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Bioinformatics analysis revealed hub genes and pathways involved in sorafenib resistance in hepatocellular carcinoma

  • Received: 27 March 2019 Accepted: 27 June 2019 Published: 08 July 2019
  • Hepatocellular carcinoma (HCC) is increasingly known as a serious, worldwide public health concern. Sorafenib resistance is the main challenge faced by many advanced HCC patients. The specific mechanisms of sorafenib resistance remind unclear. In the current study, GEO2R was conducted to identify differentially expressed genes (DEGs) between sorafenib-resistant samples and the control group by using RNA-sequence analysis and analyzing dataset GSE109211. Next, protein-protein interaction (PPI) network was built to explore key targets proteins in sorafenib-resistant HCC. Furthermore, gene ontology (GO) analysis was used to research the underlying roles of key proteins. Moreover, the Kaplan-Meier survival analysis was performed to display the effect of key proteins on overall survival in HCC. Western blotting was performed to detected resistance-related proteins and CCK-8 assay was employed to measured cell viability. In the present research, 164 sorafenib resistance-related DEGs in HCC were identified by using RNA-sequence analysis and analyzing the dataset GSE109211. GO analysis revealed DEGs were involved in regulating multiple biological processes and molecular functions. DYNLL2, H2AFJ, SHANK2, ZWILCH, CDC14A, IFT20, MTA3, SERPINA1 and TCF4 were confirmed as key genes in this process. Moreover, our study showed Akt signaling was aberrantly activated and inhibition of Akt signaling enhanced anti-tumor capacity of sorafenib in sorafenib-resistant HCC cells. Identification of the DEGs in sorafenib resistant HCC cells may further provide the new insights of underlying sorafenib-resistant mechanisms and offer latent targets for early diagnosis and new therapies to improve clinical efficacy for sorafenib-resistant HCC patients.

    Citation: Jing Liu, Wancheng Qiu, Xiaoying Shen, Guangchun Sun. Bioinformatics analysis revealed hub genes and pathways involved in sorafenib resistance in hepatocellular carcinoma[J]. Mathematical Biosciences and Engineering, 2019, 16(6): 6319-6334. doi: 10.3934/mbe.2019315

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  • Hepatocellular carcinoma (HCC) is increasingly known as a serious, worldwide public health concern. Sorafenib resistance is the main challenge faced by many advanced HCC patients. The specific mechanisms of sorafenib resistance remind unclear. In the current study, GEO2R was conducted to identify differentially expressed genes (DEGs) between sorafenib-resistant samples and the control group by using RNA-sequence analysis and analyzing dataset GSE109211. Next, protein-protein interaction (PPI) network was built to explore key targets proteins in sorafenib-resistant HCC. Furthermore, gene ontology (GO) analysis was used to research the underlying roles of key proteins. Moreover, the Kaplan-Meier survival analysis was performed to display the effect of key proteins on overall survival in HCC. Western blotting was performed to detected resistance-related proteins and CCK-8 assay was employed to measured cell viability. In the present research, 164 sorafenib resistance-related DEGs in HCC were identified by using RNA-sequence analysis and analyzing the dataset GSE109211. GO analysis revealed DEGs were involved in regulating multiple biological processes and molecular functions. DYNLL2, H2AFJ, SHANK2, ZWILCH, CDC14A, IFT20, MTA3, SERPINA1 and TCF4 were confirmed as key genes in this process. Moreover, our study showed Akt signaling was aberrantly activated and inhibition of Akt signaling enhanced anti-tumor capacity of sorafenib in sorafenib-resistant HCC cells. Identification of the DEGs in sorafenib resistant HCC cells may further provide the new insights of underlying sorafenib-resistant mechanisms and offer latent targets for early diagnosis and new therapies to improve clinical efficacy for sorafenib-resistant HCC patients.


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    [1] L. A. Torre, F. Bray, R. L. Siegel, et al., Global cancer statistics, 2012, CA. Cancer J. Clin., 65(2015), 87–108.
    [2] R. Romagnoli, V. Mazzaferro and J. Bruix, Surgical resection for hepatocellular carcinoma: Moving from what can be done to what is worth doing, Hepatology, 62 (2015), 340–342.
    [3] N. F. Esnaola, G. Y. Lauwers, N. Q. Mirza, et al., Predictors of microvascular invasion in patients with hepatocellular carcinoma who are candidates for orthotopic liver transplantation, J. Gastrointest. Surg., 6 (2002), 224–232; discussion 232.
    [4] S. D'Angelo, M. Secondulfo, R. De Cristofano, et al., Selection and management of hepatocellular carcinoma patients with sorafenib: recommendations and opinions from an Italian liver unit, Future Oncol., 9 (2013), 485–491.
