Relation between microRNAs and Apoptosis in Hepatocellular Carcinoma

Refaat R. Kamel; Khalda Said Amr; Mie Afify; Yasser A. Elhosary; Abdelfattah E. Hegazy; Hoda H. Fahim; Wafaa M. Ezzat

doi:10.3889/oamjms.2016.038

Authors

Refaat R. Kamel Surgery Department, Faculty of Medicine, Ain Shams University, Cairo
Khalda Said Amr Medical Molecular Genetics Department, National Research Center, Cairo
Mie Afify Biochemistry Department, National Research Centre, Cairo
Yasser A. Elhosary Internal Medicine Department, National Research Centre, Cairo
Abdelfattah E. Hegazy Surgery Department, Elsahel Teaching Hospital, Cairo
Hoda H. Fahim Anesthesia Department, Elsahel Teaching Hospital, Cairo
Wafaa M. Ezzat Internal Medicine Department, National Research Centre, Cairo

DOI:

https://doi.org/10.3889/oamjms.2016.038

Keywords:

HCC, apoptosis, pathogenesis, microRNAs, HCV

Abstract

AIM: To determine the relation between serum microRNAs and apoptotic markers as regards development of HCC to understand the underlying mechanism of HCV related hepatocarcinogenesis.

PATIENTS AND METHODS: A total of 65 serum samples (25 samples from controls, 20 samples from hepatitis and 20 samples from HCC patients) were collected for miRNAs (mir 21, mir 199-a, and mir 155) detection. Human Programmed cell death protein-4 (PDCD-4) and Human Cytochrome-C (CYT-C) were determined.

RESULTS: miRNAs 21 and 155 were over expressed in sera of patients with HCC compared to patients with chronic hepatitis (p < 0.0001). While serum means values of miR 199a was significantly decreased among HCC group patients when compared to patients with chronic hepatitis (p < 0.0001). The serum levels of PCDC4 and CYTC were increased in patients with HCC when compared to chronic hepatitis patients. They were also increased in patients with chronic hepatitis when compared to controls (p < 0.05, significant). There was direct correlations between apoptotic markers and oncomirs miRNAs 21 and 155 while apoptotic markers were inversely correlated with miRNA 199-a.

CONCLUSION: Both microRNAs and apoptotic markers have roles in HCC pathogenesis. It seems that oncogenic microRNAs induce liver carcinogenesis in HCV patients irrespective of suppression of apoptosis.

AIM: To determine the relation between serum microRNAs and apoptotic markers as regards development of HCC to understand the underlying mechanism of HCV related hepatocarcinogenesis.

PATIENTS AND METHODS: A total of 65 serum samples (25 samples from controls, 20 samples from hepatitis and 20 samples from HCC patients) were collected for miRNAs (mir 21, mir 199-a, and mir 155) detection. Human Programmed cell death protein-4 (PDCD-4) and Human Cytochrome-C (CYT-C) were determined.

RESULTS: miRNAs 21 and 155 were over expressed in sera of patients with HCC compared to patients with chronic hepatitis (p < 0.0001). While serum means values of miR 199a was significantly decreased among HCC group patients when compared to patients with chronic hepatitis (p < 0.0001). The serum levels of PCDC4 and CYTC were increased in patients with HCC when compared to chronic hepatitis patients. They were also increased in patients with chronic hepatitis when compared to controls (p < 0.05, significant). There was direct correlations between apoptotic markers and oncomirs miRNAs 21 and 155 while apoptotic markers were inversely correlated with miRNA 199-a.

CONCLUSION: Both microRNAs and apoptotic markers have roles in HCC pathogenesis. It seems that oncogenic microRNAs induce liver carcinogenesis in HCV patients irrespective of suppression of apoptosis.

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References

Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74â€“108.

http://dx.doi.org/10.3322/canjclin.55.2.74 DOI: https://doi.org/10.3322/canjclin.55.2.74

PMid:15761078

Su H, Zhao J, Xiong Y, et al. Large-scale analysis of the genetic and epigenetic alterations in hepatocellular carcinoma from Southeast China. Mutat Res. 2008;641:27â€“35.

http://dx.doi.org/10.1016/j.mrfmmm.2008.02.005 DOI: https://doi.org/10.1016/j.mrfmmm.2008.02.005

PMid:18358501

Negrini M, Nicoloso MS, Calin GA. MicroRNAs and cancerâ€”new paradigms in molecular oncology. Curr Opin Cell Biol. 2009;21:470-479.

