Screening and expression verification of key genes in hepatocellular carcinoma by bioinformatics analysis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

WANG Hebin ^1,2 , LIU Deqin ² , YANG Maohui ² , YING Wei ¹ , ZHOU Guojun ¹ , FENG Yanchao ¹ , ZHONG Xiaorong ¹ ,  LI Wenbo ¹ ,  LENG Zhengwei ¹

1. Department of Hepatobiliary Surgery II, Affiliated Hospital of North Sichuan Medical College/Cancer Stem Cell Research Center of Affiliated Hospital of North Sichuan Medical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P. R. China;
2. Department of Hepatobiliary, Panzhihua Hospital of Integrated Traditional Chinese and Western Medicine, Panzhihua, Sichuan 617000, P. R. China;

Corresponding author：

LI Wenbo, Email: liwenbojh@163.com; LENG Zhengwei, Email: lengzhengwei@163.com

Keywords：

hepatocellular carcinoma; bioinformatics analysis; key gene

DOI：

10.7507/1007-9424.202010071

Video：

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Objective To explore the clinical significance and possible potential mechanism of hepatocellular carcinoma through the screening of key genes in hepatocellular carcinoma.Methods Hepatocellular carcinoma gene chip was obtained from GEO database, differentially expressed genes (DEGs) were screened by GEO2R online tools and Venn map, GO analysis and KEGG pathway analysis were performed in DAVID database, core genes were screened by STRING and Cytscape software, core genes were analyzed in Kaplan-Meier Plotter for survival analysis, and expression was analyzed by GEPIA database. The core genes related to prognosis and highly expressed in hepatocellular carcinoma were analyzed by Metascape online tool for function and pathway enrichment analysis. Finally, the key genes were verified in hepatocellular carcinoma and paracancerous tissues.Results A total of 94 DEGs were screened from three gene chips GSE14520, GSE60502, and GSE102079, obtained from GEO. After the selected DEGs was analyzed by GO function analysis, KEGG pathway enrichment analysis, STRING and Cytscape software by DAVID, 19 core DEGs were screened. After 19 core DEGs were analyzed by Kaplan-Meier Plotter website, 9 genes [ribonucleotide reductase M2 (RRM2), polycomb repressive complex 1 (PRC1), topoisomerase Ⅱ alpha (TOP2A), aurora kinase A (AURKA), nucleolar spindle-associated protein 1 (NUSAP1), Rac-GTPase activating protein 1 (RACGAP1), abnormal spindle-like microcephaly-associated (ASPM), cyclin dependent kinase 1 (CDK1) and GINS complex subunit 1 (GINS1)] were found to be associated with the prognosis of hepatocellular carcinoma. The expressions of these 9 genes were analyzed by GEPIA, and the results showed that all 9 genes were highly expressed in hepatocellular carcinoma tissues. The functions and pathways of 9 highly expressed genes were analyzed by metascape website. Finally, RRM2 was selected for verification in hepatocellular carcinoma tissues and adjacent tissues, and it was found that the staining score of RRM2 in hepatocellular carcinoma tissues was (10.9±1.5) points, which was significantly higher than its staining score in adjacent tissues [(4.5±1.2) points], P<0.001.Conclusion The nine genes identified by bioinformatics analysis may be the key genes in the occurrence and development of hepatocellular carcinoma, which can provide reference for further study on the pathogenesis, diagnosis and treatment of hepatocellular carcinoma.

Citation： WANG Hebin, LIU Deqin, YANG Maohui, YING Wei, ZHOU Guojun, FENG Yanchao, ZHONG Xiaorong, LI Wenbo, LENG Zhengwei. Screening and expression verification of key genes in hepatocellular carcinoma by bioinformatics analysis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2021, 28(6): 743-750. doi: 10.7507/1007-9424.202010071 Copy

