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Cancer Cell International
Published in: Cancer Cell International 1/2020

Open Access 01-12-2020 | Colorectal Cancer | Primary research

Integrative in silico and in vitro transcriptomics analysis revealed new lncRNAs related to intrinsic apoptotic genes in colorectal cancer

Authors: Fatemeh Akbari, Maryam Peymani, Ali Salehzadeh, Kamran Ghaedi

Published in: Cancer Cell International | Issue 1/2020

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Abstract

Background

Pathogenesis of colorectal cancer (CRC) is connected to deregulation of apoptosis while the effect of lncRNAs, as critical regulatory molecules, on this pathway is not clear well. The present study aimed to identify differential expression of genes and their related lncRNAs which are significantly associated with intrinsic apoptotic pathway in CRC.

Methods

The connection between CRC and apoptosis was investigated by literature reviews and the genes were enriched by using Enrichr. At the next step, differential expression of enriched genes were evaluated between normal and tumor populations in data sets and were downloaded from GEO. Then, meta-analysis and probe re-annotation were performed. For lncRNAs selection through the highest expression correlation with each of candidate genes, mRNA-lncRNA interaction of screened genes and all of lncRNAs were visualized using Cytoscape. Identified differential expression genes and lncRNAs were validated using TCGA-COAD and the obtained data were confirmed by in vitro studies in the presence of Ag@Glu-TSC nanoparticle as an apoptotic inducer. Cytotoxicity and apoptosis induction effect of Ag@Glu-TSC on Caco-2 cells was determined via MTT and Annexin V/PI, respectively. The expression of genes and lncRNAs were assayed in presence of mentioned nanoparticle. Finally, the expression level of desired genes and lncRNAs were proven in CRC tissues compared to adjacent normal tissues.

Results

After detection of 48 genes associated with intrinsic apoptosis in CRC according to literature, Enrichr screened 12 common genes involved in this pathway. Among them, 6 genes including BCL2, BCL2L11, BAD, CASP7, CASP9, and CYCS expression reduced in tumor tissue compared to normal according to meta-analysis studies and RNA-seq TCGA data. Afterwards, association of 8 lncRNAs comprising CDKN2B-AS1, LOC102724156, HAGLR, ABCC13, LOC101929340, LINC00675, FAM120AOS, PDCD4-AS1 with more than 5 candidate genes were identified. In vitro studies revealed that four selected lncRNAs including, CDKN2B-AS1, LOC102724156, HAGLR and FAM120AOS were significantly increased in the presence of in optimum concentration of Ag@Glu/TSC and decreased in tumor tissues versus adjacent normal tissues.