http://dx.doi.org/10.1016/j.ceb.2009.03.002 DOI: https://doi.org/10.1016/j.ceb.2009.03.002

PMid:19411171

Garzon R, Calin GA, Croce CM. MicroRNAs in cancer. Annu Rev Med. 2009;60:167-179.

http://dx.doi.org/10.1146/annurev.med.59.053006.104707 DOI: https://doi.org/10.1146/annurev.med.59.053006.104707

PMid:19630570

Huang JL, Zheng L, Hu YW, Wang Q. Characteristics of long non-coding RNA and its relation to hepatocellular carcinoma. Carcinogenesis. 2014;35:507â€“514.

http://dx.doi.org/10.1093/carcin/bgt405 DOI: https://doi.org/10.1093/carcin/bgt405

PMid:24296588

Rui Chu, Guangquan Mo, Zhijun Duan, Mei Huang, Jiuyang Chang, Xiaodong Li and Pixu Liu. miRNAs affect the development of hepatocellular carcinoma via dysregulation of their biogenesis and expression. Cell Communication and Signaling. 2014;12:45

http://dx.doi.org/10.1186/s12964-014-0045-y

PMid:25012758 PMCid:PMC4117189

Braconi C, Valeri N, Gasparini P, Huang N, Taccioli C, Nuovo G, Suzuki T, Croce CM, Patel T. Hepatitis C virus proteins modulate microRNA expression and chemosensitivity in malignant hepatocytes. Clin Cancer Res. 2010;16:957â€“966.

http://dx.doi.org/10.1158/1078-0432.CCR-09-2123 DOI: https://doi.org/10.1158/1078-0432.CCR-09-2123

PMid:20103677 PMCid:PMC2818698

Gong J, Zhang JP, Li B, Zeng C, You K, Chen MX, Yuan Y, Zhuang SM. MicroRNA-125b promotes apoptosis by regulating the expression of Mcl-1, Bcl-w and IL-6R. Oncogene. 2013, 32:3071â€“3079.

http://dx.doi.org/10.1038/onc.2012.318 DOI: https://doi.org/10.1038/onc.2012.318

PMid:22824797

Shimizu S, Takehara T, Hikita H, Kodama T, Miyagi T, Hosui A, Tatsumi T, Ishida H, Noda T, Nagano H, Doki Y, Mori M, Hayashi N. The let-7 family of microRNAs inhibits Bcl-xL expression and potentiates sorafenib-induced apoptosis in human hepatocellular carcinoma. J Hepatol 2010, 52:698â€“704.

http://dx.doi.org/10.1016/j.jhep.2009.12.024 DOI: https://doi.org/10.1016/j.jhep.2009.12.024

PMid:20347499

Wang H, Garzon R, Sun H, Ladner KJ, Singh R, Dahlman J, et al. NFkappaB- YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma. Cancer Cell. 2008;14:369-381.

http://dx.doi.org/10.1016/j.ccr.2008.10.006 DOI: https://doi.org/10.1016/j.ccr.2008.10.006

PMid:18977326 PMCid:PMC3829205

Fabbri M, Garzon R, Cimmino A, Liu Z, Zanesi N, Callegari E, et al. MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B. Proc Natl Acad Sci USA. 2007;104:15805â€“15810.

http://dx.doi.org/10.1073/pnas.0707628104 DOI: https://doi.org/10.1073/pnas.0707628104

PMid:17890317 PMCid:PMC2000384

Yujuan Xiong, Jian-Hong Fang, Jing-Ping Yun, Jine Yang, Ying Zhang, Wei-Hua Jia, and Shi-Mei Zhuang. Effects of MicroRNA-29 on Apoptosis, Tumorigenicity, and Prognosis of Hepatocellular Carcinoma. Hepatology. 2010;51:836-845. DOI: https://doi.org/10.1002/hep.23380

PMid:20041405

Harnois DM. Hepatitis C virus infection and the rising incidence of hepatocellular carcinoma. Mayo Clin Proc. 2012;87:7â€“8.

http://dx.doi.org/10.1016/j.mayocp.2011.11.004 DOI: https://doi.org/10.1016/j.mayocp.2011.11.004

PMid:22212962 PMCid:PMC3498411

Levrero M. Viral hepatitis and liver cancer: the case of hepatitis C. Oncogene. 2006;25:3834â€“3847.

http://dx.doi.org/10.1038/sj.onc.1209562 DOI: https://doi.org/10.1038/sj.onc.1209562

PMid:16799625

Malhi H, Gores GJ. Cellular and molecular mechanisms of liver injury. Gastroenterology. 2008;134:1641â€“1654.

