Curcumin inhibits hypoxia inducible factor‑1α‑induced epithelial‑mesenchymal transition in HepG2 hepatocellular carcinoma cells

Duan,Wanxing; Chang,Yuanhong; Li,Rong; Xu,Qinhong; Lei,Jianjun; Yin,Caiqiao; Li,Ting; Wu,Yanzhao; Ma,Qingyong; Li,Xuqi

doi:10.3892/mmr.2014.2551

Curcumin inhibits hypoxia inducible factor‑1α‑induced epithelial‑mesenchymal transition in HepG2 hepatocellular carcinoma cells

Authors:
- Wanxing Duan
- Yuanhong Chang
- Rong Li
- Qinhong Xu
- Jianjun Lei
- Caiqiao Yin
- Ting Li
- Yanzhao Wu
- Qingyong Ma
- Xuqi Li
View Affiliations

Affiliations: Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of Gastroenterology, Xi'an No. 4 Hospital, Affiliated Guangren Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China, Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China, Department of General Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China
Published online on: September 9, 2014 https://doi.org/10.3892/mmr.2014.2551
Pages: 2505-2510

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Hepatocellular carcinoma (HCC) accounts for the majority of liver cancers. A hypoxic microenvironment is a common feature of HCC, and is associated with malignant invasion, metastasis and epithelial-mesenchymal transition (EMT) changes. Curcumin is a botanical agent derived from the dried rhizome of Curcuma longa. Although a number of preclinical studies have shown that curcumin has anticancer properties when administered in a normoxic microenvironment, no studies have directly examined the effect of curcumin on preventing HCC invasion and metastasis under hypoxic conditions. This study aimed to determine whether curcumin has effects on the hypoxia-induced malignant biological behavior of HCC. CoCl2 was used to establish a hypoxia model in vitro. The results showed that curcumin significantly decreased hypoxia-induced hypoxia inducible factor-1α (HIF-1α) protein level in HepG2 cells. Furthermore, cell proliferation, migration and invasiveness, as well as EMT changes associated with HIF-1α accumulation generated by a hypoxic microenvironment, were eliminated by curcumin. In conclusion, these data indicate that curcumin may be a viable anticancer agent in the treatment of HCC.

