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

Lin,Bi-Yun; Xiao,Chuan-Xing; Zhao,Wen-Xiu; Xiao,Li; Chen,Xu; Li,Ping; Wang,Xiao-Min

doi:10.3892/mmr.2015.3453

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

Authors:
- Bi-Yun Lin
- Chuan-Xing Xiao
- Wen-Xiu Zhao
- Li Xiao
- Xu Chen
- Ping Li
- Xiao-Min Wang
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Affiliations: Fujian Provincial Key Laboratory of Chronic Liver Disease and Hepatocellular Carcinoma, Department of Hepatobiliary Surgery, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, Fujian 361004, P.R. China, Department of Gastroenterology, Zhongshan Hospital Affiliated to Xiamen University, Xiamen, Fujian 361004, P.R. China
Published online on: March 9, 2015 https://doi.org/10.3892/mmr.2015.3453
Pages: 1421-1428

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Abstract

Enoyl-coenzyme A hydratase short chain 1 (ECHS1) regulates fatty acid metabolism and is an essential factor in tumor development. The present study aimed to investigate the molecular mechanisms of ECHS1 in hepatocellular carcinogenesis by studying proliferation and survival in ECHS1 knocked-down hepatocellular carcinoma (HCC) cell lines, HepG2 and HuH7. The effect of ECHS1 on tumor development was investigated by tumor transplantation in nude mice, and the signaling pathways involved in the ECHS1-mediated regulation of HCC cell proliferation were identified by western blot analysis. The silencing of ECHS1 suppressed HCC cell proliferation in vitro and suppressed the growth of transplanted tumors in vivo. In addition, the phosphorylation of EGFR and its downstream effectors ERK1/2 and AKT was downregulated in ECHS1 knocked-down cells and tumor tissues. Furthermore, knockdown of ECHS1 in HCC suppressed cyclin D3 and cyclin dependent kinase 6 expression, whilst enhancing p16 and p21 expression. Therefore, ECHS1 may also be involved in cell cycle progression in HCC cells. These results suggested that ECHS1 may promote cell proliferation in HCC in an EGFR-dependent manner.

