The role of CCR7 and its atypical chemokine receptor, CCRL1, in lymph node metastasis AND Does Rad6 alter p53 function via pituitary tumour transforming gene 1 (PTTG1) – binding factor (PBF)?

[摘要] Project 1: Background: Metastasis is a highly complex process and the detailed molecular mechanisms are not fully understood. In recent years, a role for chemokine receptors in tumour growth and metastasis has emerged. CCR7 is involved in the regulation of leukocyte homing to regional lymph nodes. Interestingly, invasion of lymphatic vessels by tumour cells and their migration towards draining lymph nodes resembles this process. Several lines of evidence exist to implicate CCR7 in lymph node metastasis. In contrast, little is known about the contribution of CCRL1 to lymph node metastasis.Aims: The main objective was to investigate CCR7-driven metastasis in the lymph node and to assess whether CCRL1 expression affects this process.Methods: Tumour growth was assessed through the immunofluorescent staining of murine lymph node sections. Tumour kinetics was assessed by inoculation of WT and CCRL1-knockout mice with CCR7-expressing B16 melanoma cells.Results: CCR7-expressing B16 melanoma establishes in the B cell areas of the lymph node and suppresses both CCRL1 and CCL21 expression in the sinus. Depletion of CCRL1 does not affect metastatic growth. However, CCRL1-knockout mice develop primary melanoma tumours with enhanced kinetics.Discussion: These findings provide further insight into the role of chemokine receptors in melanoma metastasis. Project 2: Background: DNA damage checkpoints are essential for the suppression of genome instability, one of the main driving forces of tumour progression. The tumour suppressor, p53, is indispensible for the repair of damaged DNA and, as such, is tightly regulated. Pituitary tumour transforming gene 1 (PTTG1)-binding factor (PBF), a poorly characterised proto-oncogene, and Rad6, an E2 ubiquitin ligase, have both been reported to regulate p53 stability and function. Furthermore, Rad6 expression appears to be induced by overexpression of PBF.Aims: The main objective was to investigate whether oncogenic levels of PBF promote p53 turnover through Rad6 activity. Further research involved determining whether Rad6 expression is altered in thyroid cancer.Methods: Western blotting and Taqman RT-PCR were used to assess the level of PBF, Rad6 and p53 expression in thyroid cancer cell lines and in matched human normal and thyroid cancer specimens. Co-immunoprecipitation assays were performed to determine whether Rad6 and PBF physically interact.Results: PBF directly binds to Rad6 and may regulate p53 stability and function via this interaction. In addition, Rad6 expression is induced in thyroid cancer and appears to positively correlate with PBF expression.Discussion: The report demonstrates a potential mechanism by which PBF may be regulating p53 stability.

[发布机构] University:University of Birmingham;Department:School of Immunity and Infection

[关键词] Q Science;QH Natural history;QH426 Genetics