View Figures

View References

1	Jelic S and Sotiropoulos GC: ESMO Guidelines Working Group: Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 21:v59–v64. 2010. View Article : Google Scholar
2	Altekruse SF, McGlynn KA and Reichman ME: Hepatocellular carcinoma incidence, mortality and survival trends in the United States from 1975 to 2005. J Clin Oncol. 27:1485–1491. 2009. View Article : Google Scholar : PubMed/NCBI
3	El-Serag HB: Hepatocellular carcinoma. N Engl J Med. 365:1118–1127. 2011. View Article : Google Scholar : PubMed/NCBI
4	Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI
5	Brabletz T, Jung A, Spaderna S, et al: Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat Rev Cancer. 5:744–749. 2005. View Article : Google Scholar : PubMed/NCBI
6	Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009. View Article : Google Scholar : PubMed/NCBI
7	Peinado H, Ballestar E, Esteller M and Cano A: Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol Cell Biol. 24:306–319. 2004. View Article : Google Scholar : PubMed/NCBI
8	Jou J and Diehl AM: Epithelial-mesenchymal transitions and hepatocarcinogenesis. J Clin Invest. 120:1031–1034. 2010. View Article : Google Scholar : PubMed/NCBI
9	Li X, Li P, Chang Y, et al: The SDF-1/CXCR4 axis induces epithelial–mesenchymal transition in hepatocellular carcinoma. Mol Cell Biochem. 392:77–84. 2014.
10	Vaupel P and Mayer A: Hypoxia in cancer: significance and impact on clinical outcome. Cancer Metastasis Rev. 26:225–239. 2007. View Article : Google Scholar : PubMed/NCBI
11	Lu X and Kang Y: Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res. 16:5928–5935. 2010. View Article : Google Scholar : PubMed/NCBI
12	Dong ZZ, Yao M, Wang L, et al: Hypoxia-inducible factor-1alpha: molecular-targeted therapy for hepatocellular carcinoma. Mini Rev Med Chem. 13:1295–1304. 2013. View Article : Google Scholar : PubMed/NCBI
13	Chan DA, Sutphin PD, Yen SE and Giaccia AJ: Coordinate regulation of the oxygen-dependent degradation domains of hypoxia-inducible factor 1 alpha. Mol Cell Biol. 25:6415–6426. 2005. View Article : Google Scholar : PubMed/NCBI
14	Nyberg P, Salo T and Kalluri R: Tumor microenvironment and angiogenesis. Front Biosci. 13:6537–6553. 2008. View Article : Google Scholar : PubMed/NCBI
15	Zhao JH, Luo Y, Jiang YG, et al: Knockdown of β-Catenin through shRNA cause a reversal of EMT and metastatic phenotypes induced by HIF-1α. Cancer Invest. 29:377–382. 2011.
16	Singh S and Khar A: Biological effects of curcumin and its role in cancer chemoprevention and therapy. Anticancer Agents Med Chem. 6:259–270. 2006. View Article : Google Scholar : PubMed/NCBI
17	De R, Kundu P, Swarnakar S, et al: Antimicrobial activity of curcumin against Helicobacter pylori isolates from India and during infections in mice. Antimicrob Agents Chemother. 53:1592–1597. 2009.PubMed/NCBI
18	Wang J, Du XX, Jiang H and Xie JX: Curcumin attenuates 6-hydroxydopamine-induced cytotoxicity by anti-oxidation and nuclear factor-kappa B modulation in MES23.5 cells. Biochem Pharmacol. 78:178–183. 2009. View Article : Google Scholar : PubMed/NCBI
19	Jurenka JS: Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev. 14:141–153. 2009.PubMed/NCBI
20	Kim DC, Ku SK and Bae JS: Anticoagulant activities of curcumin and its derivative. BMB Rep. 45:221–226. 2012. View Article : Google Scholar : PubMed/NCBI
21	Olszanecki R, Jawień J, Gajda M, et al: Effect of curcumin on atherosclerosis in apoE/LDLR-double knockout mice. J Physiol Pharmacol. 56:627–635. 2005.PubMed/NCBI
22	Shishodia S, Chaturvedi MM and Aggarwal BB: Role of curcumin in cancer therapy. Curr Probl Cancer. 31:243–305. 2007. View Article : Google Scholar : PubMed/NCBI
23	Jobin C, Bradham CA, Russo MP, et al: Curcumin blocks cytokine-mediated NF-kappa B activation and proinflammatory gene expression by inhibiting inhibitory factor I-kappa B kinase activity. J Immunol. 163:3474–3483. 1999.PubMed/NCBI
24	Prakobwong S, Gupta SC, Kim JH, et al: Curcumin suppresses proliferation and induces apoptosis in human biliary cancer cells through modulation of multiple cell signaling pathways. Carcinogenesis. 32:1372–1380. 2011. View Article : Google Scholar
25	Yang CL, Liu YY, Ma YG, et al: Curcumin blocks small cell lung cancer cells migration, invasion, angiogenesis, cell cycle and neoplasia through Janus kinase-STAT3 signalling pathway. PLoS One. 7:e379602012. View Article : Google Scholar : PubMed/NCBI
