Rabbit Anti-Human RRAS2 Polyclonal antibody

Mouse models of cancers are routinely used to study cancer biology. However, it remains unclear whether carcinogenesis in mice is driven by the same spectrum of genomic alterations found in humans. Here we conducted a comprehensive genomic analysis of 9,10-dimethyl-1,2-benzanthracene (DMBA)-induced skin cancer, the most commonly used skin cancer model, which appears as benign papillomas that progress into squamous cell carcinomas (SCCs). We also studied genetically induced SCCs that expressed G12D mutant Kras (Kras G12D) but were deficient for p53. Using whole-exome sequencing, we uncovered a characteristic mutational signature of DMBA-induced SCCs. We found that the vast majority of DMBA-induced SCCs presented recurrent mutations in Hras, Kras or Rras2 and mutations in several additional putative oncogenes and tumor-suppressor genes. Similar genes were recurrently mutated in mouse and human SCCs that were from different organs or had been exposed to different carcinogens. Invasive SCCs, but not papillomas, presented substantial chromosomal aberrations, especially in DMBA-induced and genetically induced Trp53-mutated SCCs. Metastasis occurred through sequential spreading, with relatively few additional genetic events. This study provides a framework for future functional cancer genomic studies in mice.

MicroRNA (miRNA)-mediated regulation of the cellular transcriptome is an important epigenetic mechanism for fine-tuning regulatory pathways. These include processes related to skin cancer development, progression and metastasis. However, little is known about the role of microRNA as an intermediary in the carcinogenic processes following exposure to UV-radiation. We now show that UV irradiation of human primary keratinocytes modulates the expression of several cellular miRNAs. A common set of miRNAs was influenced by exposure to both UVA and UVB. However, each wavelength band also activated a distinct subset of miRNAs. Common sets of UVA- and UVB-regulated miRNAs harbor the regulatory elements GLYCA-nTRE, GATA-1-undefined-site-13 or Hox-2.3-undefined-site-2 in their promoters. In silico analysis indicates that the differentially expressed miRNAs responding to UV have potential functions in the cellular pathways of cell growth and proliferation. Interestingly, the expression of miR-23b, which is a differentiation marker of human keratinocytes, is remarkably up-regulated after UVA irradiation. Studying the interaction between miR-23b and its putative skin-relevant targets using a Luciferase reporter assay revealed that RRAS2 (related RAS viral oncogene homolog 2), which is strongly expressed in highly aggressive malignant skin cancer, to be a direct target of miR-23b. This study demonstrates for the first time a differential miRNA response to UVA and UVB in human primary keratinocytes. This suggests that selective regulation of signaling pathways occurs in response to different UV energies. This may shed new light on miRNA-regulated carcinogenic processes involved in UV-induced skin carcinogenesis.