• Users Online: 251
  • Home
  • Print this page
  • Email this page
Home About us Editorial board Ahead of print Current issue Search Archives Submit article Instructions Subscribe Contacts Login 

 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 1  |  Page : 11-18

In silico analysis of miRNA role in resistance of hepatocellular carcinoma Bel-7402 cells to TRAIL


1 Department of Pharmacognosy and Pharmaceutical Biotechnology, School of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran
2 Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah, Iran

Date of Submission21-Feb-2019
Date of Acceptance03-Dec-2019
Date of Web Publication26-Jun-2020

Correspondence Address:
Dr. Omid Tavallaei
Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah.
Iran
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jrptps.JRPTPS_18_19

Rights and Permissions
  Abstract 

Context: To this date, the exact basics of microRNAs (miRNAs) mechanisms in inducing a resistance to tumor necrosis factor –related apoptosis-inducing ligand (TRAIL) signaling pathways remain unclear. Aims: The aim of this study was to analyze miRNA signaling pathways in TRAIL-resistant Bel-7402 cell line. Materials and Methods: The Gene Expression Omnibus (GEO) database was studied for miRNA expression profiling studies in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells. By searching through databases of DIANAmT, miRanda, miRDB, miRWalk, and PICTAR using the online tools of miRWalk and TargetScan, target genes of miRNAs were predicted to express differentially by up to 50% in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells. Afterwards, signaling pathways and biological functions of miRNA target genes in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells were analyzed by the DAVID database. Results: A total of 352 miRNAs (186 up- and 166 downregulated miRNAs) were obtained from GSE74130 GEO DataSets accession item. The upregulated miRNAs including hsa-mir-145, hsa-mir-188, hsa-mir-221, hsa-mir-4802-5p, hsa-mir-198, hsa-mir-1184, and hsa-mir-345-3p were significantly intensified in apoptotic signaling pathway and process. The downregulated miRNAs including hsa-mir-138, hsa-mir-375, hsa-mir-449, hsa-mir-637, hsa-mir-208-3p, hsa-mir-4783-5p, hsa-mir-548b-3p, hsa-mir-127-3p, hsa-mir-92b-5p, hsa-mir-375, hsa-mir-503-5p, hsa-mir-499a-3p, and hsa-mir-154-3p were significantly raised in expression in cancer stem cell pathways. Conclusions: Analysis of miRNA expression profile revealed that some of the upregulated miRNAs negatively contributed to the regulation of apoptosis signaling pathways and cell cycle arrest as well as promoting TRAIL-induced apoptosis resistance in TRAIL-resistant Bel-7402 cells. Also, down-regulated miRNAs were probably involved in cancer stem cell processing.

Keywords: Apoptosis, miRNA expression data, neoplasms, signaling pathways, TRAIL


How to cite this article:
Salehi Z, Seydi H, Hadadi P, Tavallaei O. In silico analysis of miRNA role in resistance of hepatocellular carcinoma Bel-7402 cells to TRAIL. J Rep Pharma Sci 2020;9:11-8

How to cite this URL:
Salehi Z, Seydi H, Hadadi P, Tavallaei O. In silico analysis of miRNA role in resistance of hepatocellular carcinoma Bel-7402 cells to TRAIL. J Rep Pharma Sci [serial online] 2020 [cited 2020 Jul 10];9:11-8. Available from: http://www.jrpsjournal.com/text.asp?2020/9/1/11/287583


  Introduction Top


MicroRNAs (miRNAs), a new class of 22 nucleotides nonprotein-encoding RNAs, have been verified as important tumor suppressors or oncogenes in a wide range of cancers such as hepatocellular carcinoma (HCC).[1],[2],[3] These nonprotein encoding RNAs regulate gene expression through interacting with the 3′ untranslated region (3′ UTR), 5′ UTR, coding sequence, and also the gene promoter of targets in order to trigger mRNA degradation and, therefore, translational repression.[1] MiRNAs are involved in numerous biological processes (BPs) including proliferation, differentiation, angiogenesis, migration, and carcinogenesis.[4] In addition, different miRNA profiles may have diverse distributions and functions in apoptosis signaling pathways.[5] Among these are oncogenic miRNAs (oncomiRs) overexpressed in cancers and contribute to cancer phenotype by inhibiting the expression of tumor suppressors.[6] In contrast, tumor suppressor miRNAs, which usually under-expressed in cancers, inhibit the expression of oncogenic proteins, leading to suppress the cancer phenotype.[7]

