MiR‑221 and miR‑222 regulate cell cycle progression and affect chemosensitivity in breast cancer by targeting ANXA3
Ju‐Yeon KimEun‐Jung JungJae‐Myung KimYoungsim SonHan Shine LeeSeung-Jin KwagJi‐Ho ParkJin-Kyu ChoHan-Gil KimTaejin ParkSang-Ho JeongChi‐Young JeongYoung‐Tae Ju
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Abstract:
Breast malignancy remains one of the most common causes of cancer‑associated mortalities among women. MicroRNA (miR)‑221 and miR‑222 are homologous miRs and have a substantial impact on cancer progression. In the present study, the regulatory mechanisms of miR‑221/222 and its target annexin A3 (ANXA3) in breast cancer cells were investigated. Breast tissue samples were collected to evaluate the expression patterns of miR‑221/222 levels in breast cancer cell lines and cancer tissues according to clinical characteristics. The levels of miR‑221/222 were increased or decreased in cancer cell lines compared with normal breast cell lines according to cell line subtype. Subsequently, the changes in the progression and invasion of breast cancer cells were investigated using cell proliferation, invasion assay, gap closure and colony formation assays. Western blotting of cell cycle proteins and flow cytometry were performed to evaluate the possible pathway of miR‑221/222 and ANXA3 axis. Chemosensitivity tests were performed to explore the suitability of the miR‑221/222 and ANXA3 axis as a therapeutic target in breast cancer. The expression levels of miR‑221/222 were associated with aggressive characteristics of breast cancer subtypes. Cell transfection assay demonstrated the regulation of breast cancer proliferation and invasiveness by miR‑221/222. MiR‑221/222 directly targeted the 3'‑untranslated region of ANXA3 and suppressed the expression of ANXA3 at the mRNA and protein levels. In addition, miR‑221/222 negatively regulated cell proliferation and the cell cycle pathway in breast cancer cells by targeting ANXA3. In combination with adriamycin, downregulation of ANXA3 may sensitize adriamycin‑induced cell death to induction of persistent G2/M and G0/G1 arrest. Decreased expression of ANXA3 through increased expression of miR‑221/222 reduced breast cancer progression and increased the effectiveness of the chemotherapy drug. The present results indicated the miR‑221/222 and ANXA3 axis to be a possible novel therapeutic target for the treatment of breast cancer.Objective To investigate the effect of miR-20b on cell proliferation and cell cycle in gastric cancer because of up-regulation of miR-20b in gastric cancer.Methods miR-20b mimics and its inhibitor were respectively transfected into MGC 803 gas-tric cancer cell and methyl thiazolyl tetrazolium （ MTT ） and fluorescence-activated cell sorting （ FACS ） were used to analyze cell growth and cell cycle.Western blot was used to explore the molecular basis of miR-20b.Results Compared with its control, cell growth was obvious elevated and the cell cycle transition was also increased from G 1 to S phase after miR-20b mimics transfection .After transfecting miR-20b inhibitor, cell growth was markedly decreased and cell cycle transition was also delayed from G 1 to S phase.Fur-thermore, miR-20b induced the expression of cyclin D1 （CCND1） and C-Myc, decreased the expressions of p21 and p15.Conclu-sions miR-20b was considered as a potential oncogene to modulate cell growth and cell cycle transition through regulating the expres -sion of cell cycle-related genes .
Key words:
微RNAs; MicroRNAs; Stomach neoplasms; Cell proliferation
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The effects of gamigeonsim-tang (GGT) on cellular proliferation and expression of cell cycle-related genes were investigated in human smooth muscle cell HISM. HISM cells were treated with an aqueous extract of GGT. Cellular proliferation was investigated by an immunocytometric analysis of PCNA expression and a flow cytometric analysis of the cell cycle progression. Reduced expression of PCNA and a significant accumulation of G1 phase cells were observed following treatment, indicating that GGT inhibits cellular proliferation of human smooth muscle cells. To explore whether GGT affects the transcription of cell cycle-regulating genes, we evaluated mRNA expression of p53, p21Waf1 PCNA, Cyclin D1, Cdc2, Histone H3, c-Myc, and c-Fos using a quantitative RT-PCR analysis. While increased expressions of two negative cell cycle regulators, p53 and p21Waf1 were found, reduced expressions of cell cycle stimulators, PCNA, c-Fos, and c-Myc, were identified following treatment. Taken together, our study demonstrates that GGT inhibits cellular proliferation of human smooth muscle cell through the up- and down-regulation of growth-inhibiting and growth-promoting genes, respectively.
