Our results suggested that epigenetic inactivation on multiple TSGs may serve as a key mechanism for the progressive behaviors of SDH-mutated HNPGLs. Thus, an interplay between genetic status, epigenetic alterations, and clinical features might be established in the disease.
The loss of the tumor suppressor neurofibromatosis type 2 gene, encoding merlin, has been considered to be a fundamental event during the malignant progression of various cell types. However, a consensus for the mainstream mechanism, by which merlin deficiency contributes to uncontrolled cellular proliferation, has not been reached. The present study aimed to determine whether silencing of merlin using lentivirus-based short hairpin RNA potentiates cellular proliferation and cell cycle progression in human colon carcinoma HCT116 cell lines, expressing p53. The present results demonstrated that merlin knockdown contributed to cellular proliferation and G1/S cell cycle progression to a greater extent in HCT116 cells wide-type for p53 (p53wt) compared with p53-null (p53−/−) cells. This was supported by overexpression experiments which demonstrated a significant inhibitory effect of excess merlin on cellular proliferation only in HCT116 p53wt cells. In order to investigate the underlying mechanisms of action, the expression of p53-involved G1/S transition genes was evaluated by western blot analysis. For HCT116 p53wt cells, merlin loss suppressed p53 expression, and therefore the dysregulation of cell cycle regulatory proteins, including p21, cyclin D1/cyclin-dependent kinase (CDK)4 and cyclin E1/CDK2 complexes. However, merlin knockdowns had no impact on the expression of any of the aforementioned molecules in p53−/− cells, indicating that lack of merlin resulted in G1/S cell cycle progression, and thereby uncontrolled cellular proliferation mainly via the regulation of p53-mediated pathways. Taken together, it was proposed that p53 performs an essential role in mediating the oncogenic stimulus triggered by merlin loss, and p53 is a molecule that should be investigated for its potential in targeted drug therapy for merlin-deficient malignancies.
Background: Oral lichen planus (OLP) is a mucocutaneous inflammatory disease affecting 1% general population. Tripartite motif-containing protein 21 (TRIM21) shows a significant role in OLP. This study aimed to explore the function and mechanism of TRIM21 in T cells of OLP. Methods: Differential gene expression profile in OLP versus healthy controls (HCs) was constructed by RNA sequencing. Protein expression level and infiltration sites of TRIM21 in OLP were detected by immunoblot, immunohistochemistry, and immunofluorescence. Expression of proinflammatory cytokines and chemokines including IL-6, TNF-α, ICAM1, CXCL1, CXCL8, CXCL9, and CXCL11 in CD3 + TRIM21 hi T cells were measured by quantitative real-time polymerase chain reaction analysis. Downstream pathways and substrates of TRIM21 were explored by immunoblot and immunoprecipitation. Whether TRIM21 ubiquitination its substrate and ubiquitination form were tested by ubiquitination assay in vitro.Results: Compared with HCs, TRIM21 exhibited a higher level in OLP, which expressed mainly in CD3 + T lymphocytes in OLP tissues. Overexpressed TRIM21 enhanced the expression of IL-6, TNF-α, CXCL1, CXCL8, CXCL9, and CXCL11 in CD3 + T cell line through ubiquitinating nuclear factor-κB (NF-κB) via a lysine 63 (K63) linkage, which eventually activating NF-κB signaling pathway.
Conclusions:In OLP, TRIM21 promoted inflammation through ubiquitylating NF-κB and activating NF-κB signaling pathway.
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