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Published in: BMC Cancer 1/2023

Open Access 01-12-2023 | Hepatocellular Carcinoma | Research

Elucidating the role of missense SNP of protein kinase C epsilon in HCV-induced hepatocellular carcinoma

Authors: Areeba Rehman, Maria Shabbir, Yasmin Badshah, Khushbukhat Khan, Janeen H. Trembley, Naeem Mahmood Ashraf, Tayyaba Afsar, Ali Almajwal, Nawaf W. Alruwaili, Ali Alshamari, Tariq Nahar Alanezi, Suhail Razak

Published in: BMC Cancer | Issue 1/2023

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Abstract

Background

The protein kinase C (PKC) family of serine/threonine kinases contains more than ten isozymes that are involved in multiple signaling pathways, including cell cycle regulation and carcinogenesis. The PKCε isozyme is an oncogene known to be upregulated in various signaling pathways involved in hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC). However, there is no known association of missense SNPs in PKCε with this disease, which can be a potential biomarker for early diagnosis and treatment. This research reveals a novel missense SNP in PKCε that is associated with HCV-induced HCC in the Pakistani population.

Methods

The PKCε SNP with amino acid substitution of E14K was chosen for wet lab analysis. Tetra ARMS-PCR was employed for the identification of high-risk SNP in PKCε of HCV-induced HCC patients. Liver function testing was also performed for comparison between the liver condition of the HCC patient and control group, and the viral load of HCC patient samples was evaluated to determine any alteration in the viral infectivity between different genotypes of the selected high-risk PKCε variant SNP.

Results

Frequency distribution of the homozygous GG genotype was found to be highest among HCV-induced HCC patients and was also found to be significantly associated with disease development and progression. The p values of comparative data obtained for the other two genotypes, heterozygous AG and homozygous AA, of the SNP also showed the significance of the data for these alleles. Still, their odds ratio and relative risk analysis did not indicate their association with HCV-induced HCC.

