Abstract
Hepatocellular carcinoma is a multifaceted and genomically complex disease and rapidly emerging experimental evidence has started to shed light on wide ranging molecular mechanisms which underlie its development and progression. It is now known that Overexpression of oncogenes, inactivation of tumor suppressor genes, dysregulation of spatio-temporally controlled intracellular signaling cascades, genetic/epigenetic mutations, loss of apoptosis and intra-tumor heterogeneity contribute significantly. Research over the years has gradually revealed intricate role of intracellular signaling cascades both in growth, development and cancer. Misrepresentation of EGFR induced intracellular signaling has been shown to fuel cancer development and progression. We partition this review into how EGFR modulates protein machinery in hepatocellular carcinoma and also summarize most recent updates on preclinical and clinical trials. Better and deeper understanding of the molecular mechanisms of HCC will be helpful in getting a step closer to individualized medicine.
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References
Chong CR, Jänne PA (2013) The quest to overcome resistance to EGFR-targeted therapies in cancer. Nat Med 19(11):1389–1400. doi:10.1038/nm.3388
Wheeler DL, Dunn EF, Harari PM (2010) Understanding resistance to EGFR inhibitors-impact on future treatment strategies. Nat Rev Clin Oncol 7(9):493–507. doi:10.1038/nrclinonc.2010.97
Ye QH, Zhu WW, Zhang JB, Qin Y, Lu M, Lin GL, Guo L, Zhang B, Lin ZH, Roessler S, Forgues M, Jia HL, Lu L, Zhang XF, Lian BF, Xie L, Dong QZ, Tang ZY, Wang XW, Qin LX (2016) GOLM1 modulates EGFR/RTK cell-surface recycling to drive hepatocellular carcinoma metastasis. Cancer Cell 30(3):444–458
Leng C, Zhang ZG, Chen WX, Luo HP, Song J, Dong W, Zhu XR, Chen XP, Liang HF, Zhang BX (2016) An integrin beta4-EGFR unit promotes hepatocellular carcinoma lung metastases by enhancing anchorage independence through activation of FAK-AKT pathway. Cancer Lett 376(1):188–196
Huan H, Wen X, Chen X, Wu L, Liu W, Habib NA, Bie P, Xia F (2016) C/EBPα short-activating RNA suppresses metastasis of hepatocellular carcinoma through inhibiting EGFR/β-catenin signaling mediated EMT. PLoS One 11(4):e0153117
Steinway SN, Dang H, You H, Rountree CB, Ding W (2015) The EGFR/ErbB3 pathway acts as a compensatory survival mechanism upon c-Met inhibition in human c-Met+ hepatocellular carcinoma. PLoS One 10(5):e0128159
Gong C, Zhang J, Zhang L, Wang Y, Ma H, Wu W, Cui J, Wang Y, Ren Z (2015) Dynamin2 downregulation delays EGFR endocytic trafficking and promotes EGFR signaling and invasion in hepatocellular carcinoma. Am J Cancer Res 5(2):702–713
Wang ZC, Gao Q, Shi JY, Guo WJ, Yang LX, Liu XY, Liu LZ, Ma LJ, Duan M, Zhao YJ, Wu YN, Gao DM, Wang XY, Shi GM, Ding ZB, Ke AW, Tang QQ, Cao Y, Zhou J, Fan J (2015) Protein tyrosine phosphatase receptor S acts as a metastatic suppressor in hepatocellular carcinoma by control of epithermal growth factor receptor-induced epithelial-mesenchymal transition. Hepatology 62(4):1201–1214
Lin BY, Xiao CX, Zhao WX, Xiao L, Chen X, Li P, Wang XM (2015) Enoyl-coenzyme A hydratase short chain 1 silencing attenuates the proliferation of hepatocellular carcinoma by inhibiting epidermal growth factor signaling in vitro and in vivo. Mol Med Rep 12(1):1421–1428
Huang MJ, Hu RH, Chou CH, Hsu CL, Liu YW, Huang J, Hung JS, Lai IR, Juan HF, Yu SL, Wu YM, Huang MC (2015) Knockdown of GALNT1 suppresses malignant phenotype of hepatocellular carcinoma by suppressing EGFR signaling. Oncotarget. 6(8):5650–5665
