MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non–small-cell lung cancer through BIM down-regulation

Romano, Giulia; Acunzo, Mario; Garofalo, Michela; Leva, Gianpiero Di; Cascione, Luciano; Zanca, Ciro; Bolon, Brad; Condorelli, Gerolama; Croce, Carlo M.

doi:10.1073/pnas.1207917109

Cited by 150 publications

(143 citation statements)

References 31 publications

(33 reference statements)

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“…24 Searching in different databases, we did not identify previous reports relating the other 13 miRNAs reported in Figure 3 and Table 1 with resistance of NSCLC cells to doxorubicin or other chemotherapeutic agents. This finding adds new miRNAs and opens the avenue for new targets/predictors to improve the response of lung cancer cells to chemotherapy.…”

Section: Discussionmentioning

confidence: 83%

Epigenetics and miRNA as predictive markers and targets for lung cancer chemotherapy

El‐Awady

Hersi

Al-Tunaiji

et al. 2015

Cancer Biology & Therapy

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Abbreviations: 5AZA, 5-aza-2 0 -deoxycytidine; BSA, bovine serum albumin; DMSO, dimethyl sulfoxide; DNMT, DNA methyltransferase; HAT, histone acetyl transferase; HDAC, histone deacetylase; NSCLC, non-small cell lung cancer; PBS, phosphate-buffered saline; SCLC, small-cell lung cancer; TSA, trichostatin A; 5mc, 5-methyl cytosine.Lung cancer cells show inherent and acquired resistance to chemotherapy. The lack of good predictive markers/ novel targets and the incomplete understanding of the mechanisms of resistance limit the success of lung cancer response to chemotherapy. In the present study, we used an isogenic pair of lung adenocarcinoma cell lines; A549 (wild-type) and A549DOX11 (doxorubicin resistant) to study the role of epigenetics and miRNA in resistance/response of non-small cell lung cancer (NSCLC) cells to doxorubicin. Our results demonstrate differential expression of epigenetic markers whereby the level of HDACs 1, 2, 3 and4, DNA methyltransferase, acetylated H2B and acetylated H3 were lower in A549DOX11 compared to A549 cells. Fourteen miRNAs were dys-regulated in A549DOX11 cells compared to A549 cells, of these 14 miRNAs, 4 (has-mir-1973, 494, 4286 and 29b-3p) have shown 2.99 -4.44 fold increase in their expression. This was associated with reduced apoptosis and higher resistance of A549DOX11cells to doxorubicin and etoposide. Sequential treatment with the epigenetic modifiers trichostatin A or 5-aza-2'-deoxycytidine followed by doxorubicin resulted in: (i) enhanced sensitivity of both cell lines to doxorubicin especially at low concentrations, (ii) enhanced doxorubicin-induced DNA damage in both cell lines, (iii) dysregulation of some miRNAs in A549 cells. In conclusion, A549DOX11 cells resistant to DNA damaging drugs have epigenetic profile and miRNA expression different from the sensitive cells. Moreover, epigenetic modifiers may reverse the resistance of certain NSCLC cells to DNA damaging agents by enhancing induction of DNA damage. This may open the door for using epigenetic profile/miRNA expression of some cancer cells as resistance markers/targets to improve response of resistant cells to doxorubicin and for the use of combination doxorubicin/epigenetic modifiers to reduce doxorubicin toxicity.

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Section: Discussionmentioning

confidence: 83%

Epigenetics and miRNA as predictive markers and targets for lung cancer chemotherapy

El‐Awady

Hersi

Al-Tunaiji

et al. 2015

Cancer Biology & Therapy

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“…Ohdaira et al found that miR-494 suppressed cell proliferation and induced senescence in A549 lung cancer cells (Ohdaira et al 2012). Furthermore, Romano et al (2012) found that miR-494 was regulated by ERK1/2 and modulated by tumor necrosis factorrelated apoptosis-inducing ligand-induced apoptosis in non-small-cell lung cancer through BIM downregulation. The findings by Kim et al (2011) indicated that miR-494 was a negative regulator of KIT in gastrointestinal stromal tumors (GISTs), and overexpressing miR-494 in GISTs might be a promising approach to GIST treatment.…”

Section: Discussionmentioning

confidence: 99%

Correlation of miR-494 expression with tumor progression and patient survival in pancreatic cancer

Yb¹,

Gx²,

Jx³

et al. 2015

Genet. Mol. Res.