Conclusion

The distribution of a genotype GG of PKCε has been found in HCV- induced HCC patients. Therefore, these PKCε SNP have the potential to be biomarkers for HCV-induced HCC. Further investigation using a larger sample size would provide additional insight into these initial data and open a new avenue for a better prognosis of this disease.
Literature
1.
2.
go back to reference Webb BL, Hirst SJ, Giembycz MA. Protein kinase C isoenzymes: a review of their structure, regulation and role in regulating airways smooth muscle tone and mitogenesis. Br J Pharmacol. 2000;130(7):1433–52.CrossRefPubMedPubMedCentral Webb BL, Hirst SJ, Giembycz MA. Protein kinase C isoenzymes: a review of their structure, regulation and role in regulating airways smooth muscle tone and mitogenesis. Br J Pharmacol. 2000;130(7):1433–52.CrossRefPubMedPubMedCentral
4.
go back to reference Akita Y. Protein kinase C-ε (PKC-ε): its unique structure and function. J Biochem. 2002;132(6):847–52.CrossRefPubMed Akita Y. Protein kinase C-ε (PKC-ε): its unique structure and function. J Biochem. 2002;132(6):847–52.CrossRefPubMed
5.
go back to reference Aksoy E, Goldman M, Willems F. Protein kinase C epsilon: a new target to control inflammation and immune-mediated disorders. Int J Biochem Cell Biol. 2004;36(2):183–8.CrossRefPubMed Aksoy E, Goldman M, Willems F. Protein kinase C epsilon: a new target to control inflammation and immune-mediated disorders. Int J Biochem Cell Biol. 2004;36(2):183–8.CrossRefPubMed
6.
go back to reference Obis T, et al. The novel protein kinase C epsilon isoform modulates acetylcholine release in the rat neuromuscular junction. Mol Brain. 2015;8(1):1–16.CrossRef Obis T, et al. The novel protein kinase C epsilon isoform modulates acetylcholine release in the rat neuromuscular junction. Mol Brain. 2015;8(1):1–16.CrossRef
7.
go back to reference Kang J-H. Protein kinase C (PKC) isozymes and cancer New Journal of Science, 2014. 2014. Kang J-H. Protein kinase C (PKC) isozymes and cancer New Journal of Science, 2014. 2014.
9.
go back to reference Gorin MA, Pan Q. Protein kinase Cε: an oncogene and emerging tumor biomarker. Mol Cancer. 2009;8(1):1–8.CrossRef Gorin MA, Pan Q. Protein kinase Cε: an oncogene and emerging tumor biomarker. Mol Cancer. 2009;8(1):1–8.CrossRef
10.
go back to reference Khan K et al. Unravelling Structure, Localization, and Genetic Crosstalk of KLF3 in Human Breast Cancer BioMed research international, 2020. 2020. Khan K et al. Unravelling Structure, Localization, and Genetic Crosstalk of KLF3 in Human Breast Cancer BioMed research international, 2020. 2020.
11.
go back to reference Safi S, et al. Predicting 3D structure, Cross Talks, and Prognostic significance of KLF9 in Cervical Cancer. Front Oncol. 2021;11:797007–7.CrossRefPubMed Safi S, et al. Predicting 3D structure, Cross Talks, and Prognostic significance of KLF9 in Cervical Cancer. Front Oncol. 2021;11:797007–7.CrossRefPubMed
12.
go back to reference Zhang J, et al. Functional proteomic analysis of a three-tier PKCε-Akt-eNOS signaling module in cardiac protection. Am J Physiol Heart Circ Physiol. 2005;288(2):H954–61.CrossRefPubMed Zhang J, et al. Functional proteomic analysis of a three-tier PKCε-Akt-eNOS signaling module in cardiac protection. Am J Physiol Heart Circ Physiol. 2005;288(2):H954–61.CrossRefPubMed
13.
go back to reference Xu W, et al. Crosstalk of protein kinase C ε with Smad2/3 promotes tumor cell proliferation in prostate cancer cells by enhancing aerobic glycolysis. Cell Mol Life Sci. 2018;75(24):4583–98.CrossRefPubMed Xu W, et al. Crosstalk of protein kinase C ε with Smad2/3 promotes tumor cell proliferation in prostate cancer cells by enhancing aerobic glycolysis. Cell Mol Life Sci. 2018;75(24):4583–98.CrossRefPubMed
14.
go back to reference Doumit R, et al. The role of protein kinase C isoforms in telomerase activity and alphafetoprotein secretion by the hepatocellular carcinoma cell lines. Cancer Res. 2016;76(14Supplement):940–0.CrossRef Doumit R, et al. The role of protein kinase C isoforms in telomerase activity and alphafetoprotein secretion by the hepatocellular carcinoma cell lines. Cancer Res. 2016;76(14Supplement):940–0.CrossRef
15.
go back to reference Liu LF, Purushotham A, Belury M. Activation of peroxisome proliferator-activated receptor (PPAR) α by conjugated linoleic acid is modulated by protein kinase C ε. Wiley Online Library; 2006. Liu LF, Purushotham A, Belury M. Activation of peroxisome proliferator-activated receptor (PPAR) α by conjugated linoleic acid is modulated by protein kinase C ε. Wiley Online Library; 2006.