Tumor necrosis factor (TNF)–related apoptosis-inducing ligand (TRAIL) is an anti-inflammatory agent and a member of the TNF superfamily, which is highly expressed in cancer. As a consequence, it is a selective killing ligand for treating cancer.[8] This factor triggers a caspase cascade to induce cellular apoptosis by interacting with its death receptors of DR4 and DR5 in human.[9] TRAIL and its receptors are expressed not only in tumor cells but also in normal immune cell types such as natural killer cells (NK cells), T cells, dendritic cells (DCs), and macrophages.[10] TRAIL receptors activate the initiator caspase-8 that can in turn trigger an apoptosis signal through a direct cleavage of downstream effector caspases such as caspase-3, -6, and -7. The effector caspases would activate certain kinases down the cascade.[11] Various studies show that TRAIL is able to potently induce the extrinsic pathway of apoptosis in many cancer cell lines and, therefore, is a selective killing ligand for cancer therapy.[12]

The sixth most common malignancy and the third principal cause of cancer deaths worldwide is HCC.[13] The changes in miRNA expression pattern of HCC Bel-7402 cells treated with TRAIL-targeting agents were verified by noncoding RNA profiling that reported in GSE74130 accession item of Gene Expression Omnibus (GEO) DataSets.

Interestingly, several studies have clearly shown that miRNAs are involved in TRAIL-induced apoptosis in different cancers.[14],[15] The molecular basics of mechanisms miRNAs use to interfere with TRAIL-induced apoptosis resistance remain unknown. It could be hypothesized that modulating the miRNA profile might affect the sensitivity/resistancy in human cancer to TRAIL-induced apoptosis.

With all this in mind, our aim was to predict the miRNA target genes differentially expressed in TRAIL-resistant Bel-7402 cells and to analyze miRNA functions, apoptosis signaling, and BPs. We also examined the possible effects in cancer stem cell–related signaling with respect to cellular processes such as self-renewal, apoptosis, migration, and differentiation through Hedgehog, Wnt/β-catenin, Notch, mTOR, EGF, TGF-β, MAPK, PI3k-Akt, and NF-κB signaling pathways.


  Materials and Methods Top


Data sources and preprocessing

The miRNA expression profile of TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells was obtained from the National Center for Biotechnology Information GEO with accession number of GSE74130 (http://www.ncbi.nlm.nih.gov/geo/). Using R version 3.4.1, we retained the fold change of differential miRNA expression higher than 50% when comparing TRAIL-resistant with TRAIL-sensitive Bel-7402 cells.

miRNA target prediction

Using the results from the analysis of differential miRNA expressions (TRAIL-resistant vs. TRAIL-sensitive), gene–miRNA interactions were predicted using miRNA target computational prediction methods including DIANAmT, miRanda, miRDB, miRWalk, PICTAR, and TargetScan through the online tools of miRWalk (http://www.umm.uni-heidelberg.de/apps/zmf/mirwalk/). MiRNA target genes common in these six databases in miRWalk tools were selected (P value < 0.05). The target genes of all miRNAs were also predicted using TargetScan database with context score <−0.2 (http://www.targetscan.org).

Functional enrichment analysis

Gene ontology (GO) was used to analyze the gene sets data for common descriptive framework and functional annotation and classification. GO functional analyses were performed to identify significantly enriched BPs in the targets of the deregulated miRNAs in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells using the online tool of the database for annotation, visualization, and integrated discovery (DAVID; http://david.abcc.ncifcrf.gov/), version 6.7, with P value < 0.01.[16] All miRNA target genes were listed and uploaded into DAVID database, after selecting the “entire human genome,” as background control. We also filtered out the specific gene expressed in “human cancer biology” module of the DAVID database. Then, we classified genetic features screening in the DAVID database by the modules of GO BP analysis. In addition to DAVID, we repeat our analysis using GenCLiP 2.0 database, which is a web server for functional clustering of genes (http://ci.smu.edu.cn/).