Cyclin A
Cyclin B1
Restriction point
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Effects of all-trans retinoic acid on cell cycle and proliferation of MCF-7 and expression of restin
To study the role of all-trans retinoic acid(ATRA) in cell cycle, proliferation, differentiation and apoptosis of breast cancer cell line MCF-7 and the expression of restin gene. Methods: The cell cycle was observed by means of flow cytometry(FCM) , the cell proliferation was detected by MTT assay and the expression of restin mRNA was examined by RT-PCR. Results: Under the treatment by ATRA, the cell growth arrested at G1 phase and the proliferation was inhibited greatly. The level of restin mRNA was found to be up-regulated by ATRA in MCF-7 cell. Conclusion: G1 phase arrest and proliferation inhibition were involved in the process that ATRA induces MCF-7 cell differentiation and apoptosis, and restin maybe play an important role in this process, especially the cell apoptosis.
MCF-7
MTT assay
G1 phase
Tretinoin
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Radiotherapy is an important therapeutic strategy for the treatment of numerous types of malignant tumors, including glioma. However, radioresistance and anti‑apoptotic mechanisms decrease the efficacy of radiotherapy in many patients with glioma. BMI1 polycomb ring finger oncogene (Bmi‑1) is an oncogene associated with radioresistance in tumor cells. MicroRNA (miRNA)‑128a is a brain-specific miRNA, which suppresses Bmi‑1 expression. The present study investigated the effects of various radiation intensities on U‑87 MG glioma cells, as well as the role of reactive oxygen species (ROS), Bmi‑1, and miRNA‑128a in the cellular response to radiotherapy. The response of U‑87 MG cells following exposure to X‑ray radiation was assessed using a cell growth curve and inhibition ratio. Cell cycle distribution and the levels of intracellular ROS were evaluated by flow cytometry. The mRNA expression levels of Bmi‑1 and those of miRNA‑128a in U‑87 MG cells exposed to X‑ray radiation were evaluated by reverse transcription‑quantitative polymerase chain reaction. X‑ray radiation did not decrease the number of U‑87 MG cells; however, it did inhibit cellular growth in a dose‑dependent manner. Following exposure to X‑ray radiation for 24 h, cell cycle distribution was altered, with an increase in the number of cells in G0/G1 phase. The mRNA expression levels of Bmi‑1 were downregulated in the 1 and 2 Gy groups, and upregulated in the 6 and 8 Gy groups. The expression levels of miRNA‑128a were upregulated in the 1 and 2 Gy groups, and downregulated in the 8 Gy group. The levels of ROS were increased following exposure to ≥2 Gy, and treatment with N-acetyl cysteine was able to induce radioresistance. These results suggested that U‑87 MG cells exhibited radioresistance. High doses of X‑ray radiation increased the expression levels of Bmi‑1, which may be associated with the evasion of cellular senescence. miRNA‑128a and its downstream target gene Bmi‑1 may have an important role in the radioresistance of U‑87 MG glioma cells. In addition, ROS may be involved in the mechanisms underlying the inhibitory effects of X‑ray radiation in U‑87 MG cells, and the downregulation of ROS may induce radioresistance.
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BMI1
Radiosensitivity
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MicroRNAs (miRNAs/miRs) serve a key role in regulating the cell cycle and inducing tumorigenesis. Subgroup J of the avian leukosis virus (ALV-J) belongs to the family Retroviridae, subfamily Orthoretrovirinae and genus Alpharetrovirus that causes tumors in susceptible chickens. gga-miR-375 is downregulated and Yes-associated protein 1 (YAP1) is upregulated in ALV-J-induced tumors in the livers of chickens, and it has been further identified that YAP1 is the direct target gene of gga-miR-375. In the present study, it was found that ALV-J infection promoted the cell cycle and proliferation in DF-1 cells. As the cell cycle and cell proliferation are closely associated with tumorigenesis, further experiments were performed to determine whether gga-miR-375 and YAP1 were involved in these cellular processes. It was demonstrated that gga-miR-375 significantly inhibited the cell cycle by inhibiting G1 to S/G2 stage transition and decreasing cell proliferation, while YAP1 significantly promoted the cell cycle and proliferation. Furthermore, these cellular processes in DF-1 cells were affected by gga-miR-375 through the targeting of YAP1. Collectively, the present results suggested that gga-miR-375, downregulated by ALV-J infection, negatively regulated the cell cycle and proliferation via the targeting of YAP1.