16.
go back to reference Hung C-H, et al. Insulin resistance is associated with hepatocellular carcinoma in chronic hepatitis C infection. World J gastroenterology: WJG. 2010;16(18):2265.CrossRefPubMedCentral Hung C-H, et al. Insulin resistance is associated with hepatocellular carcinoma in chronic hepatitis C infection. World J gastroenterology: WJG. 2010;16(18):2265.CrossRefPubMedCentral
17.
go back to reference Mu W, et al. Potential nexus of non-alcoholic fatty liver disease and type 2 diabetes mellitus: insulin resistance between hepatic and peripheral tissues. Front Pharmacol. 2019;9:1566.CrossRefPubMedPubMedCentral Mu W, et al. Potential nexus of non-alcoholic fatty liver disease and type 2 diabetes mellitus: insulin resistance between hepatic and peripheral tissues. Front Pharmacol. 2019;9:1566.CrossRefPubMedPubMedCentral
18.
go back to reference Yoon S, Shin B, Woo HG. Endoplasmic reticulum stress induces CAP2 expression promoting epithelial-mesenchymal transition in Liver Cancer cells. Mol Cells. 2021;44(8):569.CrossRefPubMedPubMedCentral Yoon S, Shin B, Woo HG. Endoplasmic reticulum stress induces CAP2 expression promoting epithelial-mesenchymal transition in Liver Cancer cells. Mol Cells. 2021;44(8):569.CrossRefPubMedPubMedCentral
19.
go back to reference Parzefall T et al. PRKCA overexpression is frequent in young oral tongue squamous cell carcinoma patients and is associated with poor prognosis Cancers, 2021;13(9):p. 2082. Parzefall T et al. PRKCA overexpression is frequent in young oral tongue squamous cell carcinoma patients and is associated with poor prognosis Cancers, 2021;13(9):p. 2082.
20.
go back to reference Liu X, et al. Genetic variants of the peroxisome proliferator-activated receptor (PPAR) signaling pathway genes and risk of pancreatic cancer. Mol Carcinog. 2020;59(8):930–9.CrossRefPubMedPubMedCentral Liu X, et al. Genetic variants of the peroxisome proliferator-activated receptor (PPAR) signaling pathway genes and risk of pancreatic cancer. Mol Carcinog. 2020;59(8):930–9.CrossRefPubMedPubMedCentral
21.
go back to reference Khan K, et al. Influence of PRKCE non-synonymous variants on protein dynamics and functionality. Human Molecular Genetics; 2022. Khan K, et al. Influence of PRKCE non-synonymous variants on protein dynamics and functionality. Human Molecular Genetics; 2022.
23.
go back to reference Srivatanakul P, Sriplung H, Deerasamee S. Epidemiology of liver cancer: an overview. Asian Pac J Cancer Prev. 2004;5(2):118–25.PubMed Srivatanakul P, Sriplung H, Deerasamee S. Epidemiology of liver cancer: an overview. Asian Pac J Cancer Prev. 2004;5(2):118–25.PubMed
25.
go back to reference Vescovo T, et al. Molecular mechanisms of hepatitis C virus–induced hepatocellular carcinoma. Clin Microbiol Infect. 2016;22(10):853–61.CrossRefPubMed Vescovo T, et al. Molecular mechanisms of hepatitis C virus–induced hepatocellular carcinoma. Clin Microbiol Infect. 2016;22(10):853–61.CrossRefPubMed
26.
go back to reference Khatun M, Ray R, Ray RB. Hepatitis C virus associated hepatocellular carcinoma. Adv Cancer Res. 2021;149:103–42.CrossRefPubMed Khatun M, Ray R, Ray RB. Hepatitis C virus associated hepatocellular carcinoma. Adv Cancer Res. 2021;149:103–42.CrossRefPubMed
27.
go back to reference Lu H-C, et al. Expression of protein kinase C family in human hepatocellular carcinoma. Pathol Oncol Res. 2010;16(3):385–91.CrossRefPubMed Lu H-C, et al. Expression of protein kinase C family in human hepatocellular carcinoma. Pathol Oncol Res. 2010;16(3):385–91.CrossRefPubMed
28.
go back to reference Yan R, Niu C-Y, Tian Y. Roles of Autophagy and protein kinase C-epsilon in lipid metabolism of nonalcoholic fatty liver cell models. Arch Med Res. 2018;49(6):381–90.CrossRefPubMed Yan R, Niu C-Y, Tian Y. Roles of Autophagy and protein kinase C-epsilon in lipid metabolism of nonalcoholic fatty liver cell models. Arch Med Res. 2018;49(6):381–90.CrossRefPubMed
29.
go back to reference Pascut D, et al. HCV Proteins modulate the host cell miRNA expression contributing to Hepatitis C pathogenesis and Hepatocellular Carcinoma Development. Cancers. 2021;13(10):2485.CrossRefPubMedPubMedCentral Pascut D, et al. HCV Proteins modulate the host cell miRNA expression contributing to Hepatitis C pathogenesis and Hepatocellular Carcinoma Development. Cancers. 2021;13(10):2485.CrossRefPubMedPubMedCentral
