miR-34a directly targets tRNA
            <sub>i</sub>
            <sup>Met</sup>
            precursors and affects cellular proliferation, cell cycle, and apoptosis

Wang, Bo; Li, Dongping; Kovalchuk, Igor; Apel, Ingrid J.; Chinnaiyan, Arul M.; Wóycicki, Rafał; Cantor, Charles R.; Kovalchuk, Olga

doi:10.1073/pnas.1703029115

Cited by 50 publications

(53 citation statements)

References 34 publications

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“…4A). miRs exert their gene expression regulatory function through translational inhibition or transcript degradation via Argonaute 2 (AGO2)-catalyzed cleavage (47). Thus, we assessed the association of Ago2 with miR-34a-5p and MET to determine whether miR-34a was recruiting AGO2 to MET mRNA.…”

Section: Resultsmentioning

confidence: 99%

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Down-regulation of tumor suppressor miR-34a contributes to head and neck cancer by up-regulating MET oncogene and modulating tumor immune evasion

Cheng

Mathew

et al. 2020

Preprint

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Background: MicroRNAs (miRs) have been shown to play an important role in tumorigenesis, including in head and neck squamous cell carcinoma (HNSCC). The miR-34a family is thought to play a role in tumor suppression, but the exact mechanism of action in HNSCC is not well understood. In addition, miR-34a is generally down-regulated HNSCC, but the role of chromosomal changes and mutation status on miR-34a expression remain unknown. Methods: Differential expression of miR-34a-3p, MET, and genomic alterations were assessed in the Cancer Genome Atlas (TCGA) datasets as well as primary HNSCC and adjacent normal tissue. The biological functions of miR-34a in HNSCC were investigated in samples derived from primary human tumors. The expression of MET was evaluated using immunohistochemistry, and the molecular interaction of miR-34a and MET were demonstrated by RNA pulldown, RNA immunoprecipitation, and rescue experiments. Lastly, mouse xenograft and locked nucleic acid anti-miRs 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. We found that miR-34a suppresses HNSCC carcinogenesis, at least in part, by downregulating MET, consequently inhibiting HNSCC proliferation. Moreover, ectopic expression of miR-34a reduces 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. In HNSCC patient samples, higher levels of miR-34a are significantly associated with a higher frequency of Th1 cells, myeloid cells, and regulatory T cells. Consistent with these findings, inhibition of miR-34a in an in vivo model of HNSCC leads to an increased number of immunosuppressive PDL1-expressing tumor-associated macrophages in the tumor microenvironment. Conclusions: Our results demonstrate that miR-34a directly targets MET and maintains anti-tumor immune activity, and could potentially represent a new therapeutic approach for HNSCC.

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Section: Resultsmentioning

confidence: 99%

“…The results were similar in HTB-43 cell lines (data not shown). miR-34a has been suggested to play a signi cant role in cancer cell proliferation, apoptosis, and migration (47). Thus, we further investigated the role of miR-34a in head and neck carcinogenesis using a miR-34a-5p mimic, a synthetic miR.…”

Section: Resultsmentioning

confidence: 99%

Down-regulation of tumor suppressor miR-34a contributes to head and neck cancer by up-regulating MET oncogene and modulating tumor immune evasion

Cheng

Mathew

et al. 2020

Preprint

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“…Additional complexity in the regulation of tRNA levels has recently been provided by a report demonstrating that the p53 induced miR-34a post-transcriptionally regulates the initiator tRNA Met [96] (Fig. 3).…”

Section: The P53 Family and Trna Deregulation In Cancermentioning

confidence: 97%

“…Although this is the only case of miRNA-tRNA interaction known so far, these two RNAs create a feedback loop that is highly relevant for human tumours. Indeed, if on one hand miR-34a decreases the levels of tRNA Met , on the other hand the overexpression of this tRNA bypasses the S/G2 cell cycle transition controlled by p53 and miR-34a thus promoting tumour initiation [96]. Furthermore, tRNA Met can sustain tumour progression by increasing the migratory and invasive potential of melanoma cells [97], a property shared with tRNA Glu and tRNA Arg in metastatic breast cancer cells [89].…”