Pathway enrichment analysis

A gene-centered database, DAVID tools, not only provides the GO BP of genes but also enriches the signaling pathways for an individual gene. In this case, Kyoto Encyclopedia of Genes and Genomes (KEGG), BioCarta, and Reactome were searched to identify significantly enriched pathways of miRNA target genes using the online tool of DAVID database (P value < 0.05).

Constructing regulatory network between miRNAs and their targets

We constructed a regulatory network for KEGG signaling pathway results of miRNAs and predicted target genes in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells with the identified miRNA–target gene interacting pairs and visualized the output with Cytoscape version 3.2.1.


  Results Top


Differentially expressed miRNAs in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells

Herein, we collected the miRNA expression profiling from GEO database (accession number: GSE74130), consisting of 2076 miRNAs differentially expressed in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells. Using R software, we selected miRNAs with fold changes higher than 1.5 TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells. Finally, 186 and 166 miRNAs were found upregulated and downregulated, respectively, in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells [Table 1], [Supplementary Table 1a and Table 1b [Additional file 1]]. Some of the up- and down regulated miRNAs that were reported in KEGG database in “pathway in cancer” item were deleted from [Supplementary Table 1a] and [1b].
Table 1: ID, names, and fold changes of up- and downregulated miRNAs in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells

Click here to view
, {Table 5}, {Table 6}

Identification of differently expressed miRNA target genes

The numbers of miRNA target genes were 9,664 and 10,978 for upregulated and downregulated miRNAs in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells, respectively.

Functional enrichment of the predicted miRNA target genes

Further into the study, we performed a functional enrichment analysis to investigate the roles of miRNA target genes through DAVID online tools. This analysis was conducted in GO BP component. Those miRNAs with significantly changed expression levels between TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells could deregulate some signaling pathways and promote resistance to TRAIL. Therefore, those miRNAs not preserved from TRAIL-sensitive to TRAIL-resistant cells may promote resistance to TRAIL and cancer stem cell signaling pathways.

The GO BP results indicated that the target genes of upregulated miRNAs are enriched in neuron apoptotic process, intrinsic apoptotic signaling pathway in response to DNA damage, extrinsic apoptotic signaling pathway via death domain receptors, negative regulation of cell growth, negative regulation of canonical Wnt signaling pathway, and DNA damage response signal transduction by p53 class mediator resulting in the cell cycle arrest. For example, hsa-mir-509-3p, hsa-mir-584al/4445-3p, hsa-mir-555, hsa-mir-662, hsa-mir-234-5p, hsa-mir-654-3p, hsa-mir-92a-1-5p, hsa-mir-1275, hsa-mir-296-3p, and hsa-mir-662 are involved in apoptosis process by targeting CSNK1D, CDK2, CDKN2B, PLK4, and PRKACA. On the other hand, the target genes of downregulated miRNAs take part in cell division, proliferation and migration, vascular endothelial growth factor receptor (VEGFR) signaling pathway, MAPK cascade, angiogenesis, positive regulation of phosphatidylinositol 3-kinase (PI3K) activity, and Wnt signaling pathway [Table 2], [Supplementary Table 1a] and [Supplementary Table 1b] for up- and downregulated miRNAs, respectively].
Table 2: MicroRNAs, their target genes, and GO BP results of up- and downregulated miRNAs of TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells

Click here to view


Signaling pathways enrichment analysis for differentially expressed miRNA target genes

We also performed KEGG, BioCarta, and Reactome pathways enrichment analysis for differentially expressed miRNA target genes. Hypergeometric test at P value < 0.05 was used as the criteria for pathway detection using the online tool of DAVID database.

KEGG pathway indicated that some of the downregulated miRNAs in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells such as hsa-mir-208-3p, hsa-mir-4783-5p, hsa-mir-548b-3p, hsa-mir-127-3p, hsa-mir-92b-5p, hsa-mir-375, hsa-mir-503-5p, hsa-mir-499a-3p, and hsa-mir-154-3p affected Wnt signaling pathway, a cancer stem cell signaling pathway, by targeting APC, WNT2, WNT7A, CSNK2A1, CCND2, MAPK8, and RHOA [Figure 1], [Supplementary Table 2a [Additional file 2]] for upregulated and [Supplementary Table 2b [Additional file 3]] for down-regulated miRNAs].
Figure 1: miRNAs, their target genes, and KEGG pathway results of downregulated miRNAs of TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells

