Livin enhances tumorigenesis by regulating the mitogen-activated protein kinase signaling pathway in human hypopharyngeal squamous cell carcinoma

Kim,Sun‑Ae; Yoon,Tae  Mi; Lee,Dong  Hoon; Lee,Joon  Kyoo; Park,Young‑Lan; Chung,Ik‑Joo; Joo,Young‑Eun; Lim,Sang  Chul

doi:10.3892/mmr.2016.5242

Livin enhances tumorigenesis by regulating the mitogen-activated protein kinase signaling pathway in human hypopharyngeal squamous cell carcinoma

Authors:
- Sun‑Ae Kim
- Tae Mi Yoon
- Dong Hoon Lee
- Joon Kyoo Lee
- Young‑Lan Park
- Ik‑Joo Chung
- Young‑Eun Joo
- Sang Chul Lim
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Affiliations: Department of Otorhinolaryngology‑Head and Neck Surgery, Chonnam National University Medical School, Gwangju 501‑757, Republic of Korea, Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501‑757, Republic of Korea
Published online on: May 11, 2016 https://doi.org/10.3892/mmr.2016.5242
Pages: 515-520

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Abstract

Livin, a member of the human inhibitor of apoptosis protein (IAP) family, is expressed at high levels in various human cancer tissues and may have prognostic significance. The aim of the present study was to evaluate the effect of Livin on tumor cell behavior and oncogenic signaling pathways in human hypopharyngeal squamous cell carcinoma (HSCC). Reverse transcription‑quantitative polymerase chain reaction and western blot analyses were used to determine the mRNA and protein expression levels, respectively. A cell proliferation assay and cell cycle analysis were used to assess the functional effects of small interfering RNA‑mediated Livin knockdown. Livin was overexpressed in fresh HSCC tissues, compared with the adjacent normal mucosa. Livin knockdown led to significantly reduced cell proliferation and cell cycle arrest in the G1 phase of the human HSCC cells. The expression levels of c‑myc, cyclin D1, cyclin D3, cyclin‑dependent kinase (CDK)4 and CDK6 were decreased. The phosphorylation levels of extracellular signal‑regulated kinase 1/2, p38, c‑Jun N-terminal kinase and Akt were also decreased by Livin knockdown in the HSCC cells. Taken together, the results of the present study suggested that Livin may enhance tumorigenesis by modulating the mitogen‑activated/Akt signaling pathways in human HSCC.