    [5] L. Adnane, P. A. Trail, I. Taylor, et al., Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature, Meth. Enzymol., 407 (2006), 597–612.
    [6] S. Wilhelm, C. Carter, M. Lynch, et al., Discovery and development of sorafenib: a multikinase inhibitor for treating cancer, Nat. Rev. Drug. Discov., 5 (2006), 835–844.
    [7] S. M. Wilhelm, C. Carter, L. Tang, et al., BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis, Cancer Res., 64 (2004), 7099–7109.
    [8] O. Waidmann and J. Trojan, Novel drugs in clinical development for hepatocellular carcinoma, Expert Opin. Investig. Drug., 24 (2015), 1075–1082.
    [9] M. J. Blivet-Van Eggelpoel, H. Chettouh, L. Fartoux, et al., Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells, J. Hepatol., 57 (2012), 108–115.
    [10] K. F. Chen, H. L. Chen, W. T. Tai, et al., Activation of phosphatidylinositol 3-kinase/Akt signaling pathway mediates acquired resistance to sorafenib in hepatocellular carcinoma cells, J. Pharmacol. Exp. Ther., 337 (2011), 155–161.
    [11] B. Zhai, F. Hu, X. Jiang, et al., Inhibition of Akt reverses the acquired resistance to sorafenib by switching protective autophagy to autophagic cell death in hepatocellular carcinoma, Mol. Cancer Ther., 13 (2014), 1589–1598.
    [12] A. K. Chow, L. Ng, C. S. Lam, et al., The Enhanced metastatic potential of hepatocellular carcinoma (HCC) cells with sorafenib resistance, PLoS One, 8 (2013), e78675.
    [13] D. Morgenszternand H. L. McLeod, PI3K/Akt/mTOR pathway as a target for cancer therapy, Anticancer Drugs, 16 (2005), 797–803.
    [14] A. Parveen, M. S. Akash, K. Rehman, et al., Dual Role of p21 in the Progression of Cancer and Its Treatment, Crit. Rev. Eukaryot. Gene Expr., 26 (2016), 49–62.
    [15] J. C. Su, P. H. Tseng, S. H. Wu, et al., SC-2001 overcomes STAT3-mediated sorafenib resistance through RFX-1/SHP-1 activation in hepatocellular carcinoma, Neoplasia, 16 (2014), 595–605.
    [16] Z. Xu, Y. Zhou, Y. Cao, et al., Identification of candidate biomarkers and analysis of prognostic values in ovarian cancer by integrated bioinformatics analysis, Med. Oncol., 33 (2016), 130.
    [17] Y. Guo, Y. Bao, M. Ma, et al., Identification of key candidate genes and pathways in colorectal cancer by integrated bioinformatical analysis, Int. J. Mol. Sci., 18 (2017).
    [18] B. Győrffy, P. Surowiak, J. Budczies, et al., Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer, PloS One., 8 (2013), e82241.
    [19] C. Stottrup, T. Tsang and Y. R. Chin, Upregulation of AKT3 confers resistance to the AKT inhibitor MK2206 in breast cancer, Mol. Cancer Ther., 15 (2016), 1964–1974.
    [20] A. Forner, J. M. Llovet and J. Bruix, Hepatocellular carcinoma, Lancet, 379 (2012), 1245–1255.
    [21] D. Huang, W. Yuan, H. Li, et al., Identification of key pathways and biomarkers in sorafenib-resistant hepatocellular carcinoma using bioinformatics analysis, Exp. Ther. Med., 16 (2018), 1850–1858.
    [22] X. Wang, W. M. Ghareeb, X. Lu, et al., Coexpression network analysis linked H2AFJ to chemoradiation resistance in colorectal cancer, J. Cell. Biochem., (2018).
    [23] K. Kohno, M. Chiba, S. Murata, et al., Identification of natural antisense transcripts involved in human colorectal cancer development, Int. J. Oncol., 37 (2010), 1425–1432.
    [24] R. Karess, Rod-Zw10-Zwilch: A key player in the spindle checkpoint, Trends Cell Biol., 15 (2005), 386–392.
    [25] Y. Yu, Z. Kovacevicand D. R. Richardson, Tuning cell cycle regulation with an iron key, Cell Cycle, 6 (2007), 1982–1994.
    [26] A. Fernandez-Vidal, A. Mazarsand S. Manenti, CDC25A: a rebel within the CDC25 phosphatases family?, Anticancer Agents Med. Chem., 8 (2008), 825–831.
    [27] M. P. Sacristan, S. Ovejeroand and A. Bueno, Human Cdc14A becomes a cell cycle gene in controlling Cdk1 activity at the G(2)/M transition, Cell Cycle, 10 (2011), 387–391.