Click here to view
, {Table 7}, {Table 8}

Reactome pathway showed that LTBR, PSMD11, PSMA8, PSMA4, PSMB4, NFKB1, SKP1, and PRKCB, as the target genes for hsa-mir-662, hsa-mir-2467-3p, hsa-mir-499a-3p, hsa-mir-146-5p, hsa-mir-4277, hsa-mir-508-3p, and hsa-mir-1269, were upregulated in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells and found to influence the NF-κB signaling pathway (R-HSA-5668541, R-HSA-1169091). Although, hsa-mir-302b-5p, one of the down-regulated miRNAs, is involved in Hedgehog signalling pathway (R-HSA-5358346 and R-HSA-5632684), it has also involved in MAPK6/MAP-K4 signalling (R-HSA-5687128), and VEGFR2 mediated cell proliferation (R-HSA-69017) by targeting PSMC6 ([Table 3], [Supplementary 3a and 3b [Additional file 4]] for up- and down-regulated miRNAs, respectively).
Table 3: MicroRNAs, their target genes, and Reactome pathway results of up- and downregulated miRNAs of TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells

Click here to view
, {Table 9}, {Table 10}

Signaling pathways enrichment analysis by BioCarta pathway showed that PRKCA, PRKCB, PPP3CA, ARHGDIB, CASP10, CASP2, PARP1, SOS1, CDKN1B, and PTEN were the target genes for hsa-mir-92a-1-5p, hsa-mir-1275, hsa-mir-296-3p, hsa-mir-662, hsa-mir-1237-3p, hsa-mir-449a, hsa-mir-330, hsa-mir-4534/8082, hsa-mir-555, hsa-mir-555, hsa-mir-4708-3p, hsa-mir-188-3p, hsa-mir-610, hsa-mir-1184, hsa-mir-512-3p, hsa-mir-198, and hsa-mir-534 as upregulated miRNAs in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells. These miRNAs were therefore found to be involved in the apoptosis signaling pathway. On the other hand, many of the downregulated miRNAs in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells take part in cancer stem cell signaling pathways. For instance, miRNAs including hsa-mir-138, hsa-mir-875-3p, and hsa-mir-1206 play roles in AKT signaling pathway by targeting AKT1, EIF2S1, PPP2CA, and RPS6KB1 [Table 4], [Supplementary Table 4a and Table 4b [Additional file 5]] for up- and down-regulated miRNAs, respectively].
Table 4: MicroRNAs, their target genes, and BioCarta pathway results of up- and downregulated miRNAs of TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells

Click here to view
, {Table 11}, {Table 12}

Gene cluster with literature profiles

We used GenCLiP 2.0 database for functional clustering of genes with P value ≤ 1e-4. The complete results were reported in [Supplementary Table 5a and Table 5b [Additional file 6]] for up- and downregulated miRNAs, respectively.{Table 13}, {Table 14}


  Discussion and Conclusions Top


miRNAs have been established as an important tumor suppressors or oncogenes in a wide range of cancers and play crucial roles in a variety of BPs such as differentiation, development, proliferation, and apoptosis.[17 In addition],[ different miRNAs are of a diverse distribution and with some functioning in apoptosis signaling pathways.[18]

TRAIL, a ligand in the tumor necrosis factor superfamily, is an apoptosis-inducible cytokine highly expressed in cancers.[12] TRAIL induces the formation of death-inducing signaling complex formation and then the signal transmits intracellularly to trigger extrinsic pathway of apoptosis.[9] TRAIL is one of the most promising candidates for cancer therapy as it can induce apoptosis through tumor-specific cytotoxic activity.[8] Although various tumor cells are susceptible to TRAIL-mediated apoptosis by the expression of certain decoy receptors and intracellular inhibitors, many human cancers are resistant to TRAIL-induced apoptosis.[19] The mechanism of this resistance has not been extensively studied.

