miRNA-214 modulates radiotherapy response of non-small cell lung cancer cells through regulation of p38MAPK, apoptosis and senescence

Salim, Hogir; Akbar, Nadeem S.; Zong, Dali; Vaculová, Alena Hyršlová; Lewensohn, Rolf; Moshfegh, Ali; Viktorsson, Kristina; Zhivotovsky, Boris

doi:10.1038/bjc.2012.382

Cited by 102 publications

(74 citation statements)

References 57 publications

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“…p38 MAPK could promote apoptosis of lung adenocarcinoma cells via the regulation of the expression of the apoptosis-related proteins Bax and Bcl2 (29). The downregulation of p38 MAPK could reverse the radiotherapy resistance caused by the overexpression of miRNA (30). The present study found that after FANCD2 was silenced by shRNA interference, the expression of the p38 protein in the cells of the experimental group was decreased, while the expression of the p-p38 protein was increased compared with the expression in the control groups.…”

Section: Discussionmentioning

confidence: 99%

Silencing of FANCD2 enhances the radiosensitivity of metastatic cervical lymph node-derived head and neck squamous cell carcinoma HSC-4 cells

Feng

Bao

Zeng

et al. 2017

International Journal of Oncology

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Abstract. Fanconi anemia complementation group D2 (FANCD2) is involved in the key steps of the Fanconi anemia (FA) pathway, which plays a role in the repair of DNA crosslink damage. However, the role of FANCD2 during radiotherapy for head and neck squamous cell carcinoma (HNSCC) is unclear. In this study, the HNSCC cell line HSC-4 was used. Western blotting was used to evaluate the expression of the FANCD2 in HSC-4 cells. We investigated the impact of FANCD2 on the radiosensitivity of HSC-4 cells in vitro and in vivo. TUNEL, western blotting and immunohistochemistry were used to analyze the apoptosis and proteins involved in apoptosisrelated pathways after radiotherapy to investigate the relevant mechanism. The present study showed that shRNA interference could effectively and stably silence FANCD2 expression in HSC-4 cells. In vitro, the silencing of FANCD2 inhibited cell proliferation, decreased the survival rate, increased apoptosis and induced S phase arrest in HSC-4 cells after radiotherapy. In vivo, the silencing of FANCD2 could prolong the tumor-forming time and slow tumor growth. In addition, the tumor volume was significantly reduced, the weight was deceased, and the tumor inhibition rate was increased after radiotherapy. TUNEL showed that the silencing of FANCD2 significantly increased apoptosis in HSC-4 cells induced by radiotherapy. Both in vitro and in vivo esperiments revealed that the expression of the Bax and p-p38 proteins in HSC-4 cells, in which FANCD2 had been silenced, was increased after radiotherapy, whereas the expression of the p38 and Bcl2 proteins was decreased. Our results suggested that the silencing of FANCD2 enhanced the radiosensitivity of HSC-4 cells, and its mechanism involves the activation of the p38 MAPK signaling pathway and the regulation of the expression of Bax and Bcl2 proteins. This study provides a novel candidate target for HNSCC therapy.

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Section: Discussionmentioning

confidence: 99%

Silencing of FANCD2 enhances the radiosensitivity of metastatic cervical lymph node-derived head and neck squamous cell carcinoma HSC-4 cells

Feng

Bao

Zeng

et al. 2017

International Journal of Oncology

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“…There were also several studies showing that miRNAs were associated with radiosensitivity in lung cancer. Radiotherapy response of lung cancer cells was modulated by miR‐214 through regulation of p38 MAPK, apoptosis, and senescence 19. The radiosensitization of lung cancer cells was induced by miR‐122 via targeting BCL‐W and IGF1R 59.…”

Section: Discussionmentioning

confidence: 99%

“…Usually, one miRNA regulates multiple targets and could be regulated by multiple genes 13. It has been reported that miRNAs are involved in tumorigenesis, cell cycle, cell proliferation, apoptosis, tumor microenviroment, and radioresistance, acting as tumor suppressors or tumor promoters 14, 15, 16, 17, 18, 19, 20. It has also been verified that miRNAs are related to biological characteristics of cancer stem‐like cells, such as self‐renewal, proliferation, invasion, and radiotherapy or chemotherapy resistance 21, 22…”

Section: Introductionmentioning

confidence: 98%

Radiosensitizing effects of miR‐18a‐5p on lung cancer stem‐like cells via downregulating both ATM and HIF‐1α

