miR-199a-5p Represses Protective Autophagy and Overcomes Chemoresistance by Directly Targeting DRAM1 in Acute Myeloid Leukemia

Yang, Li; Zhang, Guojun; Wu, Bin; Yang, Wenyan; Liu, Zhuogang

doi:10.1155/2019/5613417

Cited by 24 publications

(21 citation statements)

References 52 publications

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“…Previous studies have reported the downregulation of miR-199a-5p levels in drug-resistant cell lines compared with those in the corresponding parental cell lines (19)(20)(21). However, the present study was the first to reveal that the levels of miR-199a-5p were upregulated in MDR lung cancer cells compared with those in the parental cell lines.…”

Section: Discussioncontrasting

confidence: 69%

“…However, the present study was the first to reveal that the levels of miR-199a-5p were upregulated in MDR lung cancer cells compared with those in the parental cell lines. In the present study, RT-qPCR results demonstrated that the levels of miR-199a-5p were upregulated in PTX-resistant A549/T cells compared with those in the parental cells, which was different from imatinib-resistant K562, cisplatin-treated MG63 and Adriamycin-resistant K562 cells in previous studies (19)(20)(21). These results suggested that the effects of miR-199a-5p on MDR induction were cell line-specific.…”

Section: Discussioncontrasting

confidence: 44%

“…Notably, miR-199a-5p is involved in autophagy and drug resistance in osteosarcoma cells (19). Previous studies have demonstrated the miR-199a-5p reverses drug resistance by targeting DNA damage-regulated autophagy modulator 1 to inhibit protective autophagy or by repressing the Wnt2-mediated autophagy signaling pathway in leukemia cells (20,21). However, the direct target and detailed mechanism of miR-199a-5p in autophagy regulation in multidrug-resistant lung cancer cells have not been clarified to date.…”

Section: Introductionmentioning

confidence: 99%

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Autophagy inhibition and microRNA‑199a‑5p upregulation in paclitaxel‑resistant A549/T lung cancer cells

Zeng

Zhang

et al. 2021

Oncol Rep

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Multidrug resistance (MDR) is one of the major reasons for the clinical failure of cancer chemotherapy. Autophagy activation serves a crucial role in MDR. However, the specific molecular mechanism linking autophagy with MDR remains unknown. The results of the present study demonstrated that autophagy was inhibited and microRNA (miR)-199a-5p levels were upregulated in MDR model lung cancer cells (A549/T and H1299/T) compared with those in the parental cell lines. Paclitaxel (PTX) treatment increased the expression levels of miR-199a-5p in parental lung cancer cells compared with those in PTX-untreated cells, and these expression levels were negatively correlated with PTX sensitivity of the cells. miR-199a-5p knockdown in A549/T cells induced autophagy and resensitized cells to multiple chemotherapeutic drugs including PTX, taxotere, topotecan, SN38, oxaliplatin and vinorelbine. By contrast, miR-199a-5p overexpression in A549 cells suppressed autophagy and desensitized cells to these chemotherapeutic drugs. Mechanistically, the results of the present study demonstrated that miR-199a-5p blocked autophagy by activating the PI3K/Akt/mTOR signaling pathway and inhibiting the protein expression of autophagy-related 5. Furthermore, p62 protein was identified as a direct target of miR-199a-5p; miR-199a-5p bound to p62 mRNA to decrease its mRNA and protein expression levels. In conclusion, the results of the present study suggested that miR-199a-5p may contribute to MDR development in lung cancer cells by inhibiting autophagy and targeting p62. The regulatory effect of miR-199a-5p on autophagy may provide novel insights for future multidrug-resistant lung cancer chemotherapy.

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Section: Discussioncontrasting

confidence: 69%

Section: Discussioncontrasting

confidence: 44%

Section: Introductionmentioning

confidence: 99%

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Autophagy inhibition and microRNA‑199a‑5p upregulation in paclitaxel‑resistant A549/T lung cancer cells

Zeng

Zhang

et al. 2021

Oncol Rep

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“…Upregulation of DRAM1 has been associated with increased levels of irradiation-induced autophagy in breast cancer cells 41 . While downregulation of DRAM1 gene suppressed autophagy and increased chemosensitivity of acute myeloid leukemia (AML) cells 42 . In the present study, we found that FTSJ1 could interact with DRAM1 in NSCLC cells, our findings underscored the complicity of tRNA modifications and their regulatory enzymes in NSCLC.…”

Section: Discussionmentioning

confidence: 99%

FTSJ1 regulates tRNA 2ʹ-O-methyladenosine modification and suppresses the malignancy of NSCLC via inhibiting DRAM1 expression