miRNAs that we found to be differentially expressed between the two cell lines are probably involved in apoptosis and cancer stem cell signaling pathways such as Hedgehog, Wnt/bcatenin, Notch, mTOR, EGF, PI3K-Akt, and TGF-β, as well as promote angiogenesis, invasion, metastasis to lymph nodes, and tumor progression in HCC. Signaling pathway analysis through KEGG, BioCarta, and Reactome pathways and also GO BP analysis module in the DAVID database indicated that the target genes of upregulated miRNAs in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells are enriched in neuron apoptotic process, NF-κB pathways, and intrinsic apoptotic signaling pathway. These upregulated miRNAs in turn downregulate certain group of target genes. Our results indicated that upregulated miRNAs such as hsa-mir-4802-5p, hsa-mir-198, hsa-mir-345-3p, hsa-mir-1184, hsa-mir-4787-5p, hsa-mir-345-3p, hsa-mir-1184, hsa-mir-92a-1-5p, hsa-mir-1275, hsa-mir-296-3p, hsa-mir-662, hsa-mir-92, hsa-mir-449a, hsa-mir-221, hsa-mir-145-5p, hsa-mir-142-3p, hsa-mir-512-3p, hsa-mir-145, hsa-mir-555, hsa-mir-4708-3p, hsa-mir-188-3p, hsa-mir-610, and hsa-mir-1184 downregulated target genes of BAX, BCL2, TRADD, TNF, PRKCA, PRKCB, PPP3CA, ARHGDIB, CASP10, CASP2, PARP1, and SOS1. Interestingly enough, these genes actively take part in apoptosis process. So, it is safe to claim that the mentioned upregulated miRNAs are capable of negatively regulating apoptosis signaling pathways and cell cycle arrest, and also promote TRAIL-induced apoptosis resistance in TRAIL-resistant Bel-7402 cells. Many studies have shown that hsa-mir-145 and hsa-mir-188 block caspase-3 activation and are involved in regulating ligand-induced apoptosis.[20] We showed that hsa-mir-185-5p, hsa-mir-221, hsa-mir-555, hsa-mir-665, hsa-mir-234-5p, hsa-mir-662, hsa-mir-665, and hsa-mir-451 as up-regulated miRNAs in TRAIL-resistant Bel-7402 cells could induce cell cycle arrest by targeting specific mRNAs such as CCND2, CDK6, and CDKN2D. Results from various studies have already established the role of hsa-mir-185-5p overexpression in growth suppression and cell cycle arrest of human lung cancer cell lines.[21] Moreover, hsa-mir-17–92 cluster is found to be consistently upregulated and plays a role in the apoptotic pathway.[22] Also, hsa-mir-221 inhibits normal erythropoiesis and erythroleukemic cell growth and controls CDKN1C/p57 and CDKN1B/p27 expression in human HCC.[23],[24]

The results from software analysis showed that many of the downregulated miRNAs are engaged in cancer stem cell signaling cascades such as Hedgehog, Wnt/b-catenin, PI3K-Akt, mTOR, EGF, and TGF-β signaling pathways along with promoting angiogenesis, invasion, and metastasis of the cancer cells. Our results also indicated that the target genes of hsa-mir-138 are responsible for regulating VEGF, MAPK, PI3K-Akt, TGF-β, and Wnt signaling pathways. The target genes of hsa-mir-138 that promote cancer stem cell signaling pathways were found to be upregulated upon downregulation of hsa-mir-138. Besides, hsa-mir-138 has been frequently studied in HCC as the overexpression of this miRNA has been associated with suppressed cell proliferation, migration, and invasion in HCC.[8],[25] Results of our analysis clearly showed that downregulation of hsa-mir-375 negatively affects Wnt, MAPK, and proliferation pathways of cancer stem cell as it is responsible of upregulating target genes key to these signaling pathways. Similar to our results, recent studies on HCC indicate that hsa-mir-375 suppresses liver cancer cell growth both in vitro and in vivo.[26],[27] Our software analyses on downregulated miRNAs in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells showed that hsa-mir-449 plays role in MAPK, VEGF, PI3K-Akt, and Hedgehog signaling pathways. So, as Buurman et al.[28] have already shown in their research, down-expression of hsa-mir-449 activates hepatocyte growth factor signaling in HCC cells. Downregulated hsa-mir-637 was found to be involved in Hedgehog signaling pathway as Zhang et al.[29] has stated that hsa-mir-637 inhibits tumorigenesis in HCC. Interestingly, our results pointed out that some up- and downregulated miRNAs have dual roles in cancer progression as oncogenes and tumor suppressor genes. These results are shown in [Tables 2–4].

