Adaptor proteins are essential proteins involved in the regulation of signal transduction pathways. XB130 is one type of adaptor proteins, which functions as an intracellular mediator for regulating cellular activities, such as cell proliferation, cell survival, cell migration, invasion, and cytoskeleton regulation, in various normal and cancer cells. Currently, the exact physiological roles of XB130 in in vivo tumorigenesis remain unknown. To investigate its functions, two studies were performed using XB130-deleted mice: (1) a two-stage dimethylbenzanthracene (DMBA)/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced skin tumorigenesis study, and (2) a study on spontaneous tumorigenesis of aged mice.
First, through the carcinogen-induced tumorigenesis approach, XB130 is identified as a putative tumor suppressor and regulator of inflammatory response. The multiplicity and size of DMBA (mutagen)/TPA (tumor promoter)-induced epidermal tumors in XB130 knockout (XB130-/-) males were significantly increased compared with those of wild-type (XB130+/+) littermate males. In the absence of XB130, keratinocyte proliferation, edema formation, neutrophil infiltration, expression of pro-inflammatory cytokines, as well as inflammation- and cell proliferation-related signaling pathways were altered dramatically in response to repeated TPA stimuli in males. These changes may have orchestrated tumor microenvironment favoring the skin tumorigenesis in XB130-/- mice.
In the second study, aged XB130-/- mice had increased spontaneous occurrence of benign enlarged thyroid glands with various nodules, which were diagnosed as multinodular goiters. XB130-/- thyroid glands exhibited architectural distortion with higher proliferation of follicular cells in nodules, as well as disrupted expression and distribution of cytoskeleton elements and junction proteins. XB130-/- mice were hypothyroid, displaying defective organification of iodide during perchlorate discharge test and reduced expression of iodinated thyroglobulin. XB130 was confirmed to be localized at the apical side of thyroid follicles at which thyroglobulin iodination normally occurs. As compensatory mechanism to the loss of XB130, thyroperoxidase (TPO) activity was enhanced in aged XB130-/- thyroid glands, with increased affinity of TPO for iodide and higher expression of TPO protein. Thus, XB130 deficiency led to the pathogenesis of benign multinodular goiters as the manifestation of dyshormonogenic hypothyroidism.
In summary, this work highlighted the tumor-suppressive role of XB130 in carcinogen-induced tumorigenesis study and introduced its novel involvement in thyroid function through spontaneous tumorigenesis study.Ph.D.2021-11-30 00:00:0