Yang

Gao

et al. 2020

Cell Death Dis

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Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality worldwide. The mechanisms underlying NSCLC tumorigenesis are incompletely understood. Transfer RNA (tRNA) modification is emerging as a novel regulatory mechanism for carcinogenesis. However, the role of tRNA modification in NSCLC remains obscure. In this study, HPLC/MS assay was used to quantify tRNA modification levels in NSCLC tissues and cells. tRNA-modifying enzyme genes were identified by comparative genomics and validated by qRT-PCR analysis. The biological functions of tRNA-modifying gene in NSCLC were investigated in vitro and in vivo. The mechanisms of tRNA-modifying gene in NSCLC were explored by RNA-seq, qRT-PCR, and rescue assays. The results showed that a total of 18 types of tRNA modifications and up to seven tRNA-modifying genes were significantly downregulated in NSCLC tumor tissues compared with that in normal tissues, with the 2ʹ-O-methyladenosine (Am) modification displaying the lowest level in tumor tissues. Loss-and gain-of-function assays revealed that the amount of Am in tRNAs was significantly associated with expression levels of FTSJ1, which was also downregulated in NSCLC tissues and cells. Upregulation of FTSJ1 inhibited proliferation, migration, and promoted apoptosis of NSCLC cells in vitro. Silencing of FTSJ1 resulted in the opposite effects. In vivo assay confirmed that overexpression of FTSJ1 significantly suppressed the growth of NSCLC cells. Mechanistically, overexpression of FTSJ1 led to a decreased expression of DRAM1. Whereas knockdown of FTSJ1 resulted in an increased expression of DRAM1. Furthermore, silencing of DRAM1 substantially augmented the antitumor effect of FTSJ1 on NSCLC cells. Our findings suggested an important mechanism of tRNA modifications in NSCLC and demonstrated novel roles of FTSJ1 as both tRNA Am modifier and tumor suppressor in NSCLC.

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“…miRNAs participate in the regulation of various biological events, including tumor growth, invasion, metastasis and angiogenesis ( 15 ). miRNA (miR)-199a-5p belongs to the miR-199a family, which has been demonstrated to participate in the progression of multiple diseases such as acute myeloid leukemia ( 16 ) and cervical cancer ( 17 ). Dai et al ( 18 ) reported that miR-199a-5p prevented hepatocyte damage induced by bile acid.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA‑199a‑5p suppresses cell proliferation, migration and invasion by targeting ITGA3 in colorectal cancer

Tian

Chen

et al. 2020

Mol Med Rep

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as a member of the integrin family, integrin α3β1 (iTGa3) has been linked to intercellular communication and serves an important role in the signaling among cells and the extracellular matrix. Microrna (mir)-199a-5p has been demonstrated to be related to the pathogenesis and progression of multiple malignant diseases. However, the biological functions of mir-199a-5p and iTGa3 in colorectal cancer (crc) have rarely been reported. The aim of the present study was to explore the roles of mir-199a-5p and iTGa3 in crc. immunohistochemistry staining and western blotting were applied to detect the protein expression of iTGa3 in crc tissues and cells. reverse transcription-quantitative Pcr was performed to investigate the expression of mir-199a-5p and iTGa3 mrna. HcT-116 cells were transfected with mir-199a-5p mimics, mimics control, short hairpin rna targeting iTGa3, or pcdna-iTGa3 for the functional experiments. dual luciferase reporter assay was applied to confirm whether mir-199a-5p targeted the 3' untranslated region (3'uTr) of iTGa3. The MTT, Transwell and wound healing assays were used to evaluate the proliferation, invasion and migration of CRC cells. Immunofluorescence assay was used to monitor the epithelial-mesenchymal transition (eMT) biomarker expression. The results demonstrated downregulation of mir-199a-5p and upregulation of iTGa3 in crc tissues and cell lines. mir-199a-5p mimics and knockdown of iTGa3 suppressed the proliferation, invasion and migration of crc cells. Bioinformatics analysis and luciferase reporter assay indicated that mir-199a-5p targeted the 3'uTr of the iTGa3 transcript, and overexpression of iTGa3 reversed the tumor-suppressive effects of mir-199a-5p elevation. In addition, the immunofluorescence assay suggested that mir-199a-5p mimics suppressed the eMT of crc cells, whereas the overexpression of iTGa3 restored this effect. in conclusion, mir-199a-5p may act as a tumor suppressor by targeting and negatively regulating iTGa3 in crc.

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miR-199a-5p Represses Protective Autophagy and Overcomes Chemoresistance by Directly Targeting DRAM1 in Acute Myeloid Leukemia

Cited by 24 publications

References 52 publications

Autophagy inhibition and microRNA‑199a‑5p upregulation in paclitaxel‑resistant A549/T lung cancer cells

Autophagy inhibition and microRNA‑199a‑5p upregulation in paclitaxel‑resistant A549/T lung cancer cells

FTSJ1 regulates tRNA 2ʹ-O-methyladenosine modification and suppresses the malignancy of NSCLC via inhibiting DRAM1 expression

MicroRNA‑199a‑5p suppresses cell proliferation, migration and invasion by targeting ITGA3 in colorectal cancer

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