In conclusion, it could be interpreted from our results that up- and downregulated miRNAs could regulate apoptosis and cancer stem cell signaling in TRAIL-resistant versus TRAIL-sensitive Bel-7402 cells. Moreover, we showed that the upregulated miRNAs probably negatively regulate apoptosis signaling pathways and cell cycle arrest and promote TRAIL-induced apoptosis resistance in TRAIL-resistant Bel-7402 cells. Downregulated miRNAs on the other hand are possibly involved in cancer stem cell cascades such as Hedgehog, Wnt/b-catenin, PI3K-Akt Notch, mTOR, EGF, and TGF-β signaling pathways and promote angiogenesis, invasion, and metastasis in HCC.

Although Bel-7402 cells are sensitive to TRAIL, they could become resistant after certain treatments. Some of the downregulated miRNAs target genes vital to cancer stem cells signaling pathways in TRAIL-resistant Bel-7402 cells. So, we expect the cancer stem cells signaling pathways to activate upon down-expression of these miRNAs. On the other hand, some of the upregulated miRNAs target apoptosis signaling pathways and therefore, we predict deactivation of apoptosis process in TRAIL-resistant Bel-7402 cells.

Acknowledgement

Nil.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
O’Brien J, Hayder H, Zayed Y, Peng C. Overview of microRNA biogenesis, mechanisms of actions, and circulation. Front Endocrinol (Lausanne) 2018;9:402.  Back to cited text no. 1
    
2.
Xu X, Tao Y, Shan L, Chen R, Jiang H, Qian Z, et al. The role of microRNAs in hepatocellular carcinoma. J Cancer 2018;9:3557-69.  Back to cited text no. 2
    
3.
Zhang B, Pan X, Cobb GP, Anderson TA. MicroRNAs as oncogenes and tumor suppressors. Dev Biol 2007;302:1-12.  Back to cited text no. 3
    
4.
Malla RR, Kumari S, Gavara MM, Badana AK, Gugalavath S, Kumar DKG, et al. A perspective on the diagnostics, prognostics, and therapeutics of microRNAs of triple-negative breast cancer. Biophys Rev 2019;11:227-34.  Back to cited text no. 4
    
5.
Shirjang S, Mansoori B, Asghari S, Duijf PHG, Mohammadi A, Gjerstorff M, et al. MicroRNAs in cancer cell death pathways: Apoptosis and necroptosis. Free Radic Biol Med 2019;139:1-15.  Back to cited text no. 5
    
6.
Esquela-Kerscher A, Slack FJ. Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 2006;6:259-69.  Back to cited text no. 6
    
7.
Svoronos AA, Engelman DM, Slack FJ. Oncomir or tumor suppressor? The duplicity of microRNAs in cancer. Cancer Res 2016;76:3666-70.  Back to cited text no. 7
    
8.
Farooqi A, Shu C-W, Huang H-W, Wang H-R, Chang Y-T, Fayyaz S, et al. TRAIL, Wnt, sonic hedgehog, TGFβ, and miRNA signalings are potential targets for oral cancer therapy. Int J Mol Sci 2017;18:1523.  Back to cited text no. 8
    
9.
Kischkel FC, Lawrence DA, Chuntharapai A, Schow P, Kim KJ, Ashkenazi A. Apo2l/TRAIL-dependent recruitment of endogenous FADD and caspase-8 to death receptors 4 and 5. Immunity 2000;12:611-20.  Back to cited text no. 9
    
10.
Falschlehner C, Schaefer U, Walczak H. Following TRAIL’S path in the immune system. Immunology 2009;127:145-54.  Back to cited text no. 10
    
11.
Song JJ, Lee YJ. Differential cleavage of mst1 by caspase-7/-3 is responsible for TRAIL-induced activation of the MAPK superfamily. Cell Signal 2008;20:892-906.  Back to cited text no. 11
    
12.
Malhi H, Gores GJ. TRAIL resistance results in cancer progression: A TRAIL to perdition? Oncogene 2006;25:7333-5.  Back to cited text no. 12
    