1.	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin, 2020, 70(1): 7-30.
2.	Islami F, Goding Sauer A, Miller KD, et al. Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States. CA Cancer J Clin, 2018, 68(1): 31-54.
3.	Degasperi E, Colombo M. Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease. Lancet Gastroenterol Hepatol, 2016, 1(2): 156-164.
4.	Yang JD, Hainaut P, Gores GJ, et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol, 2019, 16(10): 589-604.
5.	Feng H, Fang F, Yuan L, et al. Downregulated expression of CFHL1 is associated with unfavorable prognosis in postoperative patients with hepatocellular carcinoma. Exp Ther Med, 2019, 17(5): 4073-4079.
6.	Cao H, Xu Z, Wang J, et al. Functional role of SGK3 in PI3K/Pten driven liver tumor development. BMC Cancer, 2019, 19(1): 343.
7.	Kristensen VN, Lingjærde OC, Russnes HG, et al. Principles and methods of integrative genomic analyses in cancer. Nat Rev Cancer, 2014, 14(5): 299-313.
8.	D’Angiolella V, Donato V, Forrester FM, et al. Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome integrity and DNA repair. Cell, 2012, 149(5): 1023-1034.
9.	Engström Y, Eriksson S, Jildevik I, et al. Cell cycle-dependent expression of mammalian ribonucleotide reductase. Differential regulation of the two subunits. J Biol Chem, 1985, 260(16): 9114-9116.
10.	Wang J, Yi Y, Chen Y, et al. Potential mechanism of RRM2 for promoting Cervical Cancer based on weighted gene co-expression network analysis. Int J Med Sci, 2020, 17(15): 2362-2372.
11.	Lu AG, Feng H, Wang PX, et al. Emerging roles of the ribonucleotide reductase M2 in colorectal cancer and ultraviolet-induced DNA damage repair. World J Gastroenterol, 2012, 18(34): 4704-4713.
12.	Tang Q, Wu L, Xu M, et al. Osalmid, a novel identified RRM2 inhibitor, enhances radiosensitivity of esophageal cancer. Int J Radiat Oncol Biol Phys, 2020, 108(5): 1368-1379.
13.	Zhang S, Yan L, Cui C, et al. Downregulation of RRM2 attenuates retroperitoneal liposarcoma progression via the Akt/mTOR/4EBP1 pathway: clinical, biological, and therapeutic significance. Onco Targets Ther, 2020, 13: 6523-6537.
14.	Wang S, Wang XL, Wu ZZ, et al. Overexpression of RRM2 is related to poor prognosis in oral squamous cell carcinoma. Oral Dis, 2021, 27(2): 204-214.
15.	Li S, Mai H, Zhu Y, et al. MicroRNA-4500 inhibits migration, invasion, and angiogenesis of breast cancer cells via RRM2-dependent MAPK signaling pathway. Mol Ther Nucleic Acids, 2020, 21: 278-289.
16.	Feng H, Wang Q, Xiao W, et al. LncRNA TTN-AS1 regulates miR-524-5p and RRM2 to promote breast cancer progression. Onco Targets Ther, 2020, 13: 4799-4811.
17.	Mazzu YZ, Armenia J, Nandakumar S, et al. Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancer. Mol Oncol, 2020, 14(8): 1881-1897.
18.	刘霞, 陈龙, 范丽萍, 等. 核糖核苷酸还原酶小亚基 M2 在多发性骨髓瘤患者中的表达及抑制肿瘤细胞增殖的相关机制. 中国实验血液学杂志, 2020, 28(2): 540-546.
19.	Ye BL, Zheng R, Ruan XJ, et al. Chitosan-coated doxorubicin nano-particles drug delivery system inhibits cell growth of liver cancer via p53/PRC1 pathway. Biochem Biophys Res Commun, 2018, 495(1): 414-420.
20.	Liu LM, Xiong DD, Lin P, et al. DNA topoisomerase 1 and 2A function as oncogenes in liver cancer and may be direct targets of nitidine chloride. Int J Oncol, 2018, 53(5): 1897-1912.
21.	Wu C, Lyu J, Yang EJ, et al. Targeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells. Nat Commun, 2018, 9(1): 3212.