YAP1
Hippo signaling pathway
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Retinoblastoma protein
G1 phase
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MicroRNAs are a class of small non-coding RNAs that perform a crucial function in posttranscriptional gene regulation. Dysregulation of these microRNAs is associated with many types of cancer progression. In tumorigenesis, downregulated microRNAs might function as a tumour suppressor by repressing oncogenes, whereas overexpressed miRs might function as oncogenes by suppressing tumour suppressor. Similarly, Metadherin (also known as AEG-1/ LYRIC), is an oncogene, the levels of which are found to be very high in various cancers and play a crucial role in the proliferation of cells and invasion. Our review focuses on the study, which shows the alteration of microRNA expression profile and suppression of carcinogenesis when MTDH/AEG-1 is targeted. It summarises the studies where downregulation and upregulation of AEG-1 and microRNAs, respectively, alter the biological functions of the cell, such as proliferation and apoptosis. Studies have reported that AEG-1 can be direct or indirect target of microRNA, which could provide a new-insight to know the underlying molecular mechanism and might contribute to the progress of new therapeutic strategies for the disease.
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Objective To explore the mechanism of Qipiyin on treating psoriasis,and effects on cell cycle and proliferation.Methods The effect of Qipiyin and its components on HaCaT proliferation was measured through MTT method,and flow cytometry analysis was used to detect the content of DNA and cell cycle in various concentrations at different time points.Results Qipiyin could markedly inhibited the proliferation of HaCaT,and the effect was enhanced with concentration.The medicine could also disturbed the distribution of HaCaT cell cycle obviously,which showed that the cell percentage of HaCaT in G0/G1 phase increased and that in S phase decreased.Conclusion The mechanism of Qipiyin inhibiting the proliferation of keratinocyte may be related to the change of cell cycle.
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MTT assay
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B7 homolog 6 (B7‑H6) was recently discovered to act as a co‑stimulatory molecule. In particular, the expression of B7‑H6 has been found to play an important biological role in several types of tumors. The aim of the present study was to determine the role of B7‑H6 in cervical cancer. Immunohistochemistry was used to analyze the expression levels of B7‑H6 in cervical precancerous and cancerous tissues. Furthermore, the expression of B7‑H6 was knocked down in HeLa cells using short hairpin RNA and the effects of B7‑H6 on HeLa cell proliferation, migration and invasion were determined using Cell Counting Kit‑8, colony formation, wound healing and Transwell invasion assays, respectively. In addition, flow cytometry was used to analyze the levels of cell apoptosis and the cell cycle distribution. The results of the immunohistochemical staining revealed that the expression levels of B7‑H6 were upregulated in cervical lesions. Furthermore, the expression levels of B7‑H6 were positively associated with the clinical stage of the cervical lesions. B7‑H6 knockdown suppressed the invasive, migratory and proliferative abilities of HeLa cells, and promoted G1 cell cycle arrest and apoptosis. In conclusion, the findings of the present study suggested that B7‑H6 may serve as a novel oncogene and may hold promise as a potential therapeutic target for cervical cancer.
HeLa
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Emerging evidence suggests the critical function of microRNAs in regulating the growth of cancer cells. In the present study, it was demonstrated that miR‑221‑3p was overexpressed in non‑small cell lung cancer (NSCLC) tissues and cell lines compared with that noted in the normal controls. Downregulation of miR‑221‑3p suppressed the proliferation, colony formation and invasion of NSCLC cells. To further understand the molecular mechanisms underlying the potential oncogenic function of miR‑221‑3p in NSCLC, the downstream targets of miR‑221‑3p were predicted using bioinformatic databases. The prediction suggested the cell cycle regulator p27 as one of the targets of miR‑221‑3p. Molecular experiments showed that miR‑221‑3p was able to bind with the 3'‑untranslated region (UTR) of p27 and decreased the expression of p27 in NSCLC cells. Consistent with the suppressive role of p27 in controlling cell cycle progression, overexpression of miR‑221‑3p decreased the expression of p27 and promoted cell cycle progression from G1 to S phase. Collectively, our findings identified miR‑221‑3p as a novel regulator of NSCLC cell growth via modulating the expression of p27.
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