13.
Bie B, Sun J, Li J, Guo Y, Jiang W, Huang C, et al. Baicalein, a natural anti-cancer compound, alters microRNA expression profiles in Bel-7402 human hepatocellular carcinoma cells. Cell Physiol Biochem 2017;41:1519-31.  Back to cited text no. 13
    
14.
Lu T, Shao N, Ji C. Targeting microRNAs to modulate TRAIL-induced apoptosis of cancer cells. Cancer Gene Ther 2013;20: 33-7.  Back to cited text no. 14
    
15.
Jin X, Cai L, Wang C, Deng X, Yi S, Lei Z, et al. CASC2/mir-24/mir-221 modulates the TRAIL resistance of hepatocellular carcinoma cell through caspase-8/caspase-3. Cell Death Dis 2018; 9:318.  Back to cited text no. 15
    
16.
Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 2009;4:44-57.  Back to cited text no. 16
    
17.
Oliveto S, Mancino M, Manfrini N, Biffo S. Role of microRNAs in translation regulation and cancer. World J Biol Chem 2017;8: 45-56.  Back to cited text no. 17
    
18.
Pileczki V, Cojocneanu-Petric R, Maralani M, Neagoe IB, Sandulescu R. MicroRNAs as regulators of apoptosis mechanisms in cancer. Clujul Med 2016;89:50-5.  Back to cited text no. 18
    
19.
Eberle J. Countering TRAIL resistance in melanoma. Cancers2019;11:565.  Back to cited text no. 19
    
20.
Garofalo M, Condorelli GL, Croce CM, Condorelli G. MicroRNAs as regulators of death receptors signaling. Cell Death Differ 2010;17:200-8.  Back to cited text no. 20
    
21.
Takahashi Y, Forrest AR, Maeno E, Hashimoto T, Daub CO, Yasuda J. MiR-107 and MiR-185 can induce cell cycle arrest in human non small cell lung cancer cell lines. PLoS One 2009;4:e6677.  Back to cited text no. 21
    
22.
Inomata M, Tagawa H, Guo YM, Kameoka Y, Takahashi N, Sawada K. MicroRNA-17-92 down-regulates expression of distinct targets in different B-cell lymphoma subtypes. Blood 2009;113:396-402.  Back to cited text no. 22
    
23.
Felli N, Fontana L, Pelosi E, Botta R, Bonci D, Facchiano F, et al. MicroRNAs 221 and 222 inhibit normal erythropoiesis and erythroleukemic cell growth via kit receptor down-modulation. Proc Natl Acad Sci U S A 2005;102:18081-6.  Back to cited text no. 23
    
24.
Fornari F, Gramantieri L, Ferracin M, Veronese A, Sabbioni S, Calin GA, et al. MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene 2008;27:5651-61.  Back to cited text no. 24
    
25.
Zhu Z, Zhang X, Wang G, Zheng H. Role of microRNAs in hepatocellular carcinoma. Hepat Mon 2014;14:e18672.  Back to cited text no. 25
    
26.
Chang Y, Yan W, He X, Zhang L, Li C, Huang H, et al. MiR-375 inhibits autophagy and reduces viability of hepatocellular carcinoma cells under hypoxic conditions. Gastroenterology 2012;143:177-87.e8.  Back to cited text no. 26
    
27.
He XX, Chang Y, Meng FY, Wang MY, Xie QH, Tang F, et al. MicroRNA-375 targets AEG-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo. Oncogene 2012;31:3357-69.  Back to cited text no. 27
    
28.
Buurman R, Gürlevik E, Schäffer V, Eilers M, Sandbothe M, Kreipe H, et al. Histone deacetylases activate hepatocyte growth factor signaling by repressing microRNA-449 in hepatocellular carcinoma cells. Gastroenterology 2012;143:811-20.e15.  Back to cited text no. 28
    
29.
Zhang JF, He ML, Fu WM, Wang H, Chen LZ, Zhu X, et al. Primate-specific microRNA-637 inhibits tumorigenesis in hepatocellular carcinoma by disrupting signal transducer and activator of transcription 3 signaling. Hepatology 2011;54:2137-48.  Back to cited text no. 29
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion and C...
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed104    
    Printed0    
    Emailed0    
    PDF Downloaded37    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]