Loss of miR-100 enhances migration, invasion, epithelialmesenchymal transition and stemness properties in prostate cancer cells through targeting Argonaute 2

MicroRNAs (miRNAs) are a class of post-transcriptional regulators of gene expression, and AGO2 is essential for miRNA activity. In this study, we focused on the regulation of AGO2 by miR-346 and the consequences in cervical cancer cells. miR-346 enhanced the expression of AGO2, resulting in the increased activity of other miRNAs and contributing to the malignancy of HeLa cells. GRSF1 participated in the regulation of AGO2 by miR-346, and the middle sequence of miR-346 was vital for the synergy effect of miR-346 and GRSF1. We determined that miR-346 promoted the migration and invasion of HeLa cells. In summary, we are the first to report that AGO2 is regulated positively by miRNA and that GRSF1 participates in the miRNA pathway.Cervical cancer is one of the most prevalent gynecological cancers worldwide, accounting for ϳ12% of all cancers globally (1). The etiology of cervical cancer varies, and high-risk human papilloma virus infection is one of the most prominent features of cervical cancer (2). Recently, the role of microRNAs (miRNAs), 2 a class of small RNAs that post-transcriptionally regulate target gene expression in a sequence-specific manner, has received widespread attention (3, 4). The dysregulation of miRNAs affects many aspects of cervical cancer, including cellular apoptosis, cell cycle progression, and cell migration and invasion (5-7). miRNAs are transcribed as long primary transcripts that are subsequently processed by the RNase III proteins Drosha and Dicer to form mature microRNAs (8). Then, a strand of mature miRNA is incorporated into an RNA-induced silencing complex (RISC), where it exerts its effects. AGO2 is a key component of the RISC and is the only AGO2 protein with intrinsic endonuclease activity (9). The expression of AGO2 is tightly regulated at both transcriptional and post-transcriptional levels (10). Dysregulation of AGO2 has been reported in many tumors, including lung cancer (11), prostate cancer (12, 13), hepatocarcinoma (14), and melanoma (15), but the role of AGO2 and how its expression is regulated in cervical cancer have not been well studied.In this study, we found that AGO2 was expressed in cervical cancers and that its expression was enhanced by miR-346 and GRSF1 independent of an increase in AGO2 stability. The increased expression of AGO2 augmented the activity of other miRNAs and promoted the malignant phenotype of cervical cancer cells. These findings could provide new insights into the regulation of AGO2 expression and the mechanisms by which miRNAs up-regulate the expression of their target genes. Materials and Methods Cell Lines and Clinical Tissue Samples-The cancer cell lines used in this study were preserved in liquid nitrogen in our laboratory, and the cells were maintained in standard culture medium as recommended by the ATCC. All transfections were performed with Lipofectamine TM 2000 reagent (Invitrogen) according to the recommendations of the manufacturer. Fourteen pairs of clinical cervical cancer tissues and respective adjacent non-cancerous tissues were...

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“…The expression of AGO2 is dysregulated in many types of cancer (13,15,38), and the dysregulation of AGO2 results in altered miRNA activity.…”

Section: Discussionmentioning

confidence: 99%

“…The expression of AGO2 is tightly regulated at both transcriptional and post-transcriptional levels (10). Dysregulation of AGO2 has been reported in many tumors, including lung cancer (11), prostate cancer (12,13), hepatocarcinoma (14), and melanoma (15), but the role of AGO2 and how its expression is regulated in cervical cancer have not been well studied.…”

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confidence: 99%

miR-346 Up-regulates Argonaute 2 (AGO2) Protein Expression to Augment the Activity of Other MicroRNAs (miRNAs) and Contributes to Cervical Cancer Cell Malignancy

Guo

Liu

et al. 2015

Journal of Biological Chemistry

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“…miRNAs regulate downstream target gene expression at a post-transcriptional level by binding with specific sequences in the 3'-untranslated region (3'-UTR) of downstream target genes, leading to mRNA degradation and/or translational inhibition (12). Several lines of evidence have indicated that aberrant expression of miRNAs is involved in the progression and metastasis of different types of cancer (13)(14)(15)(16)(17)(18). Furthermore, research has indicated that upregulation or downregulation of a certain miRNA (let-7a) was directly correlated with the response to chemotherapeutic agents (19).…”

Section: Introductionmentioning

confidence: 99%

Upregulation of let‑7f‑5p promotes chemotherapeutic resistance in colorectal cancer by directly repressing several pro‑apoptotic proteins