22.	Dauch D, Rudalska R, Cossa G, et al. A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer. Nat Med, 2016, 22(7): 744-753.
23.	Zhang X, Pan Y, Fu H, et al. Nucleolar and spindle associated protein 1 (NUSAP1) inhibits cell proliferation and enhances susceptibility to epirubicin in invasive breast cancer cells by regulating cyclin D kinase (CDK1) and DLGAP5 expression. Med Sci Monit, 2018, 24: 8553-8564.
24.	Wang Y, Ju L, Xiao F, et al. Downregulation of nucleolar and spindle-associated protein 1 expression suppresses liver cancer cell function. Exp Ther Med, 2019, 17(4): 2969-2978.
25.	Yang XM, Cao XY, He P, et al. Overexpression of Rac GTPase activating protein 1 contributes to proliferation of cancer cells by reducing hippo signaling to promote cytokinesis. Gastroenterology, 2018, 155(4): 1233-1249.
26.	Chen J, Xia H, Zhang X, et al. ECT2 regulates the Rho/ERK signalling axis to promote early recurrence in human hepatocellular carcinoma. J Hepatol, 2015, 62(6): 1287-1295.
27.	Wu M, Liu Z, Zhang A, et al. Identification of key genes and pathways in hepatocellular carcinoma: A preliminary bioinformatics analysis. Medicine (Baltimore), 2019, 98(5): e14287.
28.	Li B, Pu K, Wu X. Identifying novel biomarkers in hepatocellular carcinoma by weighted gene co-expression network analysis. J Cell Biochem, 2019, Feb 11. Online ahead of print.
29.	Pai VC, Hsu CC, Chan TS, et al. ASPM promotes prostate cancer stemness and progression by augmenting Wnt-Dvl-3-β-catenin signaling. Oncogene, 2019, 38(8): 1340-1353.
30.	Wang F, Chang Y, Li J, et al. Strong correlation between ASPM gene expression and HCV cirrhosis progression identified by co-expression analysis. Dig Liver Dis, 2017, 49(1): 70-76.
31.	Ito Y, Takeda T, Sakon M, et al. Expression and prognostic role of cyclin-dependent kinase 1 (cdc2) in hepatocellular carcinoma. Oncology, 2000, 59(1): 68-74.
32.	Zhou J, Han S, Qian W, et al. Metformin induces miR-378 to downregulate the CDK1, leading to suppression of cell proliferation in hepatocellular carcinoma. Onco Targets Ther, 2018, 11: 4451-4459.
33.	Yang F, Cui P, Lu Y, et al. Requirement of the transcription factor YB-1 for maintaining the stemness of cancer stem cells and reverting differentiated cancer cells into cancer stem cells. Stem Cell Res Ther, 2019, 10(1): 233.
34.	Lian YF, Li SS, Huang YL, et al. Up-regulated and interrelated expressions of GINS subunits predict poor prognosis in hepatocellular carcinoma. Biosci Rep, 2018, 38(6): BSR20181178.
35.	Lee B, Ha SY, Song DH, et al. High expression of ribonucleotide reductase subunit M2 correlates with poor prognosis of hepatocellular carcinoma. Gut Liver, 2014, 8(6): 662-668.
36.	Wang Y, Zhi Q, Ye Q, et al. SCYL1-BP1 affects cell cycle arrest in human hepatocellular carcinoma cells via cyclin F and RRM2. Anticancer Agents Med Chem, 2016, 16(4): 440-446.
37.	Satow R, Shitashige M, Kanai Y, et al. Combined functional genome survey of therapeutic targets for hepatocellular carcinoma. Clin Cancer Res, 2010, 16(9): 2518-2528.
38.	Ricardo-Lax I, Ramanan V, Michailidis E, et al. Hepatitis B virus induces RNR-R2 expression via DNA damage response activation. J Hepatol, 2015, 63(4): 789-796.
39.	Liu X, Xu Z, Hou C, et al. Inhibition of hepatitis B virus replication by targeting ribonucleotide reductase M2 protein. Biochem Pharmacol, 2016, 103: 118-128.