Fang Z, Zhou L, Jiang S, Cao L, Yu L (2015) UNC50 prompts G1/S transition and proliferation in HCC by regulation of epidermal growth factor receptor trafficking. PLoS One 10(3):e0119338
Hung CM, Huang WC, Pan HL, Chien PH, Lin CW, Chen LC, Chien YF, Lin CC, Leow KH, Chen WS, Chen JY, Ho CY, Hou PS, Chen YJ (2014) Hepatitis B virus X upregulates HuR protein level to stabilize HER2 expression in hepatocellular carcinoma cells. Biomed Res Int 2014:827415
Li SX, Liu LJ, Dong LW, Shi HG, Pan YF, Tan YX, Zhang J, Zhang B, Ding ZW, Jiang TY, Hu HP, Wang HY (2014) CKAP4 inhibited growth and metastasis of hepatocellular carcinoma through regulating EGFR signaling. Tumour Biol 35(8):7999–8005
Luo X, Xie H, Long X, Zhou M, Xu Z, Shi B, Jiang H, Li Z (2013) EGFRvIII mediates hepatocellular carcinoma cell invasion by promoting S100 calcium binding protein A11 expression. PLoS One 8(12):e83332
Wang L, Sun H, Wang X, Hou N, Zhao L, Tong D, He K, Yang Y, Song T, Yang J, Huang C (2016) EGR1 mediates miR-203a suppress the hepatocellular carcinoma cells progression by targeting HOXD3 through EGFR signaling pathway. Oncotarget 7(29):45302–45316. doi:10.18632/oncotarget.9605
Wang X, Zhang W, Tang J, Huang R, Li J, Xu D, Xie Y, Jiang R, Deng L, Zhang X, Chai Y, Qin X, Sun B (2016) LINC01225 promotes occurrence and metastasis of hepatocellular carcinoma in an epidermal growth factor receptor-dependent pathway. Cell Death Dis 7:e2130. doi:10.1038/cddis.2016.26
Higuchi T, Todaka H, Sugiyama Y, Ono M, Tamaki N, Hatano E, Takezaki Y, Hanazaki K, Miwa T, Chin See LS, Morisawa K, Tsuda M, Taniguchi T, Sakamoto S (2016) Suppression of miR-7 biogenesis by NF90-NF45 controls cell proliferation in hepatocellular carcinoma. J Biol Chem 291(40):21074–21084. doi:10.1074/jbc.M116.748210
Zou CD, Zhao WM, Wang XN, Li Q, Huang H, Cheng WP, Jin JF, Zhang H, Wu MJ, Tai S, Zou CX, Gao X (2016) MicroRNA-107: a novel promoter of tumor progression that targets the CPEB3/EGFR axis in human hepatocellular carcinoma. Oncotarget. 7(1):266–278
Qi HL, Li CS, Qian CW, Xiao YS, Yuan YF, Liu QY, Liu ZS (2016) The long noncoding RNA, EGFR-AS1, a target of GHR, increases the expression of EGFR in hepatocellular carcinoma. Tumour Biol 37(1):1079–1089
Chen W, Qiu Y (2015) Ginsenoside Rh2 targets EGFR by up-regulation of miR-491 to enhance anti-tumor activity in hepatitis B virus-related hepatocellular carcinoma. Cell Biochem Biophys 72(2):325–331
Huang S, He R, Rong M, Dang Y, Chen G (2014) Synergistic effect of MiR-146a mimic and cetuximab on hepatocellular carcinoma cells. Biomed Res Int 2014:384121
Fang T, Hou J, He M, Wang L, Zheng M, Wang X, Xia J (2016) Actinidia chinensis Planch root extract (acRoots) inhibits hepatocellular carcinoma progression by inhibiting EP3 expression. Cell Biol Toxicol 32(6):499–511
Liu X, Tian S, Liu M, Jian L, Zhao L (2016) Wogonin inhibits the proliferation and invasion, and induces the apoptosis of HepG2 and Bel7402 HCC cells through NF-κB/Bcl-2, EGFR and EGFR downstream ERK/AKT signaling. Int J Mol Med 38(4):1250–1256
Qian L, Liu Y, Xu Y, Ji W, Wu Q, Liu Y, Gao Q, Su C (2015) Matrine derivative WM130 inhibits hepatocellular carcinoma by suppressing EGFR/ERK/MMP-2 and PTEN/AKT signaling pathways. Cancer Lett 368(1):126–134
Gu HR, Park SC, Choi SJ, Lee JC, Kim YC, Han CJ, Kim J, Yang KY, Kim YJ, Noh GY, No SH, Jeong JH (2015) Combined treatment with silibinin and either sorafenib or gefitinib enhances their growth-inhibiting effects in hepatocellular carcinoma cells. Clin Mol Hepatol 21(1):49–59
