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Abstract: hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality globally. It accounts for the majority of primary liver cancer cases. amyloid precursor protein (APP), a cell membrane protein, plays a vital role in the pathogenesis of Alzheimer’s disease, and has been found to be implicated in tumor growth and metastasis. Therefore, to understand the relationship between APP and 5-fluorouracil (5-FU) resistance in liver cancer, Cell Counting Kit-8, apoptosis and cell cycle assays, western blotting, and reverse transcription-quantitative polymerase chain reaction (qPCR) analysis were performed. The results demonstrated that APP expression in Bel7402-5-FU cells was significantly up-regulated, as compared with that in Bel7402 cells. Through successful construction of APP-silenced (siAPP) and overexpressed (OE) Bel7402 cell lines, data revealed that the Bel7402-APP^751-OE cell line was insensitive, while the Bel7402-siAPP cell line was sensitive to 5-FU in comparison to the matched control group. Furthermore, APP overexpression decreased, while APP silencing increased 5-FU-induced apoptosis in Bel7402 cells. Mechanistically, APP overexpression and silencing can regulate the mitochondrial apoptotic pathway and the expression of apoptotic suppressor genes (B-cell lymphoma-2 (Bcl-2) and B-cell lymphoma-extra large (Bcl-xl)). Taken together, these results preliminarily revealed that APP overexpression contributes to the resistance of liver cancer cells to 5-FU, providing a new perspective for drug resistance.

淀粉样前体蛋白通过抑制线粒体凋亡通路调节人肝癌细胞对5-氟尿嘧啶的抗性

[1]Allemani C, Matsuda T, di Carlo V, et al., 2018. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3):analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet, 391(10125):1023-1075.

[2]Belmokhtar CA, Hillion J, Ségal-Bendirdjian E, 2001. Staurosporine induces apoptosis through both caspase-dependent and caspase-independent mechanisms. Oncogene, 20(26):3354-3362.

[3]Bukhari H, Glotzbach A, Kolbe K, et al., 2017. Small things matter: implications of APP intracellular domain AICD nuclear signaling in the progression and pathogenesis of Alzheimer’s disease. Prog Neurobiol, 156:189-213.

[4]Ceballos MP, Decándido G, Quiroga AD, et al., 2018. Inhibition of sirtuins 1 and 2 impairs cell survival and migration and modulates the expression of P-glycoprotein and MRP3 in hepatocellular carcinoma cell lines. Toxicol Lett, 289:63-74.

[5]Dai W, Gao QG, Qiu JP, et al., 2016. Quercetin induces apoptosis and enhances 5-FU therapeutic efficacy in hepatocellular carcinoma. Tumor Biol, 37(5):6307-6313.

[6]Gao SY, Lin J, Wang T, et al., 2019. Qingxin Kaiqiao Fang ameliorates memory impairment and inhibits apoptosis in APP/PS1 double transgenic mice through the MAPK pathway. Drug Des Devel Ther, 13:459-475.

[7]Gehrke A, Lee SS, Hilton K, et al., 2018. Development of the cancer survivor profile-breast cancer (CSPro-BC) app: patient and nurse perspectives on a new navigation tool. J Cancer Surviv, 12(3):291-305.

[8]Gough M, Blanthorn-Hazell S, Delury C, et al., 2014. The E1 copper binding domain of full-length amyloid precursor protein mitigates copper-induced growth inhibition in brain metastatic prostate cancer DU145 cells. Biochem Biophys Res Commun, 453(4):741-747.

[9]Guo YK, Shi M, Qin YL, et al., 2017. Mechanism of apoptosis for resveratrol-mediated reversing the drug-resistance of AML HL-60/ADR cells. J Exp Hematol, 25(3):736-742 (in Chinese).

[10]Hansel DE, Rahman A, Wehner S, et al., 2003. Increased expression and processing of the Alzheimer amyloid precursor protein in pancreatic cancer may influence cellular proliferation. Cancer Res, 63(21):7032-7037.

[11]Harder H, Holroyd P, Burkinshaw L, et al., 2017. A user-centred approach to developing bWell, a mobile app for arm and shoulder exercises after breast cancer treatment. J Cancer Surviv, 11(6):732-742.

[12]Hardy J, 2017. The discovery of Alzheimer-causing mutations in the APP gene and the formulation of the “amyloid cascade hypothesis”. FEBS J, 284(7):1040-1044.

[13]Hirata H, Sugimachi K, Takahashi Y, et al., 2015. Downregulation of PRRX1 confers cancer stem cell-like properties and predicts poor prognosis in hepatocellular carcinoma. Ann Surg Oncol, 22(S3):1402-1409.

[14]Ikeda M, Morizane C, Ueno M, et al., 2018. Chemotherapy for hepatocellular carcinoma: current status and future perspectives. Jpn J Clin Oncol, 48(2):103-114.

[15]Kallop DY, Meilandt WJ, Gogineni A, et al., 2014. A death receptor 6-amyloid precursor protein pathway regulates synapse density in the mature CNS but does not contribute to Alzheimer’s disease-related pathophysiology in murine models. J Neurosci, 34(19):6425-6437.

