MiR-193 inhibits bladder cancer progression by targeting N-myc
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ABSTRACT:
PROVIDER: PRJNA691550 | ENA |
REPOSITORIES: ENA
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Project description:Growing evidence has indicated that miR-193 is involved in the initiation and progression of malignancy, such as bladder cancer, hepatocellular carcinoma, renal cell carcinoma, and colorectal cancer. Nevertheless, the mechanisms of miR-193 in the development of metastatic bladder cancer remains unknown. In the current study, we clarified the association of miR-193/N-myc was implicated in cancer metastasis. miR-193 expression increased in metastatic bladder cancer biopsies compared to the primary cases. Moreover, the elevation of miR-193 was correlated with the invasiveness, lymph node metastasis, and advanced stages of bladder cancer significantly. Downregulation of miR-193 by shRNA hampered proliferation and migration while inducing cell apoptosis. Furthermore, miR-193 sponged N-myc and diminished miR-103 expression. Overexpression of miR-193 released oncogene N-myc expression, leading to the promotion of cell proliferation and migration. Besides, knockout of miR-193 suppressed tumor growth in the human T24 mice models. Briefly, the present findings suggested that miR-193-N-myc were novel promising pathways for conquering bladder cancer progression.
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Project description:Tumor necrosis factor (TNF) receptor-associated factor (TRAF)-interacting protein (TRAIP), a RING domain-containing E3 ligase, has emerged as a key player in safeguarding genome integrity and is closely linked to cancer. Here, we discovered that TRAIP exhibits low expression in bladder cancer (BLCA), which correlates with poor prognosis. TRAIP exerts inhibitory effects on bladder cancer cell proliferation and migration both in vitro and in vivo. MYC serves as a newly identified target for TRAIP, with direct interaction leading to the promotion of K48 polyubiquitination at K428/430 lysine residues, subsequently resulting in proteasome-dependent degradation and downregulation of MYC's transcriptional activity. This process effectively hinders the progression of bladder cancer. Restoration of MYC expression rescues the suppressed proliferation and migration of bladder cancer cells induced by TRAIP. Furthermore, our investigation also demonstrates that MYC binds to the transcriptional start region of TRAIP, exerting regulatory control over TRAIP transcription. Consequently, this interaction establishes a negative feedback loop that prevents excessive expression of MYC. In summary, our study uncovers a novel mechanism by which TRAIP inhibits the progression of bladder cancer through the ubiquitinated degradation of MYC.
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Project description:Hitherto, most studies on POLD1 have mainly focused on the effect of POLD1 inactivation mutation in tumors. Nonetheless, the mechanism underlying high POLD1 expression in tumorigenesis remains elusive. Herein, we substantiated the pro-carcinogenic role of POLD1 in bladder cancer (BLCA) and found that POLD1 expression is related to malignancy and prognosis of BLCA. Next, we demonstrated that POLD1 could promote proliferation and metastasis of BLCA via MYC. Mechanistically, we demonstrated that POLD1 was able to stabilize MYC in a manner independent of DNA polymerase activity. POLD1 attenuated the FBXW7-mediated ubiquitination degradation of MYC by directly binding to the MYC homology box 1 domain competitively with FBXW7. Moreover, we found that POLD1 can form a complex with MYC to promote the transcriptional activity of MYC. MYC could also transcriptionally activate POLD1, forming a POLD1-MYC positive feedback loop to enhance the pro-carcinogenic effect of POLD1-MYC on BLCA. Overall, our study suggests a novel MYC-driven mechanism for BLCA, and POLD1 has the potential as a biomarker for BLCA.
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