30.
go back to reference Ghatak S, Muthukumaran RB, Nachimuthu SK. A simple method of genomic DNA extraction from human samples for PCR-RFLP analysis. J Biomol Tech. 2013;24(4):224–31.PubMedPubMedCentral Ghatak S, Muthukumaran RB, Nachimuthu SK. A simple method of genomic DNA extraction from human samples for PCR-RFLP analysis. J Biomol Tech. 2013;24(4):224–31.PubMedPubMedCentral
31.
go back to reference Perletti G, et al. ϵPKC Acts like a marker of Progressive Malignancy in Rat Liver, but fails to enhance tumorigenesis in rat hepatoma cells in culture. Biochem Biophys Res Commun. 1996;221(3):688–91.CrossRefPubMed Perletti G, et al. ϵPKC Acts like a marker of Progressive Malignancy in Rat Liver, but fails to enhance tumorigenesis in rat hepatoma cells in culture. Biochem Biophys Res Commun. 1996;221(3):688–91.CrossRefPubMed
32.
go back to reference Li Q, et al. Two novel PRKCI polymorphisms and prostate cancer risk in an Eastern Chinese Han population. Mol Carcinog. 2015;54(8):632–41.CrossRefPubMed Li Q, et al. Two novel PRKCI polymorphisms and prostate cancer risk in an Eastern Chinese Han population. Mol Carcinog. 2015;54(8):632–41.CrossRefPubMed
33.
go back to reference Wang B, et al. The association of six polymorphisms of five genes involved in three steps of nucleotide excision repair pathways with hepatocellular cancer risk. Oncotarget. 2016;7(15):20357.CrossRefPubMedPubMedCentral Wang B, et al. The association of six polymorphisms of five genes involved in three steps of nucleotide excision repair pathways with hepatocellular cancer risk. Oncotarget. 2016;7(15):20357.CrossRefPubMedPubMedCentral
34.
go back to reference Kumar CV et al. Computational analysis reveals the association of threonine 118 methionine mutation in PMP22 resulting in CMT-1A Advances in bioinformatics, 2014. 2014. Kumar CV et al. Computational analysis reveals the association of threonine 118 methionine mutation in PMP22 resulting in CMT-1A Advances in bioinformatics, 2014. 2014.
35.
go back to reference Suybeng V, et al. Comparison of pathogenicity prediction tools on somatic variants. J Mol Diagn. 2020;22(12):1383–92.CrossRefPubMed Suybeng V, et al. Comparison of pathogenicity prediction tools on somatic variants. J Mol Diagn. 2020;22(12):1383–92.CrossRefPubMed
36.
go back to reference Hayashi J, et al. A relationship between the evolution of hepatitis C virus variants, liver damage, and hepatocellular carcinoma in patients with hepatitis C viremia. J Infect Dis. 2000;181(5):1523–7.CrossRefPubMed Hayashi J, et al. A relationship between the evolution of hepatitis C virus variants, liver damage, and hepatocellular carcinoma in patients with hepatitis C viremia. J Infect Dis. 2000;181(5):1523–7.CrossRefPubMed
37.
go back to reference Anokhin VV et al. Previously unidentified single nucleotide polymorphisms in HIV/AIDS cases associate with clinical parameters and disease progression BioMed research international, 2016. 2016. Anokhin VV et al. Previously unidentified single nucleotide polymorphisms in HIV/AIDS cases associate with clinical parameters and disease progression BioMed research international, 2016. 2016.
38.
go back to reference Zhong Y-W, et al. IL28B SNP rs12979860 is the critical predictor for sustained viral response in chinese children aged 1 to 6 years with chronic hepatitis C. Int J Biol Sci. 2016;12(11):1357.CrossRefPubMedPubMedCentral Zhong Y-W, et al. IL28B SNP rs12979860 is the critical predictor for sustained viral response in chinese children aged 1 to 6 years with chronic hepatitis C. Int J Biol Sci. 2016;12(11):1357.CrossRefPubMedPubMedCentral
40.
go back to reference Hafeez S, et al. Trends in Cancer Prevalence in Punjab, Pakistan: a systematic study from 2010 to 2016. J Bioresource Manage. 2020;7(2):8.CrossRef Hafeez S, et al. Trends in Cancer Prevalence in Punjab, Pakistan: a systematic study from 2010 to 2016. J Bioresource Manage. 2020;7(2):8.CrossRef
Metadata
Title
Elucidating the role of missense SNP of protein kinase C epsilon in HCV-induced hepatocellular carcinoma
Authors
Areeba Rehman
Maria Shabbir
Yasmin Badshah
Khushbukhat Khan
Janeen H. Trembley
Naeem Mahmood Ashraf
Tayyaba Afsar
Ali Almajwal
Nawaf W. Alruwaili
Ali Alshamari
Tariq Nahar Alanezi
Suhail Razak
Publication date
01-12-2023
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2023
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-023-10618-7

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