Ding J, Wen W, Xiang D, Yin P, Liu Y, Liu C, He G, Cheng Z, Yin J, Sheng C, Zhang W, Nan F, Ye W, Zhang X, Wang H (2015) ψ-Bufarenogin, a novel anti-tumor compound, suppresses liver cancer growth by inhibiting receptor tyrosine kinase-mediated signaling. Oncotarget 6(13):11627–11639
Yan YY, Guo Y, Zhang W, Ma CG, Zhang YX, Wang C, Wang HX (2014) Celastrol enhanced the anticancer effect of lapatinib in human hepatocellular carcinoma cells in vitro. J BUON 19(2):412–418
Chang L, Wang G, Jia T, Zhang L, Li Y, Han Y, Zhang K, Lin G, Zhang R, Li J, Wang L (2016) Armored long non-coding RNA MEG3 targeting EGFR based on recombinant MS2 bacteriophage virus-like particles against hepatocellular carcinoma. Oncotarget. 7(17):23988–24004
Poojari R, Kini S, Srivastava R, Panda D (2015) A chimeric cetuximab-functionalized corona as a potent delivery system for microtubule-destabilizing nanocomplexes to hepatocellular carcinoma cells: a focus on EGFR and tubulin intracellular dynamics. Mol Pharm 12(11):3908–3923
Jiang J, Chen H, Yu C, Zhang Y, Chen M, Tian S, Sun C (2015) The promotion of salinomycin delivery to hepatocellular carcinoma cells through EGFR and CD133 aptamers conjugation by PLGA nanoparticles. Nanomedicine (Lond) 10(12):1863–1879
Bondì ML, Azzolina A, Craparo EF, Botto C, Amore E, Giammona G, Cervello M (2014) Entrapment of an EGFR inhibitor into nanostructured lipid carriers (NLC) improves its antitumor activity against human hepatocarcinoma cells. J Nanobiotechnol 12:21. doi:10.1186/1477-3155-12-21
Goyal L, Wadlow RC, Blaszkowsky LS, Wolpin BM, Abrams TA, McCleary NJ, Sheehan S, Sundaram E, Karol MD, Chen J, Zhu AX (2015) A phase I and pharmacokinetic study of ganetespib (STA-9090) in advanced hepatocellular carcinoma. Invest New Drugs 33(1):128–137
Hsu CH, Kang YK, Yang TS, Shun CT, Shao YY, Su WC, Sandoval-Tan J, Chiou TJ, Jin K, Hsu C, Cheng AL (2013) Bevacizumab with erlotinib as first-line therapy in Asian patients with advanced hepatocellular carcinoma: a multicenter phase II study. Oncology 85(1):44–52
Chen YJ, Chi CW, Su WC, Huang HL (2014) Lapatinib induces autophagic cell death and inhibits growth of human hepatocellular carcinoma. Oncotarget. 5(13):4845–4854
Jiang H, Dong Q, Luo X, Shi B, Wang H, Gao H, Kong J, Zhang J, Li Z (2014) The monoclonal antibody CH12 augments 5-fluorouracil-induced growth suppression of hepatocellular carcinoma xenografts expressing epidermal growth factor receptor variant III. Cancer Lett 342(1):113–120
Blivet-Van Eggelpoël MJ, Chettouh H, Fartoux L, Aoudjehane L, Barbu V, Rey C, Priam S, Housset C, Rosmorduc O, Desbois-Mouthon C (2012) Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. J Hepatol 57(1):108–115
Wu JR, Hu CT, You RI, Ma PL, Pan SM, Lee MC, Wu WS (2015) Preclinical trials for prevention of tumor progression of hepatocellular carcinoma by LZ-8 targeting c-Met dependent and independent pathways. PLoS One 10(1):e0114495
Li T, Dong ZR, Guo ZY, Wang CH, Zhi XT, Zhou JW, Li DK, Chen ZT, Chen ZQ, Hu SY (2015) Mannose-mediated inhibitory effects of PA-MSHA on invasion and metastasis of hepatocellular carcinoma via EGFR/Akt/IκBβ/NF-κB pathway. Liver Int 35(4):1416–1429
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Perk, A.A. et al. (2017). Targeting of EGFR Induced Signaling Network in Hepatocellular Carcinoma. In: Farooqi, A., Ismail, M. (eds) Molecular Oncology: Underlying Mechanisms and Translational Advancements. Springer, Cham. https://doi.org/10.1007/978-3-319-53082-6_7
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DOI: https://doi.org/10.1007/978-3-319-53082-6_7
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