26	Guo M, Song LP, Jiang Y, et al: Hypoxia-mimetic agents desferrioxamine and cobalt chloride induce leukemic cell apoptosis through different hypoxia-inducible factor-1alpha independent mechanisms. Apoptosis. 11:67–77. 2006. View Article : Google Scholar
27	Li W, Ma J, Ma Q, et al: Resveratrol inhibits the epithelial-mesenchymal transition of pancreatic cancer cells via suppression of the PI-3K/Akt/NF-κB pathway. Curr Med Chem. 20:4185–4194. 2013.PubMed/NCBI
28	Li X, Ma Q, Xu Q, et al: SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial-mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway. Cancer Lett. 322:169–176. 2012. View Article : Google Scholar
29	Han L, Peng B, Ma Q, et al: Indometacin ameliorates high glucose-induced proliferation and invasion via modulation of e-cadherin in pancreatic cancer cells. Curr Med Chem. 20:4142–4152. 2013. View Article : Google Scholar : PubMed/NCBI
30	Schmittgen TD and Livak KJ: Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc. 3:1101–1108. 2008. View Article : Google Scholar : PubMed/NCBI
31	Ardyanto TD, Osaki M, Tokuyasu N, et al: CoCl₂-induced HIF-1alpha expression correlates with proliferation and apoptosis in MKN-1 cells: a possible role for the PI3K/Akt pathway. Int J Oncol. 29:549–555. 2006.PubMed/NCBI
32	Kew MC: Hepatocellular carcinoma in developing countries: Prevention, diagnosis and treatment. World J Hepatol. 4:99–104. 2012. View Article : Google Scholar : PubMed/NCBI
33	Wu XZ, Xie GR and Chen D: Hypoxia and hepatocellular carcinoma: The therapeutic target for hepatocellular carcinoma. J Gastroenterol Hepatol. 22:1178–1182. 2007. View Article : Google Scholar : PubMed/NCBI
34	Anastasiadis AG, Bemis DL, Stisser BC, et al: Tumor cell hypoxia and the hypoxia-response signaling system as a target for prostate cancer therapy. Curr Drug Targets. 4:191–196. 2003. View Article : Google Scholar : PubMed/NCBI
35	Kizaka-Kondoh S, Inoue M, Harada H and Hiraoka M: Tumor hypoxia: a target for selective cancer therapy. Cancer Sci. 94:1021–1028. 2003. View Article : Google Scholar : PubMed/NCBI
36	Yasuda H: Solid tumor physiology and hypoxia-induced chemo/radio-resistance: novel strategy for cancer therapy: nitric oxide donor as a therapeutic enhancer. Nitric Oxide. 19:205–216. 2008. View Article : Google Scholar
37	Gordan JD, Bertout JA, Hu CJ, et al: HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell. 11:335–347. 2007. View Article : Google Scholar : PubMed/NCBI
38	Liao D and Johnson RS: Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev. 26:281–290. 2007. View Article : Google Scholar : PubMed/NCBI
39	Kalliomäki TM, McCallum G, Wells PG and Hill RP: Progression and metastasis in a transgenic mouse breast cancer model: effects of exposure to in vivo hypoxia. Cancer Lett. 282:98–108. 2009.PubMed/NCBI
40	Selvendiran K, Bratasz A, Kuppusamy ML, et al: Hypoxia induces chemoresistance in ovarian cancer cells by activation of signal transducer and activator of transcription 3. Int J Cancer. 125:2198–2204. 2009. View Article : Google Scholar : PubMed/NCBI
41	Liu J, Zhang J, Wang X, et al: HIF-1 and NDRG2 contribute to hypoxia-induced radioresistance of cervical cancer Hela cells. Exp Cell Res. 316:1985–1993. 2010. View Article : Google Scholar : PubMed/NCBI
42	Kim Y, Lin Q, Glazer PM and Yun Z: Hypoxic tumor microenvironment and cancer cell differentiation. Curr Mol Med. 9:425–434. 2009. View Article : Google Scholar : PubMed/NCBI
43	Chiche J, Rouleau M, Gounon P, et al: Hypoxic enlarged mitochondria protect cancer cells from apoptotic stimuli. J Cell Physiol. 222:648–657. 2010.PubMed/NCBI
44	Ke Q and Costa M: Hypoxia-inducible factor-1 (HIF-1). Mol Pharmacol. 70:1469–1480. 2006. View Article : Google Scholar : PubMed/NCBI
45	Powis G and Kirkpatrick L: Hypoxia inducible factor-1alpha as a cancer drug target. Mol Cancer Ther. 3:647–654. 2004.PubMed/NCBI
46	Zhang Q, Bai X, Chen W, et al: Wnt/β-catenin signaling enhances hypoxia-induced epithelial-mesenchymal transition in hepatocellular carcinoma via crosstalk with hif-1α signaling. Carcinogenesis. 34:962–973. 2013.
47	Xu MX, Zhao L, Deng C, et al: Curcumin suppresses proliferation and induces apoptosis of human hepatocellular carcinoma cells via the wnt signaling pathway. Int J Oncol. 43:1951–1959. 2013.PubMed/NCBI