Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • Unexpectedly the inhibition of EGFR

    2018-11-15

    Unexpectedly, the inhibition of EGFR induces expression of keratinocyte differentiation markers. Keratinocyte proliferation and differentiation are mutually incompatible: apparently, inhibiting cell proliferation diverts the cells into a differentiation pathway and consequently certain differentiation markers are induced. These include many of the \'classical\' markers, involucrin, keratins KRT1 and KRT10, but also lipid biosynthesis enzymes, lipids being an essential component of the stratum corneum. While both EGF and RA inhibit keratinocyte differentiation, Tyrphostin AG1478 promotes this process. Indeed, we find significant disparity between the effects of Tyrphostin AG1478 and RA: genes induced by one are suppressed by the other and vice versa. Conversely, there are striking parallels with the effects of JNK inhibition: SP600125 and Tyrphostin AG1478 cause similar transcriptional changes in keratinocytes, in particular, changes associated with epidermal differentiation. In a canonical pathway, EGFR activates the ERK signaling cascades. Active ERKs result in activation of, among others, the AP1 transcription factors. JNK is a component of one of the ERK pathways and it also activates AP1. However, inhibitors of EGFR, apparently through unknown, EGFR-independent mechanisms, can activate JNK in keratinocytes . We note that AP1 transcription factor glucose transport proteins are significantly over-represented among both the Tyrphostin AG1478-suppressed and the SP600125-suppressed genes. Therefore we propose that among the signaling pathways inhibited by Tyrphostin AG1478 are those activating the AP1 proteins.
    Acknowledgments
    Introduction Condyloma acuminatum (CA), a common sexually transmitted disease, is characterized by mucocutaneous benign hyperplasia attributed to human papilloma viral (HPV) infection. In the United States, the number of clinically diagnosed CA cases reaches approximately 500,000 to 1,000,000 annually, accounting for 1% of the sexually active population. Current therapies for CA, such as freezing, lasers, fulgerizing, and chemical corrosion, fail to achieve satisfactory results. Therefore, radical treatments for CA and methods to prevent or reduce its recurrence remain a clinical puzzle. To date, more than 130 HPV subtypes have been discovered, more than 40 of which have been found to induce perianal progenital CA. HPV is usually classified into low-risk and high-risk types. The low-risk types (HPV 6, 11, 40, 42, 43, and so on) are correlated with benign diseases such as genital or skin warts, whereas the high-risk types (HPV 16, 18, 31, 33, 35, and so on) are mainly responsible for lesions such as cervical intraepithelial neoplasia (CIN), squamous cell carcinoma (SCC), and so on. The immune system plays a critical role in determining the natural progression of HPV infections and the consequences of HPV-associated diseases, with the failure to establish an effective immune response resulting in the long-term presence and recurrence of CA. Effective cell-mediated immune responses to HPV infection involve viral antigen presentation, immunoreactive activation, and virus-infected target cell removal by effector cells. Patients with persistent HPV infection and those with HPV-induced cervical cancer present with immune evasion or deficiency. This is because changes in the number and functions of infected local dendritic cells (DCs) result in immune supervising system damage; thus, immune responses cannot be effectively activated and virus-infected cells are difficult to remove. Therefore, these changes play an important role in the long-term persistence of viral infection and tumorigenesis. Intraepidermal Langerhans cells (LCs) are immature skin DCs. They process, handle, and present glycolipid and lipid antigens to provide the necessary first and second signals for the activation of antigen-specific T cells, and therefore function as initiators of local specific cell-mediated immune responses and as effective T cell activators. In HPV 16/18–induced CIN and SCC tissues, the antigen presentation function of LC decreases, manifested by decreases in the number and density of LCs and failure in the upregulation of LC surface activity markers and the secreted cytokines, which are responsible for inducing Th1-type cell-mediated immune responses. Epithelial cadherin (E-cadherin) mediates the adherence between epidermal keratinocytes (KCs) and LCs, and it performs a vital role in deciding the localization and retention of LC in the epidermis. Changes in LCs are correlated with changes in the E-cadherin synthesized by HPV 16/18–infected epidermal KC. The changes in E-cadherin play a significant role in the metastasis, intraepidermal retention, activation, and differentiation of LCs. In addition, they greatly influence the KC atypical hyperplasia and malignant transformation induced by high-risk HPV. HPV immune evasion also occurs in progenital local CA skin lesions caused by low-risk HPV 6/11. However, whether similar changes in the number and function of LCs in CIN and SCC also occur under such conditions, and if so, what the detailed mechanism is remain unreported.