Expression and significance of hypoxia-inducible factor-1α and MDR1/P-glycoprotein in laryngeal carcinoma tissue and hypoxic Hep-2 cells

Xie,Jin; Li,Da-Wei; Chen,Xin-Wei; Wang,Fei; Dong,Pin

doi:10.3892/ol.2013.1321

Expression and significance of hypoxia-inducible factor-1α and MDR1/P-glycoprotein in laryngeal carcinoma tissue and hypoxic Hep-2 cells

Authors:
- Jin Xie
- Da-Wei Li
- Xin-Wei Chen
- Fei Wang
- Pin Dong
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Affiliations: Department of Otolaryngology-Head and Neck Surgery, Shanghai Jiao Tong University Affiliated First People's Hospital, Shanghai 200080, P.R. China, Department of Otolaryngology-Head and Neck Surgery, Affiliated Eye and ENT Hospital of Fudan University, Shanghai 200031, P.R. China
Published online on: April 29, 2013 https://doi.org/10.3892/ol.2013.1321
Pages: 232-238

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Abstract

The present study aimed to evaluate the expression of hypoxia‑inducible factor‑1α (HIF‑1α) and MDR1/P‑glycoprotein (P‑gp) in human laryngeal squamous cell carcinoma (LSCC) tissues, and also to investigate the regulation of MDR1 gene expression by HIF‑1α in Hep‑2 cells under hypoxic conditions. The expression of HIF‑1α and MDR1/P‑gp in human LSCC tissues was examined using immunohistochemistry. The HIF‑1α and MDR1 gene expression in the Hep‑2 cells was detected using real‑time quantitative reverse transcription (QRT)‑PCR and western blot analysis under normoxic and hypoxic conditions. In hypoxia, HIF‑1α expression was inhibited by RNA interference. HIF‑1α and MDR1/P‑gp expression was high in the LSCC tissues and was associated with the clinical stage and lymph node metastasis (P<0.05). HIF‑1α expression was positively correlated with MDR1/P‑gp expression (P<0.01). In the Hep‑2 cells, HIF‑1α and MDR1/P‑gp expression significantly increased in response to hypoxia. The inhibition of HIF‑1α expression synergistically downregulated the expression of the MDR1 gene in hypoxic Hep‑2 cells. HIF‑1α expression is positively correlated with MDR1/P‑gp expression in LSCC, and the two proteins may be able to serve as potential biomarkers for predicting the malignant progression and metastasis of LSCC. HIF‑1α may be critical for the upregulation of MDR1 gene expression induced by hypoxia in Hep‑2 cells.

