Immunological Deficiency Associated With Cigarette Smoke Inhalation by Mice

Inhalation of cigarette whole smoke (CWS) or its vapor phase (CVP) significantly impaired immune response capability in mice. Significant immunosuppressive effects on the humoral antibody response to a single antigenic stimulus were evident in animals exposed to smoke for seven days before or two days after administration of antigen. Impairment of the immunological response capability appeared to be temporary, with recovery about 14 days after exposure. Different lengths of exposure prior to antigenic stimulation neither produced an additive impairment of the immunological response nor rendered the experimental animals more tolerant to CWS or CVP. The immunological deficiency was specific to CWS and CVP inhalation rather than to nonspecific debilitating stress factors. The inductive phase was the period of the primary and secondary immune response most sensitive to impairment by exposure to CWS or CVP.     

The proto-oncogene KRAS is targeted by miR-200c

The GTPase K-ras is involved in a variety of cellular processes such as differentiation, proliferation and survival. However, activating mutations, which frequently occur in many types of cancer, turn KRAS into one of the most prominent oncogenes. Likewise, miR-200c is a key player in tumorigenesis functioning as a molecular switch between an epithelial, non-migratory, chemosensitive and a mesenchymal, migratory, chemoresistant state. While it has been reported that KRAS is modulated by several tumor suppressor miRNAs, this is the first report on the regulation of KRAS by miR-200c, both playing a pivotal role in oncogenesis. We show that KRAS is a predicted target of miR-200c and that the protein expression of KRAS inversely correlates with the miR-200c expression in a panel of human breast cancer cell lines. KRAS was experimentally validated as a target of miR-200c by Western blot analyses and luciferase reporter assays. Furthermore, the inhibitory rffect of miR-200c-dependent KRAS silencing on proliferation and cell cycle was demonstrated in dfferent breast and lung cancer cell lines. Thereby, the particular role of KRAS was dissected from the role of all the other miR-200c targets by specific knockdown experiments using siRNA against KRAS. Cell lines harboring an activating KRAS mutation were similarly affected by miR-200c as well as by the siRNA against KRAS. However, in a cell line with wild-type KRAS only miR-200c was able to change proliferation and cell cycle. Our findings suggest that miR-200c is a potent inhibitor of tumor progression and therapy resistance, by regulating a multitude of oncogenic pathways including the RAS pathway. Thus, miR-200c may cause stronger anti-tumor efffects than a specific siRNA against KRAS, emphasizing the potential role of miR-200c as tumor suppressive miRNA