Conclusion

This study developed a new data mining method to screen differentially expressed lncRNAs which are involved in regulation of intrinsic apoptosis pathway in CRC quickly using published gene expression profiling microarrays. Moreover, we could validate a number of these regulators in the cellular and laboratory disease models.
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Literature
1.
Rawla P, Sunkara T, Barsouk A. Epidemiology of colorectal cancer incidence, mortality, survival, and risk factors. Prz Gastroenterol. 2019;14:89–103.PubMedPubMedCentral
2.
3.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;2018:68394–424.
4.
Plati J, Bucur O, Khosravi-Far R. Dysregulation of apoptotic signaling in cancer: molecular mechanisms and therapeutic opportunities. J Cell Biochem. 2008;104:1124–49.PubMedPubMedCentralCrossRef
5.
Cheng Y, Geng L, Wang K, Sun J, Xu W, Gong S, Zhu Y. Long noncoding RNA expression signatures of colon cancer based on the ceRNA network and their prognostic value. Dis Mark. 2019;2019:7636757.
6.
Bermudez M, Aguilar-Medina M, Lizarraga-Verdugo E, Avendaño-Félix M, Silva-Benítez E, Ramos-Payán R, López-Camarillo C. LncRNAs as regulators of autophagy and drug resistance in colorectal cancer. Front Oncol. 2019;9:1008.PubMedPubMedCentralCrossRef
7.
Kuleshov MV, Jones MR, Rouillard AD, Fernandez NF, Duan Q, Wang Z, Koplev S, Jenkins SL, Jagodnik KM, Lachmann A, McDermott MG, Monteiro CD, Gundersen GW, Ma’ayan A. A comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016;44:90–7.CrossRef
8.
9.
Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK. limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 2015;43:43–7.CrossRef
10.
Leek JT, Johnson WE, Parker HS, Jaffe AE, Storey JD. The SVA package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 2012;28:882–3.PubMedPubMedCentralCrossRef
11.
Sztupinszki Z, Győrffy B. Colon cancer subtypes: concordance, effect on survival and selection of the most representative preclinical models. Sci Rep. 2016;2016(6):37169.CrossRef
12.
Volders PJ, Anckaert J, Verheggen K, Nuytens J, Martens L, Mestdagh P, Vandesompele J. LNCipedia 5: towards a reference set of human long non-coding RNAs. Nucleic Acids Res. 2019;47:D135–9.PubMedCrossRef
13.
Colaprico A, Silva TC, Olsen C, Garofano L, Cava C, Garolini D, Sabedot TS, Malta TM, Pagnotta SM, Castiglioni I, Ceccarelli M, Bontempi G, Noushmehr H. TCGAbiolinks: an R/Bioconductor package for integrative analysis of TCGA data. Nucleic Acids Res. 2016;44:e71.PubMedCrossRef
14.
Smoot ME, Ono K, Ruscheinski J, Wang PL, Ideker T. Cytoscape 2.8: new features for data integration and network visualization. Bioinformatics. 2010;27:431–2.PubMedPubMedCentralCrossRef
15.
Shandiz SAS, Montazeri A, Abdolhosseini M, Shahrestani SH, Hedayati M, Moradi-Shoeili Z, Salehzadeh A. Functionalization of Ag nanoparticles by glutamic acid and conjugation of Ag@Glu by thiosemicarbazide enhances the apoptosis of human breast cancer MCF-7 cells. J Clust Sci. 2018;29:1107–14.CrossRef
16.
Banck MS, Kanwar R, Kulkarni AA, Boora GK, Metge F, Kipp BR, Zhang L, Thorland EC, Minn KT, Tentu R, Eckloff BW, Wieben ED, Wu Y, Cunningham JM, Nagorney DM, Gilbert JA, Ames MM, Beutler AS. The genomic landscape of small intestine neuroendocrine tumors. J Clin Invest. 2013;123:2502–8.PubMedPubMedCentralCrossRef
17.
Suzuki A, Kusakai G, Kishimoto A, Shimojo Y, Miyamoto S, Ogura T, Ochiai A, Esumi H. Regulation of caspase-6 and FLIP by the AMPK family member ARK5. Oncogene. 2004;23:7067–75.PubMedCrossRef
18.
Farrow SN, Brown R. New members of the Bcl-2 family and their protein parterns. Curr Opin Genet Dev. 1996;6:45–9.PubMedCrossRef
19.