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1.	Wilson WR and Hay MP: Targeting hypoxia in cancer therapy. Nat Rev Cancer. 11:393–410. 2011. View Article : Google Scholar
2.	Li Y and Ye D: Cancer-therapy by targeting hypoxia-inducible factor-1. Curr Cancer Drug Targets. 10:782–796. 2010. View Article : Google Scholar : PubMed/NCBI
3.	O’Donnell JL, Joyce MR, Shannon AM, Harmey J, Geraghty J and Bouchier-Hayes D: Oncological implications of hypoxia inducible factor-1alpha (HIF-1alpha) expression. Cancer Treat Rev. 32:407–416. 2006.
4.	Liu LZ, Li C, Chen Q, et al: MiR-21 induced angiogenesis through AKT and ERK activation and HIF-1α expression. PLoS One. 6:e191392011.PubMed/NCBI
5.	Park SY, Jang WJ, Yi EY, Jang JY, Jung Y, Jeong JW and Kim YJ: Melatonin suppresses tumor angiogenesis by inhibiting HIF-1alpha stabilization under hypoxia. J Pineal Res. 48:178–184. 2010. View Article : Google Scholar : PubMed/NCBI
6.	Jing SW, Wang YD, Kuroda M, et al: HIF-1α contributes to hypoxia-induced invasion and metastasis of esophageal carcinoma via inhibiting E-cadherin and promoting MMP-2 expression. Acta Med Okayama. 66:399–407. 2012.
7.	Song G, Ouyang G, Mao Y, Ming Y, Bao S and Hu T: Osteopontin promotes gastric cancer metastasis by augmenting cell survival and invasion through Akt-mediated HIF-1alpha upregulation and MMP9 activation. J Cell Mol Med. 13:1706–1718. 2009. View Article : Google Scholar : PubMed/NCBI
8.	Huang L, Zhang Z, Zhang S, et al: Inhibitory action of Celastrol on hypoxia-mediated angiogenesis and metastasis via the HIF-1α pathway. Int J Mol Med. 27:407–415. 2011.PubMed/NCBI
9.	Rho JK, Choi YJ, Lee JK, et al: Gefitinib circumvents hypoxia-induced drug resistance by the modulation of HIF-1alpha. Oncol Rep. 21:801–807. 2009.PubMed/NCBI
10.	Huang C, Xu D, Xia Q, Wang P, Rong C and Su Y: Reversal of P-glycoprotein-mediated multidrug resistance of human hepatic cancer cells by Astragaloside II. J Pharm Pharmacol. 64:1741–1750. 2012. View Article : Google Scholar : PubMed/NCBI
11.	Wu XH, Lu YF, Hu XD, Mao JY, Ji XX, Yao HT and Zhou SH: Expression of hypoxia inducible factor-1α and its significance in laryngeal carcinoma. J Int Med Res. 38:2040–2046. 2010.
12.	Cabanillas R, Rodrigo JP, Secades P, Astudillo A, Nieto CS and Chiara MD: The relation between hypoxia-inducible factor (HIF)-1alpha expression with p53 expression and outcome in surgically treated supraglottic laryngeal cancer. J Surg Oncol. 99:373–378. 2009. View Article : Google Scholar
13.	Hao YX, He ZW, Zhu JH, Shen Q, Sun JZ, Du N and Xiao WH: Reversal of multidrug resistance in renal cell carcinoma by short hairpin RNA targeting MDR1 gene. Chin Med J (Engl). 125:2741–2745. 2012.PubMed/NCBI
14.	Li L, Jiang AC, Dong P, Wan Y and Yu ZW: The characteristics of Hep-2 cell with multiple drug resistance induced by Taxol. Otolaryngol Head Neck Surg. 137:659–664. 2007. View Article : Google Scholar : PubMed/NCBI
15.	Zhigang H, Qi Z, Jugao F, et al: Reverse multidrug resistance in laryngeal cancer cells by knockdown MDR1 gene expression. J Otolaryngol Head Neck Surg. 38:440–448. 2009.PubMed/NCBI
16.	Ding Z, Yang L, Xie X, et al: Expression and significance of hypoxia-inducible factor-1 alpha and MDR1/P-glycoprotein in human colon carcinoma tissue and cells. J Cancer Res Clin Oncol. 136:1697–1707. 2010. View Article : Google Scholar : PubMed/NCBI
17.	Zhu H, Luo SF, Wang J, et al: Effect of environmental factors on chemoresistance of HepG2 cells by regulating hypoxia-inducible factor-1α. Chin Med J (Engl). 125:1095–1103. 2012.PubMed/NCBI
18.	Psychogios G, Waldfahrer F, Bozzato A and Iro H: Evaluation of the revised TNM classification in advanced laryngeal cancer. Eur Arch Otorhinolaryngol. 267:117–121. 2010. View Article : Google Scholar : PubMed/NCBI
19.	Batmunkh E, Shimada M, Morine Y, et al: Expression of hypoxia-inducible factor-1 alpha (HIF-1alpha) in patients with the gallbladder carcinoma. Int J Clin Oncol. 15:59–64. 2010. View Article : Google Scholar : PubMed/NCBI
20.	Ng IO, Liu CL, Fan ST and Ng M: Expression of P-glycoprotein in hepatocellular carcinoma. A determinant of chemotherapy response. Am J Clin Pathol. 113:355–363. 2000. View Article : Google Scholar : PubMed/NCBI
21.	Sowter HM, Raval RR, Moore JW, Ratcliffe PJ and Harris AL: Predominant role of hypoxia-inducible transcription factor (Hif)-1alpha versus Hif-2alpha in regulation of the transcriptional response to hypoxia. Cancer Res. 63:6130–6134. 2003.PubMed/NCBI
22.	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2[-Delta Delta C(T)] Method. Methods. 25:402–408. 2001.
23.	Li L, Jiang AC, Dong P, Wang H, Xu W and Xu C: MDR1/P-gp and VEGF synergistically enhance the invasion of Hep-2 cells with multidrug resistance induced by taxol. Ann Surg Oncol. 16:1421–1428. 2009. View Article : Google Scholar : PubMed/NCBI
24.	Miletti-González KE, Chen S, Muthukumaran N, et al: The CD44 receptor interacts with P-glycoprotein to promote cell migration and invasion in cancer. Cancer Res. 65:6660–6667. 2005.PubMed/NCBI
25.	Tokunaga Y, Hosogi H, Hoppou T, Nakagami M, Tokuka A and Ohsumi K: Effects of MDR1/P-glycoprotein expression on prognosis in advanced colorectal cancer after surgery. Oncol Rep. 8:815–819. 2001.PubMed/NCBI
26.	Sagol O, Yavuzsen T, Oztop I, et al: The effect of apoptotic activity, survivin, Ki-67, and P-glycoprotein expression on prognosis in pancreatic carcinoma. Pancreas. 30:343–348. 2005. View Article : Google Scholar : PubMed/NCBI
27.	Wartenberg M, Ling FC, Müschen M, et al: Regulation of the multidrug resistance transporter P-glycoprotein in multicellular tumor spheroids by hypoxia-inducible factor (HIF-1) and reactive oxygen species. FASEB J. 17:503–505. 2003.PubMed/NCBI
28.	Xia S, Yu SY, Yuan XL and Xu SP: Effects of hypoxia on expression of P-glycoprotein and multidrug resistance protein in human lung adenocarcinoma A549 cell line. Zhonghua Yi Xue Za Zhi. 84:663–666. 2004.(In Chinese).
29.	Song X, Liu X, Chi W, Liu Y, Wei L, Wang X and Yu J: Hypoxia-induced resistance to cisplatin and doxorubicin in non-small cell lung cancer is inhibited by silencing of HIF-1alpha gene. Cancer Chemother Pharmacol. 58:776–784. 2006. View Article : Google Scholar : PubMed/NCBI
30.	Liu L, Ning X, Sun L, et al: Hypoxia-inducible factor-1 alpha contributes to hypoxia-induced chemoresistance in gastric cancer. Cancer Sci. 99:121–128. 2008.PubMed/NCBI
31.	Min L, Chen Q, He S, Liu S and Ma Y: Hypoxia-induced increases in A549/CDDP cell drug resistance are reversed by RNA interference of HIF-1α expression. Mol Med Report. 5:228–232. 2012.PubMed/NCBI