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ABSTRACT. expression is aberrant in various types of human cancer. However, the prognostic value of miR-494 in pancreatic cancer remains unclear. The level of miR-494 expression was determined in 99 pairs of primary pancreatic cancer and their corresponding, adjacent non-tumor tissues by using quantitative reverse transcriptase polymerase chain reaction. We also analyzed the associations between miR-494 expression and clinicopathological features. The survival correlations were analyzed by using the KaplanMeier method and Cox proportional hazards model. The level of miR-494 expression was significantly downregulated in pancreatic cancer tissues (mean relative expression level ± SD, 0.48 ± 0.11) as compared to matched adjacent normal tissues (1.80 ± 0.28, P < 0.05). We found 18153-18159 (2015) significant correlations between the miR-494 expression levels and TNM stage (P = 0.009), lymphatic invasion (P = 0.036), vascular invasion (P = 0.011), distant metastasis (P = 0.007), and tumor grade (P = 0.031). Pancreatic cancer patients with a low miR-494 expression level had a shorter overall survival than those with a high miR-494 expression level (P < 0.05). Reduced miR-494 expression in pancreatic cancer tissues is correlated with tumor progression and might be an independent, poor prognostic factor for patients with pancreatic cancer.

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“…Previous reports showed that mir-494 was downregulated and functioned as a tumor suppressor in human cholangiocarcinoma (21), gastric cancer (23) and lung cancer (28). However, other studies demonstrated that upregulation of mir-494 was associated with several types of human malignant solid tumors, including hepatocellular carcinoma (29), non-small cell lung cancer (30), and carcinoma induced by anti-BPDe (27). in these types of cancer, mir-494 seemed to be an oncogene, and promoted tumor cell proliferation, cell cycle, cell migration and invasion via regulation of the target genes Pten, BiM and Mcc.…”

Section: Discussionmentioning

confidence: 99%

miR-494 is an independent prognostic factor and promotes cell migration and invasion in colorectal cancer by directly targeting PTEN

Sun

Chen

et al. 2014

International Journal of Oncology

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Abstract. accumulating evidence has shown that micrornas (mirnas) are involved in multiple processes in cancer development and progression. upregulation of miRNA-494 (miR-494) has been identified as an oncogenic mirna and is associated with poor prognosis in several types of human cancer. However, the specific function of miR-494 in colorectal cancer remains unclear. in this study we found that the expression of mir-494 in colorectal cancer tissues and cell lines was much higher than in normal control tissues and cells, respectively. in addition, upregulation of mir-494 more frequently occurred in tissue specimens with adverse clinical stage and the presence of distant metastasis. Moreover, multivariate survival analyses demonstrated that overexpression of mir-494 is an independent prognostic factor for both progression-free and overall survival. in addition mir-494 promoted invasion and migration in colorectal cancer cells, and mir-494 directly inhibited the phosphatase and tensin homolog deleted on chromosome 10 (Pten) expression by targeting its 3'-untranslated region (3'-utr). Moreover, Pten is down regulated and inversely correlated with mir-494 expression in tissues. Thus, for the first time, we provided convincing evidence that upregulation of mir-494 was associated with tumor aggressiveness and tumor metastasis and promoted cell migration and invasion by targeting PTEN gene in colorectal cancer, and mir-494 is an independent prognostic marker for colorectal cancer patients. Introductioncolorectal carcinoma (crc) is the third most frequently diagnosed malignancy and the third leading cause of death among cancer patients in the united States (1). Despite current therapeutic strategies combining adjuvant chemotherapy, surgery and sometimes radiotherapy, the prognosis of crc remains poor, since most crc patients have distant metastases at diagnosis or develop recurrent metastatic crc following surgical treatment. although recent developments in molecular biology have provided insight into the molecular mechanisms of crc, the fundamental molecular mechanisms underlying metastasis in crc have not been fully elucidated. therefore, it is essential to identify metastasis-associated molecules as effective drug targets and to enhance the understanding of the mechanisms underlying the metastasis of crc.Micrornas (mirnas) are small non-coding rnas (~22 nucleotides in length), transcribed from non-protein-coding genes or introns, which regulate gene expression through repressing translation and cleaving their mrnas by binding to complementary sites in their 3'-untranslated region (3'-utr) (2). mirnas regulated the expression of a wide variety of target genes, and aberrant expression mirnas cause them to function as tumor suppressors or oncogenes according to the role of their target genes (3,4). Particularly, mirnas can regulate various biological processes of tumor cells, including cell proliferation, differentiation, progres sion, apoptosis, proliferation, migration and invasion (5-7). furthermore, increasing number...

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MiR-494 is regulated by ERK1/2 and modulates TRAIL-induced apoptosis in non–small-cell lung cancer through BIM down-regulation

Cited by 150 publications

References 31 publications

Epigenetics and miRNA as predictive markers and targets for lung cancer chemotherapy

Epigenetics and miRNA as predictive markers and targets for lung cancer chemotherapy

Correlation of miR-494 expression with tumor progression and patient survival in pancreatic cancer

miR-494 is an independent prognostic factor and promotes cell migration and invasion in colorectal cancer by directly targeting PTEN

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