNA damage is also reduced in the absence of p53. We report that proliferation of HFKs is dependent on the level of miR-203 expression and that overexpression of miR-203 can reduce overproliferation in E6/E7-expressing and p53i HFKs. In summary, these results indicate that expression of miR-203 is dependent on p53, which may explain how expression of HPV16 E6 can disrupt the balance between proliferation and differentiation, as well as the response to DNA damage, in keratinocytes.MicroRNAs (miRNAs) are small, noncoding RNA molecules that can regulate protein expression at the posttranscriptional level by targeting mRNAs for degradation or translational repression (13). Over the past decade, a growing body of evidence has shown that they play a fundamental role in the development, function, and maintenance of tissues and cells in various organisms. Their importance is perhaps best demonstrated by studies on the RNase Dicer, which plays an integral role in the processing and generation of mature miRNA molecules, as mutations in Dicer cause severe developmental defects in Caenorhabditis elegans (22), while knockout of Dicer in mice is embryonically lethal (3). Moreover, it is now known that many miRNAs are implicated in several disease states, including heart disease (2, 23), viral infection (38), and many different cancers (7, 44), leading to increased interest in the biology and function of individual miRNAs in various cell processes.In skin physiology, miRNAs have been shown to be involved both in normal processes, including epidermal development and hair follicle morphogenesis (48), and in skin-specific pathologies, such as psoriasis (37), systemic lupus erythematous (SLE) (8), and skin carcinogenesis (14). The importance of miRNAs in skin epithelial development is particularly emphasized when their expression is repressed by epidermal cellspecific deletion of Dicer in mouse models, which results in several defects, such as epidermal evagination and abnormal hair follicle development, although it is worth noting that epidermal differentiation is apparently unaffected (1, 48). To date, several individual miRNAs that are highly expressed in the skin epithelium have been identified, including m...

Background:When single-agent androgen deprivation therapy (ADT) is administered for locally advanced prostate cancer, men usually relapse within 1–2 years with more malignant castrate-resistant disease. The reason for this is currently unknown. We now hypothesise that an initial treatment response that increases tumour hypoxia drives selection of more malignant tumours.Methods:The LNCaP prostate tumour xenografts were analysed for physiological (oxygen and vasculature) and genetic (PCR array) changes during longitudinal treatment with ADT (bicalutamide, 6 or 2 mg kg−1 daily for 28 days).Results:Bicalutamide caused an immediate (within 24 h) dose-dependent fall in oxygenation in LNCaP-luc prostate tumours with a nadir of ≤0.1% oxygen within 3–7 days; this was attributed to a significant loss of tumour microvessels (window chamber study). The hypoxic nadir persisted for 10–14 days. During the next 7 days, tumours regrew, oxygenation improved and the vasculature recovered; this was inhibited by the VEGF inhibitor B20.4.1.1. Gene expression over 28 days showed marked fluctuations consistent with the physiological changes. Accompanying the angiogenic burst (day 21) was a particularly striking increase in expression of genes associated with epithelial-to-mesenchymal transition (EMT). In particular, insulin-like growth factor 1 (IGF-1) showed increases in mRNA and protein expression.Conclusions:Hypoxic stress caused by ADT promotes EMT, providing a mechanism for the cause of malignant progression in prostate cancer.

Colorectal cancer (CRC) is a significant cause of morbidity and mortality in developed countries, with both genetic and environmental factors contributing to the etiology and progression of the disease. Several risk factors have been identified, including positive family history, red meat intake, smoking, and alcohol intake. Protective factors include vegetables, calcium, hormone replacement therapy, folate, nonsteroidal anti-inflammatory drugs, and physical activity. The interaction between these environmental factors, in particular diet and genes, is an area of growing interest. Currently, oncogenes, tumor suppressor genes, and mismatch repair genes are believed to play an essential role in colorectal carcinogenesis. When considering the genetics of CRC, only 10% of cases are inherited and only 2-6% can be ascribed to the highly penetrant genes, such as APC, hMLH and hMSH2. Lower penetrance genes combined with a Western-style diet contribute to the majority of sporadic CRCs. The purpose of this article is to give a brief overview of the epidemiologic studies that have been conducted and present the major findings. Here, we examine the molecular events in CRC, with particular focus on the interaction between genes and environment, and review the most current research in this area.

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