Chen

et al. 2018

Cancer Medicine

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Lung cancer is one of the main causes of cancer mortality globally. Most patients received radiotherapy during the course of disease. However, radioresistance generally occurs in the majority of these patients, leading to poor curative effect, and the underlying mechanism remains unclear. In the present study, miR‐18a‐5p expression was downregulated in irradiated lung cancer cells. Overexpression of miR‐18a‐5p increased the radiosensitivity of lung cancer cells and inhibited the growth of A549 xenografts after radiation exposure. Dual luciferase report system and miR‐18a‐5p overexpression identified ataxia telangiectasia mutated (ATM) and hypoxia inducible factor 1 alpha (HIF‐1α) as the targets of miR‐18a‐5p. The mRNA and protein expressions of ATM and HIF‐1α were dramatically downregulated by miR‐18a‐5p in vitro and in vivo. Clinically, plasma miR‐18a‐5p expression was significantly higher in radiosensitive than in radioresistant group (P < .001). The cutoff value of miR‐18a‐5p >2.28 was obtained from receiver operating characteristic (ROC) curve. The objective response rate (ORR) was significantly higher in miR‐18a‐5p‐high group than in miR‐18a‐5p‐low group (P < .001). A tendency demonstrated that the median local progression‐free survival (PFS) from radiotherapy was longer in miR‐18a‐5p‐high than in miR‐18a‐5p‐low group (P = .082). The median overall survival (OS) from radiotherapy was numerically longer in miR‐18a‐5p‐high than in miR‐18a‐5p‐low group (P = .281). The sensitivity and specificity of plasma miR‐18a‐5p to predict radiosensitivity was 87% and 95%, respectively. Collectively, these results indicate that miR‐18a‐5p increases the radiosensitivity in lung cancer cells and CD133+ stem‐like cells via downregulating ATM and HIF‐1α expressions. Plasma miR‐18a‐5p would be an available indicator of radiosensitivity in lung cancer patients.

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“…The targets of miR-199a, V-Ki-Ras2 Kirsten rat sarcoma viral oncogene homolog and mitogen-activated protein kinase kinase 4 have been identified (28)(29)(30)(31), and the inhibitory effects of miR-199a and/or miR-214 on the expression of these target genes have been demonstrated (31). miR-199a and miR-214 may have important roles in cell growth and proliferation via the mitogen-activated protein kinase pathway (31,32).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA‑30a suppresses non‑small‑cell lung cancer by targeting Myb‑related protein B

et al. 2017

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Abstract. Non-small-cell lung cancer (NSCLC) is one of the leading causes of cancer mortality worldwide. A growing body of evidence indicates that microRNA (miR) have important and diverse roles in the proliferation, apoptosis and metastasis of human cancer cells. In the present study, the molecular regulation mechanism of miR-30a and its potential target, Myb-related protein B (MYBL2) was investigated in NSCLC. Reverse transcription-quantitative polymerase chain reaction results showed that miR-30a was significantly downregulated in NSCLC tissues compared with adjacent normal tissues (P<0.05). MYBL2 has a putative miR-30a target site in its 3'untranslated region according to previous data, prediction databases and TargetScan software. In the present study, a negative correlation was demonstrated between miR-30a and MYBL2 expression in NSCLC. Direct interaction between miR-30a and MYBL2 was also confirmed via a dual-luciferase reporter assay. miR-30a overexpression inhibited the growth of A549 and H460 cells via MTT and bromodeoxyuridine incorporation assays, whereas miR-30a downregulation promoted cell proliferation. In addition, miR-30a overexpression not only increased cell apoptosis and induced cell cycle arrest in A549 and H460 cell lines, but also attenuated tumor growth, and mRNA and protein expression levels of MYBL2. The present findings suggest that miR-30a may suppress NSCLC by targeting MYBL2.

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miRNA-214 modulates radiotherapy response of non-small cell lung cancer cells through regulation of p38MAPK, apoptosis and senescence

Cited by 102 publications

References 57 publications

Silencing of FANCD2 enhances the radiosensitivity of metastatic cervical lymph node-derived head and neck squamous cell carcinoma HSC-4 cells

Silencing of FANCD2 enhances the radiosensitivity of metastatic cervical lymph node-derived head and neck squamous cell carcinoma HSC-4 cells

Radiosensitizing effects of miR‐18a‐5p on lung cancer stem‐like cells via downregulating both ATM and HIF‐1α

MicroRNA‑30a suppresses non‑small‑cell lung cancer by targeting Myb‑related protein B

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