Knijn N, Water CVD, Vliet SH, JosMeijer J, Riemersma S, Tebar M, Punt C, Mekenkamp L, Simmer F, Nagtegaal I. Sequencing of RAS/RAF pathway genes in primary colorectal cancer and matched liver and lung metastases. BMC. 2019;39:9.
20.
Moorchung N, Kunwar SH, Ahmed KW. An evaluation of nuclear factor kappa B expression in colorectal carcinoma: an analysis of 50 cases. J Cancer Res Ther. 2014;10:631–5.PubMed
21.
Vlahopoulos S, Adamaki M, Khoury N, Zoumpourlis V, Boldogh I. Roles of DNA repair enzyme OGG1 in innate immunity and its significance for lung cancer. Pharmacol Ther. 2019;194:59–72.PubMedCrossRef
22.
Hou H, Sun D, Xiaochun Zhang XI. The role of MDM2 amplification and overexpression in therapeutic resistance of malignant tumors. Cancer Cell Int. 2019;19:216.PubMedPubMedCentralCrossRef
23.
Wang J, Pendergast AM. The emerging role of ABL kinases in solid tumors. Trends Cancer. 2016;1:110–23.CrossRef
24.
Kaori Sh, Katsuhiko N. Prognostic significance of CDKN2A (p16) promoter methylation and loss of expression in 902 colorectal cancers. Int J Cancer. 2011;128:1080–94.CrossRef
25.
26.
D’Atri S, Tentori L, Lacal PM, Graziani G, Pagani E, Benincasa E, Zambruno G, Bonmassar E, Jiricny J. Involvement of the mismatch repair system in temozolomide-induced apoptosis. Mol Pharmacol. 1998;54:334–41.PubMedCrossRef
27.
Li Y, Wei J, Xu C, Zhao Z, You T. Prognostic significance of cyclin D1 expression in colorectal cancer: a meta-analysis of observational studies. PLoS ONE. 2014;9:e94508.PubMedPubMedCentralCrossRef
28.
Yifeng FA, Xiao LI. miR-424 targets AKT3 and PSAT1 and has a tumor-suppressive role in human colorectal cancer. Cancer Manag Res. 2018;10:6537–47.CrossRef
29.
Wee HJ, Voon DC, Bae SC, Ito Y. PEBP2-β/CBF-β-dependent phosphorylation of RUNX1 and p300 by HIPK2: implications for leukemogenesis. Blood. 2008;112:3777–87.PubMedPubMedCentralCrossRef
30.
Jansson AK, Emterling AM, Arbman G, Sun XF. Noxa in colorectal cancer: a study on DNA, mRNA and protein expression. Oncogene. 2003;22:4675–8.PubMedCrossRef
31.
Acehan D, Jiang X, Morgan DG, Heuser JE, Wang X, Akey CW. Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Mol Cell. 2002;9:423–32.PubMedCrossRef
32.
Jin L, Wang Y. Surface chemistry of methanol on different ZnO surfaces studied by vibrational spectroscopy. PCCP. 2017;19:12992–3001.
33.
Barick KC, Sharma A, Neena G, Ningthoujam RS, Vatsa RK, Babu PD, Pandey BN, Hassan PA. Covalent bridging of surface functionalized Fe3O4 and YPO4: Eu nanostructures for simultaneous imaging and therapy. Dalton Trans. 2015;44:14686–96.PubMedCrossRef
34.
35.
Zhang Y, Chen X, Gueydan C, Han J. Plasma membrane changes during programmed cell deaths. Cell Res. 2018;28:9–21.PubMedCrossRef
36.
37.
Fulda S, Debatin KM. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 2006;25:4798–811.PubMedCrossRef
38.
39.
40.
Siddiqui H, Ghafari A, Choudhry H, Al DH. Roles of long non-coding RNAs in colorectal cancer tumorigenesis. Mol Clin Oncol. 2019;11:167–72.PubMedPubMedCentral
41.
Alsibai K, Vacher S, Meseure D, Nicolas A, Lae M, Schnitzler A, Chemlali W, Cros J, Longchampt E, Cacheux W, Pignot G, Callens C, Pasmant E, Allory Y, Bieche I. High positive correlations between ANRIL and p16-CDKN2A/p15-CDKN2B/p14-ARF gene cluster overexpression in multi-tumor types suggest deregulated activation of an ANRIL-ARF bidirectional promoter. Noncoding RNA. 2019;5:44.
Metadata
Title
Integrative in silico and in vitro transcriptomics analysis revealed new lncRNAs related to intrinsic apoptotic genes in colorectal cancer
Authors
Fatemeh Akbari
Maryam Peymani
Ali Salehzadeh
Kamran Ghaedi
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2020
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-020-01633-w

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