    [28] M. T. Paulsen, A. M. Starks, F. A. Derheimer, et al., The p53-targeting human phosphatase hCdc14A interacts with the Cdk1/cyclin B complex and is differentially expressed in human cancers, Mol. Cancer, 5 (2006), 25.
    [29] F. M. Schmid, K. B. Schou, M. J. Vilhelm, et al., IFT20 modulates ciliary PDGFRalpha signaling by regulating the stability of Cbl E3 ubiquitin ligases, J. Cell. Biol., 217 (2018), 151–161.
    [30] H. Dong, H. Guo, L. Xie, et al., The metastasis-associated gene MTA3, a component of the Mi-2/NuRD transcriptional repression complex, predicts prognosis of gastroesophageal junction adenocarcinoma, PLoS One, 8 (2013), e62986.
    [31] A. M. Houghton, Mechanistic links between COPD and lung cancer, Nat. Rev. Cancer, 13 (2013), 233–245.
    [32] K. Vierlinger, M. H. Mansfeld, O. Koperek, et al., Identification of SERPINA1 as single marker for papillary thyroid carcinoma through microarray meta analysis and quantification of its discriminatory power in independent validation, BMC. Med. Genomics, 4 (2011), 30.
    [33] H. J. Chan, H. Li, Z. Liu, et al., SERPINA1 is a direct estrogen receptor target gene and a predictor of survival in breast cancer patients, Oncotarget, 6 (2015), 25815–25827.
    [34] C. H. Kwon, H. J. Park, J. H. Choi, et al., Snail and serpinA1 promote tumor progression and predict prognosis in colorectal cancer, Oncotarget, 6 (2015), 20312–20326.
    [35] K. Thorsen, F. Mansilla, T. Schepeler, et al., Alternative splicing of SLC39A14 in colorectal cancer is regulated by the Wnt pathway, Mol. Cell. Proteomics, 10 (2011), M110002998.
    [36] M. Nilbert and E. Rambech, Beta-catenin activation through mutation is rare in rectal cancer, Cancer Genet. Cytogenet., 128 (2001), 43–45.
    [37] S. Yan, C. Zhou, W. Zhang, et al., β-Catenin/TCF pathway upregulates STAT3 expression in human esophageal squamous cell carcinoma, Cancer Lett., 271 (2008), 85–97.
    [38] M. Takahashi, T. Tsunoda, M. Seiki, et al., Identification of membrane-type matrix metalloproteinase-1 as a target of the beta-catenin/Tcf4 complex in human colorectal cancers, Oncogene, 21 (2002), 5861–5867.
    [39] L. Beneduce, F. Castaldi, M. Marino, et al., Improvement of liver cancer detection with simultaneous assessment of circulating levels of free alpha-fetoprotein (AFP) and AFP-IgM complexes, Int. J. Biol. Markers, 19 (2004), 155–159.
    [40] S. X. Li, L. J. Liu, L. W. Dong, et al., CKAP4 inhibited growth and metastasis of hepatocellular carcinoma through regulating EGFR signaling, Tumour Biol., 35 (2014), 7999–8005.
    [41] B. J. McMahon, L. Bulkow, A. Harpster, et al., Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study, Hepatology, 32 (2000), 842–846.
    [42] M. Abu El Makarem, An overview of biomarkers for the diagnosis of hepatocellular carcinoma, Hepat. Mon., 12 (2012), e6122.
    [43] W. J. Zheng, M. Yao, M. Fang, et al., Abnormal expression of HMGB-3 is significantly associated with malignant transformation of hepatocytes, World J. Gastroenterol., 24 (2018), 3650–3662.
    [44] Z. Jiang, X. Zhai, B. Shi, et al., KIAA1199 overexpression is associated with abnormal expression of EMT markers and is a novel independent prognostic biomarker for hepatocellular carcinoma, Onco. Targets Ther., 11 (2018), 8341–8348.
    [45] P. Han, H. Li, X. Jiang, et al., Dual inhibition of Akt and c-Met as a second-line therapy following acquired resistance to sorafenib in hepatocellular carcinoma cells, Mol. Oncol., 11 (2017), 320–334.
    [46] C. H. Wu, X. Wu and H. W. Zhang, Inhibition of acquired-resistance hepatocellular carcinoma cell growth by combining sorafenib with phosphoinositide 3-kinase and rat sarcoma inhibitor, J. Surg. Res., 206 (2016), 371–379.
    [47] X. Tian, D. Zhou, L. Chen, et al., Polo-like kinase 4 mediates epithelial-mesenchymal transition in neuroblastoma via PI3K/Akt signaling pathway, Cell Death Dis., 9 (2018), 54.
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