Section: The P53 Family and Trna Deregulation In Cancermentioning

confidence: 99%

The p53 family reaches the final frontier: the variegated regulation of the dark matter of the genome by the p53 family in cancer

Napoli

Flores

2020

RNA Biology

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The tumour suppressor p53 and its paralogues, p63 and p73, are essential to maintain cellular homoeostasis and the integrity of the cell's genetic material, thus meriting the title of 'guardians of the genome'. The p53 family members are transcription factors and fulfill their activities by controlling the expression of protein-coding and non-coding genes. Here, we review how the latter group transcended from the 'dark matter' of the transcriptome, providing unexpected and intriguing anti-cancer therapeutic strategies. ARTICLE HISTORY

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“…Several studies have highlighted the crucial influence of miRNAs on multiple biological reactions, such as cell death. The expression of microRNA‐34a (miR‐34a) is suppressed in malignancies and cellular processes, such as cell differentiation, proliferation, and death . miR‐34a was shown to contribute to senescence regulation triggered via ionizing radiation in human non‐small cell lung cancer cells .…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‐34a‐mediated death of acute myeloid leukemia stem cells through apoptosis induction and exosome shedding inhibition via histone deacetylase 2 targeting

et al. 2020

IUBMB Life

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We investigated the role of leukemia stem cells in chemoresistance and recurrence of acute myeloid leukemia. Total RNA was isolated from cells or tissues using TRIzol reagent. Cell viability was assessed with the tetrazolium assay. MicroRNA‐34a (miR‐34a), which acts on cell death regulation pathways, was noticeably downregulated in non‐M3 acute myeloid leukemia stem cells compared with normal hematopoietic stem cells. Furthermore, inhibition of miR‐34a‐mediated suppression in leukemia stem cells was associated with poor clinical outcomes and impaired treatment efficacy in acute myeloid leukemia. Transfection with a miR‐34a mimic triggered leukemia stem cell death and prevented leukemia. Bioinformatics analysis and a dual‐luciferase reporter assay showed that miR‐34a targeted the 3′‐untranslated region of histone deacetylase 2, and the reinforced expression of miR‐34a remarkably stimulated the expression of histone deacetylase 2 in leukemia stem cells. Ectopic miR‐34a expression triggered death of leukemia stem cells via pathways involving the Janus kinase 1‐signal transducer and activator of transcription 2‐p53 axis. Targeting leukemia stem cells to trigger cell death through upregulation of miR‐34a expression could be used to diagnose and treat acute myeloid leukemia.

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miR-34a directly targets tRNA _i ^Met precursors and affects cellular proliferation, cell cycle, and apoptosis

Cited by 50 publications

References 34 publications

Down-regulation of tumor suppressor miR-34a contributes to head and neck cancer by up-regulating MET oncogene and modulating tumor immune evasion

Down-regulation of tumor suppressor miR-34a contributes to head and neck cancer by up-regulating MET oncogene and modulating tumor immune evasion

The p53 family reaches the final frontier: the variegated regulation of the dark matter of the genome by the p53 family in cancer

MicroRNA‐34a‐mediated death of acute myeloid leukemia stem cells through apoptosis induction and exosome shedding inhibition via histone deacetylase 2 targeting

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miR-34a directly targets tRNA i Met precursors and affects cellular proliferation, cell cycle, and apoptosis

Cited by 50 publications

References 34 publications

Down-regulation of tumor suppressor miR-34a contributes to head and neck cancer by up-regulating MET oncogene and modulating tumor immune evasion

Down-regulation of tumor suppressor miR-34a contributes to head and neck cancer by up-regulating MET oncogene and modulating tumor immune evasion

The p53 family reaches the final frontier: the variegated regulation of the dark matter of the genome by the p53 family in cancer

MicroRNA‐34a‐mediated death of acute myeloid leukemia stem cells through apoptosis induction and exosome shedding inhibition via histone deacetylase 2 targeting

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miR-34a directly targets tRNA _i ^Met precursors and affects cellular proliferation, cell cycle, and apoptosis