1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin, 2020, 70(1): 7-30.
2. Islami F, Goding Sauer A, Miller KD, et al. Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States. CA Cancer J Clin, 2018, 68(1): 31-54.
3. Degasperi E, Colombo M. Distinctive features of hepatocellular carcinoma in non-alcoholic fatty liver disease. Lancet Gastroenterol Hepatol, 2016, 1(2): 156-164.
4. Yang JD, Hainaut P, Gores GJ, et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol, 2019, 16(10): 589-604.
5. Feng H, Fang F, Yuan L, et al. Downregulated expression of CFHL1 is associated with unfavorable prognosis in postoperative patients with hepatocellular carcinoma. Exp Ther Med, 2019, 17(5): 4073-4079.
6. Cao H, Xu Z, Wang J, et al. Functional role of SGK3 in PI3K/Pten driven liver tumor development. BMC Cancer, 2019, 19(1): 343.
7. Kristensen VN, Lingjærde OC, Russnes HG, et al. Principles and methods of integrative genomic analyses in cancer. Nat Rev Cancer, 2014, 14(5): 299-313.
8. D’Angiolella V, Donato V, Forrester FM, et al. Cyclin F-mediated degradation of ribonucleotide reductase M2 controls genome integrity and DNA repair. Cell, 2012, 149(5): 1023-1034.
9. Engström Y, Eriksson S, Jildevik I, et al. Cell cycle-dependent expression of mammalian ribonucleotide reductase. Differential regulation of the two subunits. J Biol Chem, 1985, 260(16): 9114-9116.
10. Wang J, Yi Y, Chen Y, et al. Potential mechanism of RRM2 for promoting Cervical Cancer based on weighted gene co-expression network analysis. Int J Med Sci, 2020, 17(15): 2362-2372.
11. Lu AG, Feng H, Wang PX, et al. Emerging roles of the ribonucleotide reductase M2 in colorectal cancer and ultraviolet-induced DNA damage repair. World J Gastroenterol, 2012, 18(34): 4704-4713.
12. Tang Q, Wu L, Xu M, et al. Osalmid, a novel identified RRM2 inhibitor, enhances radiosensitivity of esophageal cancer. Int J Radiat Oncol Biol Phys, 2020, 108(5): 1368-1379.
13. Zhang S, Yan L, Cui C, et al. Downregulation of RRM2 attenuates retroperitoneal liposarcoma progression via the Akt/mTOR/4EBP1 pathway: clinical, biological, and therapeutic significance. Onco Targets Ther, 2020, 13: 6523-6537.
14. Wang S, Wang XL, Wu ZZ, et al. Overexpression of RRM2 is related to poor prognosis in oral squamous cell carcinoma. Oral Dis, 2021, 27(2): 204-214.
15. Li S, Mai H, Zhu Y, et al. MicroRNA-4500 inhibits migration, invasion, and angiogenesis of breast cancer cells via RRM2-dependent MAPK signaling pathway. Mol Ther Nucleic Acids, 2020, 21: 278-289.
16. Feng H, Wang Q, Xiao W, et al. LncRNA TTN-AS1 regulates miR-524-5p and RRM2 to promote breast cancer progression. Onco Targets Ther, 2020, 13: 4799-4811.
17. Mazzu YZ, Armenia J, Nandakumar S, et al. Ribonucleotide reductase small subunit M2 is a master driver of aggressive prostate cancer. Mol Oncol, 2020, 14(8): 1881-1897.
18. 刘霞, 陈龙, 范丽萍, 等. 核糖核苷酸还原酶小亚基 M2 在多发性骨髓瘤患者中的表达及抑制肿瘤细胞增殖的相关机制. 中国实验血液学杂志, 2020, 28(2): 540-546.
19. Ye BL, Zheng R, Ruan XJ, et al. Chitosan-coated doxorubicin nano-particles drug delivery system inhibits cell growth of liver cancer via p53/PRC1 pathway. Biochem Biophys Res Commun, 2018, 495(1): 414-420.
20. Liu LM, Xiong DD, Lin P, et al. DNA topoisomerase 1 and 2A function as oncogenes in liver cancer and may be direct targets of nitidine chloride. Int J Oncol, 2018, 53(5): 1897-1912.
21. Wu C, Lyu J, Yang EJ, et al. Targeting AURKA-CDC25C axis to induce synthetic lethality in ARID1A-deficient colorectal cancer cells. Nat Commun, 2018, 9(1): 3212.