http://dx.doi.org/10.1053/j.gastro.2008.03.002 DOI: https://doi.org/10.1053/j.gastro.2008.03.002

PMid:18471544 PMCid:PMC2553363

Slack FJ, Weidhaas JB. MicroRNAs as a potential magic bullet in cancer. Future Oncol. 2006;2: 73â€“82.

http://dx.doi.org/10.2217/14796694.2.1.73 DOI: https://doi.org/10.2217/14796694.2.1.73

PMid:16556074

Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA. 2004;101:2999â€“3004.

http://dx.doi.org/10.1073/pnas.0307323101 DOI: https://doi.org/10.1073/pnas.0307323101

PMid:14973191 PMCid:PMC365734

Jovanovic M, Hengartner MO. miRNAs and apoptosis: RNAs to die for. Oncogene. 2006;25: 6176â€“6187.

http://dx.doi.org/10.1038/sj.onc.1209912 DOI: https://doi.org/10.1038/sj.onc.1209912

PMid:17028597

Hou J, Lin L, Zhou W, Wang Z, Ding G, Dong Q, Qin L, Wu X, Zheng Y, Yang Y, et al. Identification of miRNomes in human liver and hepatocellular carcinoma reveals miR-199a/b-3p as therapeutic target for hepatocellular carcinoma. Cancer Cell. 2011;19:232â€“243.

http://dx.doi.org/10.1016/j.ccr.2011.01.001 DOI: https://doi.org/10.1016/j.ccr.2011.01.001

PMid:21316602

Gao F, et al. PDCD4 gene silencing in gliomas is associated with 5= CpG island methylation and unfavorable prognosis. J Cell Mol Med.2009;13:4257â€“ 4267.

http://dx.doi.org/10.1111/j.1582-4934.2008.00497.x DOI: https://doi.org/10.1111/j.1582-4934.2008.00497.x

PMid:18793349 PMCid:PMC4496131

Mudduluru G, et al. Loss of programmed cell death 4 expression marks adenoma-carcinoma transition, correlates inversely with phosphorylated protein kinase B, and is an independent prognostic factor in resected colorectal cancer. Cancer. 2007; 110:1697â€“1707.

http://dx.doi.org/10.1002/cncr.22983 DOI: https://doi.org/10.1002/cncr.22983

PMid:17849461

Powers MA, Fay MM, Factor RE, Welm AL, Ullman KS. Protein arginine methyltransferase 5 accelerates tumor growth by arginine methylation of the tumor suppressor programmed cell death 4. Cancer Res. 2011;71:5579 â€“5587.

http://dx.doi.org/10.1158/0008-5472.CAN-11-0458 DOI: https://doi.org/10.1158/0008-5472.CAN-11-0458

PMid:21700716 PMCid:PMC3156344

Chu R, Mo G, Duan Z, Huang M, Chang J, Li X, Liu P. miRNAs affect the development of hepatocellular carcinoma via dysregulation of their biogenesis and expression. Cell Commun Signal. 2014;12:45.

http://dx.doi.org/10.1186/s12964-014-0045-y DOI: https://doi.org/10.1186/s12964-014-0045-y

PMid:25012758 PMCid:PMC4117189

Zhu Q, Wang Z, Hu Y, Li J, Li X, Zhou L, Huang Y. miR-21 promotes migration and invasion by the miR-21-PDCD4-AP-1 feedback loop in human hepatocellular carcinoma. Oncol Rep. 2012;27(5):1660-8. DOI: https://doi.org/10.3892/or.2012.1682

PMid:22322403

Chan JA, Krichevsky AM, Kosik KS. MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 2005;65:6029â€“6033.

http://dx.doi.org/10.1158/0008-5472.CAN-05-0137 DOI: https://doi.org/10.1158/0008-5472.CAN-05-0137

PMid:16024602

Cheng AM, Byrom MW, Shelton J, Ford LP. Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res. 2005;33:1290â€“1297.

http://dx.doi.org/10.1093/nar/gki200 DOI: https://doi.org/10.1093/nar/gki200

PMid:15741182 PMCid:PMC552951

Palma CA, Al Sheikha D, Lim TK, Bryant A, Vu TT, Jayaswal V, Ma DD. MicroRNA-155 as an inducer of apoptosis and cell differentiation in Acute Myeloid Leukaemia. Mol Cancer. 2014;13:79.

http://dx.doi.org/10.1186/1476-4598-13-79 DOI: https://doi.org/10.1186/1476-4598-13-79

PMid:24708856 PMCid:PMC4021368