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1	Jemal A, Siegel R, Ward E, Hao Y, Xu J and Thun MJ: Cancer statistics, 2009. CA Cancer J Clin. 59:225–249. 2009. View Article : Google Scholar : PubMed/NCBI
2	Sewnaik A, Hoorweg JJ, Kneqt PP, Wieringa MH, van der Beek JM and Kerrebijn JD: Treatment of hypopharyngeal carcinoma: Analysis of nationwide study in the Netherlands over a 10-year period. Clin Otolaryngol. 30:52–57. 2005. View Article : Google Scholar : PubMed/NCBI
3	Gupta T, Chopra S, Aqarwal JP, Laskar SG, D'cruz AK, Shrivastava SK and Dinshaw KA: Squamous cell carcinoma of the hypopharynx: Single-institution outcome analysis of a large cohort of patients treated with primary non-surgical approaches. Acta Oncol. 48:541–548. 2009. View Article : Google Scholar
4	Semrau R, Mueller RP, Stuetzer H, Staar S, Schroeder U, Guntinas-Lichius O, Kocher M, Eich HT, Dietz A, Flentje M, et al: Efficacy of intensified hyperfractionated and accelerated radiotherapy and concurrent chemotherapy with carboplatin and 5-fluorouraceil: Updated results of a randomized multicentric trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys. 64:1308–1316. 2006. View Article : Google Scholar : PubMed/NCBI
5	Ashhab Y, Alian A, Polliack A, Panet A and Ben Yehuda D: Two splicing variants of a new inhibitor of apoptosis gene with different biological properties and tissue distribution pattern. FEBS Lett. 495:56–60. 2001. View Article : Google Scholar : PubMed/NCBI
6	Deveraux QL and Reed JC: IAP family proteins-suppressors of apoptosis. Genes Dev. 13:239–252. 1999. View Article : Google Scholar : PubMed/NCBI
7	Deveraux QL, Stennicke HR, Salvesen GS and Reed JC: Endogenous inhibitors of caspases. J Clin Immunol. 19:388–398. 1999. View Article : Google Scholar
8	Liu B, Han M, Wen JK and Wang L: Livin/ML-IAP as a new target for cancer treatment. Cancer Lett. 250:168–176. 2007. View Article : Google Scholar : PubMed/NCBI
9	Wang L, Zhang Q, Liu B, Han M and Shan B: Challenge and promise: Roles for Livin in progression and therapy of cancer. Mol Cancer Ther. 7:3661–3669. 2008. View Article : Google Scholar : PubMed/NCBI
10	Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS and Dixit VM: ML-IAP, a novel inhibitor of apoptosis that is preferentially expressed in human melanomas. Curr Biol. 10:1359–1366. 2000. View Article : Google Scholar : PubMed/NCBI
11	Keshet Y and Seger R: The MAP kinase signaling cascades: A system of hundreds of components regulates a diverse array of physiological functions. Methods Mol Biol. 661:3–38. 2010. View Article : Google Scholar : PubMed/NCBI
12	Pratilas CA and Solit DB: Targeting the mitogen-activated protein kinase pathway: Physiological feedback and drug response. Clin Cancer Res. 16:3329–3334. 2010. View Article : Google Scholar : PubMed/NCBI
13	Bermudez O, Pagès G and Gimond C: The dual-specificity MAP kinase phosphatases: Critical roles in development and cancer. Am J Physiol Cell Physiol. 299:C189–C202. 2010. View Article : Google Scholar : PubMed/NCBI
14	Haagenson KK and Wu GS: Mitogen activated protein kinase phosphatases and cancer. Cancer Biol Ther. 9:337–340. 2010. View Article : Google Scholar : PubMed/NCBI
15	Lee DH, Yoon TM, Kim SA, Park YL, Lee KH, Lim SC, Lee JK and Joο YE: Relationship between expression of Livin and the biological behavior of human oral squamous cell carcinoma. Oncol Rep. 32:2453–2460. 2014.PubMed/NCBI
16	Badran A, Yoshida A, Ishikawa K, Goi T, Yamaguchi A, Ueda T and Inuzuka M: Identification of a novel splice variant of the human anti-apoptopsis gene survivin. Biochem Biophys Res Commun. 314:902–907. 2004. View Article : Google Scholar : PubMed/NCBI
17	Eckelman BP, Salvesen GS and Scott FL: Human inhibitor of apoptosis proteins: Why XIAP is the black sheep of the family. EMBO Rep. 7:988–994. 2006. View Article : Google Scholar : PubMed/NCBI
18	Roy N, Deveraux QL, Takahashi R, Salvesen GS and Reed JC: The c-IAP-1 and c-IAP-2 proteins are direct inhibitors of specific caspases. EMBO J. 16:6914–6925. 1997. View Article : Google Scholar
19	Vaux DL and Silke J: Mammalian mitochondrial IAP binding proteins. Biochem Biophys Res Commun. 304:499–504. 2003. View Article : Google Scholar : PubMed/NCBI
20	Deveraux QL, Roy N, Stennicke HR, Van Arsdale T, Zhou Q, Srinivasula SM, Alnemri ES, Salvesen GS and Reed JC: IAPs block apoptotic events induced by caspase-8 and cytochrome c by direct inhibition of distinct caspases. EMBO J. 17:2215–2223. 1998. View Article : Google Scholar : PubMed/NCBI
21	Deveraux QL, Takahashi R, Salvesen GS and Reed JC: X-linked IAP is a direct inhibitor of cell-death proteases. Nature. 388:300–304. 1997. View Article : Google Scholar : PubMed/NCBI
22	Cho SB, Lee WS, Park YL, Kim N, Oh HH, Kim MY, Oak CY, Chung CY, Park HC, Kim JS, et al: Livin is associated with the invasive and oncogenic phenotypes of human hepatocellular carcinoma cells. Hepatol Res. 45:448–457. 2015. View Article : Google Scholar
23	DeBerardinis RJ, Lum JJ, Hatzivassiliou G and Thompson CB: The biology of cancer: Metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 7:11–20. 2008. View Article : Google Scholar : PubMed/NCBI
24	Graña X and Reddy EP: Cell cycle control in mammalian cells: Role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene. 11:211–219. 1995.PubMed/NCBI
25	Kasof GM and Gomes BC: Livin, a novel inhibitor of apoptosis protein family member. J Biol Chem. 276:3238–3246. 2001. View Article : Google Scholar
26	Chen YS, Li HR, Lin M, Chen G, Xie BS, Xu NL and Lin LF: Livin abrogates apoptosis of SPC-A1 cell by regulating JNKI signaling pathway. Mol Biol Rep. 37:2241–2247. 2010. View Article : Google Scholar
27	Sanna MG, da Silva Correia J, Ducrey O, Lee J, Nomoto K, Schrantz N, Deveraux QL and Ulevitch RJ: IAP suppression of apoptosis involves distinct mechanisms: The TAK1/JNK1 signaling cascade and caspase inhibition. Mol Cell Biol. 22:1754–1766. 2002. View Article : Google Scholar : PubMed/NCBI