et al. 2018

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Abstract. Colorectal cancer (CRC) is one of the most frequently occurring primary malignant tumors worldwide. Chemotherapeutic resistance is a major clinical problem in the treatment of CRC. Therefore, it is of great importance to investigate novel biomarkers that may predict chemoresistance and facilitate the development of individualized treatment for patients with CRC. The present study reported that let-7f-5p expression was elevated in chemotherapy-resistant CRC tissues compared with chemotherapy-sensitive tissues. Furthermore, upregulating let-7f-5p increased the expression levels of the anti-apoptotic proteins, B-cell lymphoma 2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xL), and decreased the activity of caspase-3 and caspase-9 in CRC cells. By contrast, downregulating let-7f-5p yielded the opposite effect. Notably, the results indicated that let-7f-5p promoted chemotherapeutic resistance by directly repressing the expression of several pro-apoptotic proteins, including tumor protein p53, tumor protein p53-inducible nuclear protein 1, tumor protein p53-inducible nuclear protein 2 and caspase-3. Therefore, a novel mechanism by which let-7f-5p enhances the resistance of CRC cells to chemotherapeutics has been revealed, indicating that silencing let-7f-5p may become an effective therapeutic strategy against CRC. IntroductionColorectal cancer (CRC) is one of the most prevalent causes of cancer-associated mortality worldwide (1,2). Clinically, 5-fluorouracil (5-FU)-based chemotherapy serves as the initial first-line chemotherapeutic drug of choice in patients with CRC; however, the response rates to 5-FU are ~15% in patients with advanced CRC (3). Although novel therapeutic approaches, including combination chemotherapy of 5-FU and oxaliplatin (FOLFOX) or irinotecan (FOLFIRI), have presented promising potential, the majority of the patients continue to exhibit inadequate responses (4,5). The failure of chemotherapy in CRC patients is primarily attributed to therapeutic resistance following a long period of treatment (6). These observations emphasize that chemotherapeutic resistance is a major obstacle in the treatment of CRC, and that the molecular mechanisms underlying this issue remain unclear.Chemotherapeutic resistance poses a major challenge in cancer chemotherapy. Chemoresistance of tumor cells develops primarily due to acquired resistance de novo, following an initially sensitive response, and/or in combination with pre-established cell-intrinsic mechanisms (7). A number of well-established mechanisms are reported to be involved in cancer drug resistance, including failure of the drug to reach or enter the target cell, formation of efflux pumps on the surface of tumor cells, increased expression of anti-apoptotic proteins, induction of drug-detoxifying mechanisms and upregulation of DNA repair enzymes (8,9). However, there is an absence of integral understanding of acquired drug resistance in the context of CRC. Such insight may be crucial for the

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“…In addition to these, the downregulation of miR-100 was also shown in hepatocellular carcinoma, oral cancer, and adrenocortical cancer (Henson et al, 2009;Doghman et al, 2010;Chen et al, 2013). In contrast, an upregulation of miR-100 has been observed in renal cell carcinoma, acute myeloid leukemia, and prostate cancer (Akbari Moqadam et al, 2013;Wang et al, 2013;Wang et al, 2014). Previously, Oliveira et al (2011) found that miR-100 acted as a tumor suppressor in human bladder carcinoma 5637 cells.…”

Section: Discussionmentioning

confidence: 99%

Prognostic role of microRNA-100 in patients with bladder cancer

Cao¹,

Zhang²,

Xu³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. We investigated the clinical significance and prognostic value of microRNA-100 (miR-100) in bladder cancer. Quantitative realtime polymerase chain reaction was used to analyze the expression of miR-100 in 92 pairs of human bladder cancer and adjacent normal tissue samples. Overall survival (OS) curves were plotted using the Kaplan-Meier method and were evaluated for statistical significance using a log-rank test. The significance of different variables with respect to survival was analyzed using the multivariate Cox proportional hazard model. The miR-100 expression level was significantly lower in bladder cancer tissues than in normal adjacent tissues (mean ± SD: 1.49 ± 0.52 vs 2.79 ± 0.59, P < 0.05). A low miR-100 expression level was correlated with tumor stage (P = 0.023), tumor grade (P = 0.031), and regional lymph node involvement (P = 0.16). Kaplan-Meier analysis with log-rank test indicated that low miR-100 expression had a significant impact on OS (35.1 vs 75.3%; P = 0.004). Multivariate analysis revealed that the miR-100 expression level was an independent prognostic factor for OS (HR = 2.768, 95%CI = 1.287-8.992; P = 0.009) in bladder cancer patients. The present study demonstrated that the downregulation of miR-100 was associated with advanced clinical features and poor prognosis for bladder cancer patients, suggesting that 15949 Prognostic role of miR-100 in bladder cancer ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (4): 15948-15954 (2015) miR-100 downregulation may be used as an unfavorable prognostic biomarker in bladder cancer.

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Loss of miR-100 enhances migration, invasion, epithelialmesenchymal transition and stemness properties in prostate cancer cells through targeting Argonaute 2

Cited by 66 publications

References 55 publications

miR-346 Up-regulates Argonaute 2 (AGO2) Protein Expression to Augment the Activity of Other MicroRNAs (miRNAs) and Contributes to Cervical Cancer Cell Malignancy

miR-346 Up-regulates Argonaute 2 (AGO2) Protein Expression to Augment the Activity of Other MicroRNAs (miRNAs) and Contributes to Cervical Cancer Cell Malignancy

Upregulation of let‑7f‑5p promotes chemotherapeutic resistance in colorectal cancer by directly repressing several pro‑apoptotic proteins

Prognostic role of microRNA-100 in patients with bladder cancer

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