Browsing by keyword "P53"
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Down-regulation of the tumor suppressor miR-34a contributes to head and neck cancer by up-regulating the MET oncogene and modulating tumor immune evasionBACKGROUND: MicroRNAs (miRs) have been shown to play an important role in tumorigenesis, including in head and neck squamous cell carcinoma (HNSCC). The miR-34 family is thought to play a role in tumor suppression, but the exact mechanism of their action in HNSCC is not well understood. Moreover, the impact of chromosomal changes and mutation status on miR-34a expression remains unknown. METHODS: Differential expression of miR-34a, MET, and genomic alterations were assessed in the Cancer Genome Atlas (TCGA) datasets as well as in primary HNSCC and adjacent normal tissue. The biological functions of miR-34a in HNSCC were investigated in samples derived from primary human tumors and HNSCC cell lines. The expression of MET was evaluated using immunohistochemistry, and the molecular interaction of miR-34a and MET were demonstrated by RNA pulldown, RNA immunoprecipitation, luciferase reporter assay, and rescue experiments. Lastly, locked nucleic acid (LNA) miRs in mouse xenograft models were used to evaluate the clinical relevance of miR-34a in HNSCC tumor growth and modulation of the tumor microenvironment in vivo. RESULTS: Chromosome arm 1p loss and P53 mutations are both associated with lower levels of miR-34a. In HNSCC, miR-34a acts as a tumor suppressor and physically interacts with and functionally targets the proto-oncogene MET. Our studies found that miR-34a suppresses HNSCC carcinogenesis, at least in part, by downregulating MET, consequently inhibiting HNSCC proliferation. Consistent with these findings, administration of LNA-miR-34a in an in vivo model of HNSCC leads to diminished HNSCC cell proliferation and tumor burden in vitro and in vivo, represses expression of genes involved in epithelial-mesenchymal transition, and negates the oncogenic effect of MET in mouse tumors. Consistently, LNA-miR-34a induced a decreased number of immunosuppressive PDL1-expressing tumor-associated macrophages in the tumor microenvironment. In HNSCC patient samples, higher levels of miR-34a are significantly associated with a higher frequency of Th1 cells and CD8 naive T cells. CONCLUSIONS: Our results demonstrate that miR-34a directly targets MET and maintains anti-tumor immune activity. We propose miR-34a as a potential new therapeutic approach for HNSCC.
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Expression of mitochondrial membrane-linked SAB determines severity of sex-dependent acute liver injurySAB is an outer membrane docking protein for JNK mediated impaired mitochondrial function. Deletion of Sab in hepatocytes inhibits sustained JNK activation and cell death. Current work demonstrated that increasing SAB enhanced the severity of APAP liver injury. Female mice were resistant to liver injury and exhibited markedly decreased hepatic SAB protein expression versus males. The mechanism of SAB repression involved a pathway from ERalpha to p53 expression which induced miR34a-5p. miR34a-5p targeted the Sab mRNA coding region, repressing SAB expression. Fulvestrant or p53 knockdown decreased miR34a-5p and increased SAB in females leading to increased injury from APAP and TNF/galactosamine. In contrast, ERalpha agonist increased p53 and miR34a-5p which decreased SAB expression and hepatotoxicity in males. Hepatocyte-specific deletion of miR34a also increased severity of liver injury in females, which was prevented by GalNAc-ASO knockdown of Sab. Similar to mice, premenopausal human females also expressed high hepatic p53 and low SAB levels while age-matched males expressed low p53 and high SAB levels, but there was no sex difference of SAB expression in postmenopause. In conclusion, the level of SAB expression determined the severity of JNK dependent liver injury. Females expressed low hepatic SAB protein levels due to an ERalpha-p53-miR34a pathway which repressed SAB expression, accounting for resistance to liver injury.