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1	Parkin DM, Bray F, Ferlay J and Pisani P: Global cancer statistics, 2002. CA Cancer J Clin. 55:74–108. 2005. View Article : Google Scholar : PubMed/NCBI
2	Tsim NC, Frampton AE, Habib NA and Jiao LR: Surgical treatment for liver cancer. World J Gastroenterol. 16:927–933. 2010. View Article : Google Scholar : PubMed/NCBI
3	Guégan JP, Ezan F, Théret N, Langouët S and Baffet G: MAPK signaling in cisplatin-induced death: predominant role of ERK1 over ERK2 in human hepatocellular carcinoma cells. Carcinogenesis. 34:38–47. 2013. View Article : Google Scholar
4	Tsao CM, Yan MD, Shih YL, et al: SOX1 functions as a tumor suppressor by antagonizing the WNT/β-catenin signaling pathway in hepatocellular carcinoma. Hepatology. 56:2277–2287. 2012. View Article : Google Scholar : PubMed/NCBI
5	Yang J, Cai X, Lu W, Hu C, Xu X, Yu Q and Cao P: Evodiamine inhibits STAT3 signaling by inducing phosphatase shatterproof 1 in hepatocellular carcinoma cells. Cancer Lett. 328:243–251. 2013. View Article : Google Scholar
6	Yang P, Li QJ, Feng Y, et al: TGF-β-miR-34a-CCL22 signaling-induced Treg cell recruitment promotes venous metastases of HBV-positive hepatocellular carcinoma. Cancer Cell. 22:291–303. 2012. View Article : Google Scholar : PubMed/NCBI
7	Agnihotri G and Liu HW: Enoyl-CoA hydratase reaction, mechanism, and inhibition. Bioorg Med Chem. 11:9–20. 2003. View Article : Google Scholar
8	Lin JF, Xu J, Tian HY, et al: Identification of candidate prostate cancer biomarkers in prostate needle biopsy specimens using proteomic analysis. Int J Cancer. 121:2596–2605. 2007. View Article : Google Scholar : PubMed/NCBI
9	Komori T, Takemasa I, Higuchi H, et al: Identification of differentially expressed genes involved in colorectal carcinogenesis using a cDNA microarray. J Exp Clin Cancer Res. 23:521–527. 2004.PubMed/NCBI
10	Yeh CS, Wang JY, Cheng TL, Juan CH, Wu CH and Lin SR: Fatty acid metabolism pathway play an important role in carcinogenesis of human colorectal cancers by Microarray-Bioinformatics analysis. Cancer Lett. 233:297–308. 2006. View Article : Google Scholar
11	Liu X, Feng R and Du L: The role of enoyl-CoA hydratase short chain 1 and peroxiredoxin 3 in PP2-induced apoptosis in human breast cancer MCF-7 cells. FEBS Lett. 584:3185–3192. 2010. View Article : Google Scholar : PubMed/NCBI
12	Chang Y, Wang SX, Wang YB, et al: ECHS1 interacts with STAT3 and negatively regulates STAT3 signaling. FEBS Lett. 587:607–613. 2013. View Article : Google Scholar : PubMed/NCBI
13	Xiao CX, Yang XN, Huang QW, et al: ECHS1 acts as a novel HBsAg-binding protein enhancing apoptosis through the mitochondrial pathway in HepG2 cells. Cancer Lett. 330:67–73. 2013. View Article : Google Scholar
14	Kira S, Nakanishi T, Suemori S, Kitamoto M, Watanabe Y and Kajiyama G: Expression of transforming growth factor alpha and epidermal growth factor receptor in human hepatocellular carcinoma. Liver. 17:177–182. 1997. View Article : Google Scholar : PubMed/NCBI
15	Ito Y, Takeda T, Sakon M, et al: Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer. 84:1377–1383. 2001. View Article : Google Scholar : PubMed/NCBI
16	Prigent SA and Lemoine NR: The type 1 (EGFR-related) family of growth factor receptors and their ligands. Prog Growth Factor Res. 4:1–24. 1992. View Article : Google Scholar : PubMed/NCBI
17	Barnard JA, Beauchamp RD, Russell WE, Dubois RN and Coffey RJ: Epidermal growth factor-related peptides and their relevance to gastrointestinal pathophysiology. Gastroenterology. 108:564–580. 1995. View Article : Google Scholar : PubMed/NCBI
18	DeCicco LA, Kong J and Ringer DP: Carcinogen-induced alteration in liver epidermal growth factor receptor distribution during the promotion stage of hepatocarcinogenesis in rat. Cancer Lett. 111:149–156. 1997. View Article : Google Scholar : PubMed/NCBI
19	Aravalli RN, Steer CJ and Cressman EN: Molecular mechanisms of hepatocellular carcinoma. Hepatology. 48:2047–2063. 2008. View Article : Google Scholar : PubMed/NCBI
20	Whittaker S, Marais R and Zhu AX: The role of signaling pathways in the development and treatment of hepatocellular carcinoma. Oncogene. 29:4989–5005. 2010. View Article : Google Scholar : PubMed/NCBI
21	Jazag A, Ijichi H, Kanai F, et al: Smad4 silencing in pancreatic cancer cell lines using stable RNA interference and gene expression profiles induced by transforming growth factor-beta. Oncogene. 24:662–671. 2005. View Article : Google Scholar
22	Guleng B, Tateishi K, Ohta M, et al: Blockade of the stromal cell-derived factor-1/CXCR4 axis attenuates in vivo tumor growth by inhibiting angiogenesis in a vascular endothelial growth factor-independent manner. Cancer Res. 65:5864–5871. 2005. View Article : Google Scholar : PubMed/NCBI
23	Bradford MM: A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 72:248–254. 1976. View Article : Google Scholar : PubMed/NCBI
24	Llovet JM, Burroughs A and Bruix J: Hepatocellular carcinoma. Lancet. 362:1907–1917. 2003. View Article : Google Scholar : PubMed/NCBI
25	Zhu XS, Dai YC, Chen ZX, Xie JP, Zeng W, Lin YY and Tan QH: Knockdown of ECHS1 protein expression inhibits hepatocellular carcinoma cell proliferation via suppression of Akt activity. Crit Rev Eukaryot Gene Expr. 23:275–282. 2013. View Article : Google Scholar : PubMed/NCBI
26	Kelman Z and O’Donnell M: Structural and functional similarities of prokaryotic and eukaryotic DNA polymerase sliding clamps. Nucleic Acids Res. 23:3613–3620. 1995. View Article : Google Scholar : PubMed/NCBI
27	Carpenter G: Receptors for epidermal growth factor and other polypeptide mitogens. Annu Rev Biochem. 56:881–914. 1987. View Article : Google Scholar : PubMed/NCBI
28	Schlessinger J: Cell signaling by receptor tyrosine kinases. Cell. 103:211–225. 2000. View Article : Google Scholar : PubMed/NCBI
29	Yarden Y and Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2:127–137. 2001. View Article : Google Scholar : PubMed/NCBI
30	Soltoff SP, Carraway KR III, Prigent SA, Gullick WG and Cantley LC: ErbB3 is involved in activation of phosphatidylinositol 3-kinase by epidermal growth factor. Mol Cell Biol. 14:3550–3558. 1994.PubMed/NCBI
31	Schmitz KJ, Wohlschlaeger J, Lang H, et al: Activation of the ERK and AKT signalling pathway predicts poor prognosis in hepatocellular carcinoma and ERK activation in cancer tissue is associated with hepatitis C virus infection. J Hepatol. 48:83–90. 2008. View Article : Google Scholar
32	Saxena NK, Sharma D, Ding X, Lin S, Marra F, Merlin D and Anania FA: Concomitant activation of the JAK/STAT, PI3K/AKT, and ERK signaling is involved in leptin-mediated promotion of invasion and migration of hepatocellular carcinoma cells. Cancer Res. 67:2497–2507. 2007. View Article : Google Scholar : PubMed/NCBI
33	Steelman LS, Chappell WH, Abrams SL, et al: Roles of the Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR pathways in controlling growth and sensitivity to therapy-implications for cancer and aging. Aging (Albany NY). 3:192–222. 2011.
34	Bill HM, Knudsen B, Moores SL, Muthuswamy SK, Rao VR, Brugge JS and Miranti CK: Epidermal growth factor receptor-dependent regulation of integrin-mediated signaling and cell cycle entry in epithelial cells. Mol Cell Biol. 24:8586–8599. 2004. View Article : Google Scholar : PubMed/NCBI
35	Lui VW and Grandis JR: EGFR-mediated cell cycle regulation. Anticancer Res. 22:1–11. 2002.PubMed/NCBI
36	Horn S, Endl E, Fehse B, Weck MM, Mayr GW and Jücker M: Restoration of SHIP activity in a human leukemia cell line downregulates constitutively activated phosphatidylinositol 3-kinase/Akt/GSK-3beta signaling and leads to an increased transit time through the G1 phase of the cell cycle. Leukemia. 18:1839–1849. 2004. View Article : Google Scholar : PubMed/NCBI
37	Diehl JA, Cheng M, Roussel MF and Sherr CJ: Glycogen synthase kinase-3beta regulates cyclin D1 proteolysis and subcellular localization. Genes Dev. 12:3499–3511. 1998. View Article : Google Scholar : PubMed/NCBI