[16]Kovalenko PL, Kunovska L, Chen J, et al., 2012. Loss of MLK3 signaling impedes ulcer healing by modulating MAPK signaling in mouse intestinal mucosa. Am J Physiol Gastrointest Liver Physiol, 303(8):G951-G960.

[17]Li J, Duan BJ, Guo Y, et al., 2018. Baicalein sensitizes hepatocellular carcinoma cells to 5-FU and epirubicin by activating apoptosis and ameliorating P-glycoprotein activity. Biomed Pharmacother, 98:806-812.

[18]Li JQ, Wu X, Gan L, et al., 2017. Hypoxia induces universal but differential drug resistance and impairs anticancer mechanisms of 5-fluorouracil in hepatoma cells. Acta Pharmacol Sin, 38(12):1642-1654.

[19]Liu JX, Cui XP, Qu LS, et al., 2016. Overexpression of DLX2 is associated with poor prognosis and sorafenib resistance in hepatocellular carcinoma. Exp Mol Pathol, 101(1):58-65.

[20]Ma ST, Tan WH, Du BT, et al., 2016. Oridonin effectively reverses cisplatin drug resistance in human ovarian cancer cells via induction of cell apoptosis and inhibition of matrix metalloproteinase expression. Mol Med Rep, 13(4):3342-3348.

[21]Meng JY, Kataoka H, Itoh H, et al., 2001. Amyloid β protein precursor is involved in the growth of human colon carcinoma cell in vitro and in vivo. Int J Cancer, 92(1):31-39.

[22]Miyazaki T, Ikeda K, Horie-Inoue K, et al., 2014. Amyloid precursor protein regulates migration and metalloproteinase gene expression in prostate cancer cells. Biochem Biophys Res Commun, 452(3):828-833.

[23]Nikolaev A, McLaughlin T, O'Leary DDM, et al., 2009. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature, 457(7232):981-989.

[24]Niu LL, Liu LP, Yang SL, et al., 2017. New insights into sorafenib resistance in hepatocellular carcinoma: responsible mechanisms and promising strategies. Biochim Biophys Acta Rev Cancer, 1868(2):564-570.

[25]Rodríguez-Ruiz M, Moreno E, Moreno-Delgado D, et al., 2017. Heteroreceptor complexes formed by dopamine D₁, histamine H₃, and N-methyl-D-aspartate glutamate receptors as targets to prevent neuronal death in Alzheimer’s disease. Mol Neurobiol, 54(6):4537-4550.

[26]Shi YG, 2002. Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell, 9(3):459-470.

[27]Siegel RL, Miller KD, Jemal A, 2018. Cancer statistics, 2018. CA Cancer J Clin, 68(1):7-30.

[28]Song MJ, 2015. Hepatic artery infusion chemotherapy for advanced hepatocellular carcinoma. World J Gastroenterol, 21(13):3843-3849.

[29]Strilic B, Yang LD, Albarrán-Juárez J, et al., 2016. Tumour-cell-induced endothelial cell necroptosis via death receptor 6 promotes metastasis. Nature, 536(7615):215-218.

[30]Sun T, Liu H, Ming L, 2017. Multiple roles of autophagy in the sorafenib resistance of hepatocellular carcinoma. Cell Physiol Biochem, 44(2):716-727.

[31]Takayama K, Tsutsumi S, Suzuki T, et al., 2009. Amyloid precursor protein is a primary androgen target gene that promotes prostate cancer growth. Cancer Res, 69(1):137-142.

[32]Wang W, Xu B, Li QX, et al., 2018. Anti-cancer effects of a novel Pan-RAF inhibitor in a hepatocellular carcinoma cell line. Mol Med Rep, 17(4):6185-6193.

[33]Wang X, Lu XC, Zhu RL, et al., 2017. Betulinic acid induces apoptosis in differentiated PC12 cells via ROS-mediated mitochondrial pathway. Neurochem Res, 42(4):1130-1140.

[34]Woods NK, Padmanabhan J, 2013. Inhibition of amyloid precursor protein processing enhances gemcitabine-mediated cytotoxicity in pancreatic cancer cells. J Biol Chem, 288(42):30114-30124.

[35]Zha Y, Gan P, Yao Q, et al., 2014. Downregulation of Rap1 promotes 5-fluorouracil-induced apoptosis in hepatocellular carcinoma cell line HepG2. Oncol Rep, 31(4):1691-1698.

[36]Zhang J, Luo N, Tian Y, et al., 2017. USP22 knockdown enhanced chemosensitivity of hepatocellular carcinoma cells to 5-FU by up-regulation of Smad4 and suppression of Akt. Oncotarget, 8(15):24728-24740.

[37]Zhao YJ, Han HZ, Liang Y, et al., 2015. Alternative splicing of VEGFA, APP and NUMB genes in colorectal cancer. World J Gastroenterol, 21(21):6550-6560.