22. Dauch D, Rudalska R, Cossa G, et al. A MYC-aurora kinase A protein complex represents an actionable drug target in p53-altered liver cancer. Nat Med, 2016, 22(7): 744-753.
23. Zhang X, Pan Y, Fu H, et al. Nucleolar and spindle associated protein 1 (NUSAP1) inhibits cell proliferation and enhances susceptibility to epirubicin in invasive breast cancer cells by regulating cyclin D kinase (CDK1) and DLGAP5 expression. Med Sci Monit, 2018, 24: 8553-8564.
24. Wang Y, Ju L, Xiao F, et al. Downregulation of nucleolar and spindle-associated protein 1 expression suppresses liver cancer cell function. Exp Ther Med, 2019, 17(4): 2969-2978.
25. Yang XM, Cao XY, He P, et al. Overexpression of Rac GTPase activating protein 1 contributes to proliferation of cancer cells by reducing hippo signaling to promote cytokinesis. Gastroenterology, 2018, 155(4): 1233-1249.
26. Chen J, Xia H, Zhang X, et al. ECT2 regulates the Rho/ERK signalling axis to promote early recurrence in human hepatocellular carcinoma. J Hepatol, 2015, 62(6): 1287-1295.
27. Wu M, Liu Z, Zhang A, et al. Identification of key genes and pathways in hepatocellular carcinoma: A preliminary bioinformatics analysis. Medicine (Baltimore), 2019, 98(5): e14287.
28. Li B, Pu K, Wu X. Identifying novel biomarkers in hepatocellular carcinoma by weighted gene co-expression network analysis. J Cell Biochem, 2019, Feb 11. Online ahead of print.
29. Pai VC, Hsu CC, Chan TS, et al. ASPM promotes prostate cancer stemness and progression by augmenting Wnt-Dvl-3-β-catenin signaling. Oncogene, 2019, 38(8): 1340-1353.
30. Wang F, Chang Y, Li J, et al. Strong correlation between ASPM gene expression and HCV cirrhosis progression identified by co-expression analysis. Dig Liver Dis, 2017, 49(1): 70-76.
31. Ito Y, Takeda T, Sakon M, et al. Expression and prognostic role of cyclin-dependent kinase 1 (cdc2) in hepatocellular carcinoma. Oncology, 2000, 59(1): 68-74.
32. Zhou J, Han S, Qian W, et al. Metformin induces miR-378 to downregulate the CDK1, leading to suppression of cell proliferation in hepatocellular carcinoma. Onco Targets Ther, 2018, 11: 4451-4459.
33. Yang F, Cui P, Lu Y, et al. Requirement of the transcription factor YB-1 for maintaining the stemness of cancer stem cells and reverting differentiated cancer cells into cancer stem cells. Stem Cell Res Ther, 2019, 10(1): 233.
34. Lian YF, Li SS, Huang YL, et al. Up-regulated and interrelated expressions of GINS subunits predict poor prognosis in hepatocellular carcinoma. Biosci Rep, 2018, 38(6): BSR20181178.
35. Lee B, Ha SY, Song DH, et al. High expression of ribonucleotide reductase subunit M2 correlates with poor prognosis of hepatocellular carcinoma. Gut Liver, 2014, 8(6): 662-668.
36. Wang Y, Zhi Q, Ye Q, et al. SCYL1-BP1 affects cell cycle arrest in human hepatocellular carcinoma cells via cyclin F and RRM2. Anticancer Agents Med Chem, 2016, 16(4): 440-446.
37. Satow R, Shitashige M, Kanai Y, et al. Combined functional genome survey of therapeutic targets for hepatocellular carcinoma. Clin Cancer Res, 2010, 16(9): 2518-2528.
38. Ricardo-Lax I, Ramanan V, Michailidis E, et al. Hepatitis B virus induces RNR-R2 expression via DNA damage response activation. J Hepatol, 2015, 63(4): 789-796.
39. Liu X, Xu Z, Hou C, et al. Inhibition of hepatitis B virus replication by targeting ribonucleotide reductase M2 protein. Biochem Pharmacol, 2016, 103: 118-128.

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Screening and expression verification of key genes in hepatocellular carcinoma by bioinformatics analysis

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