Overexpression of interleukin-32α promotes invasion by modulating VEGF in hepatocellular carcinoma

Zhao,Wen-Bo; Wang,Quan-Li; Xu,Yan-Tian; Xu,Shi-Feng; Qiu,Yang; Zhu,Feng

doi:10.3892/or.2017.6162

Overexpression of interleukin-32α promotes invasion by modulating VEGF in hepatocellular carcinoma

Authors:
- Wen-Bo Zhao
- Quan-Li Wang
- Yan-Tian Xu
- Shi-Feng Xu
- Yang Qiu
- Feng Zhu
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Affiliations: Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China, Department of Traditional Chinese Medicine, County People's Hospital of Wulian, Rizhao, Shandong 262300, P.R. China, Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong 250021, P.R. China, Department of Hematology and Oncology, Affiliated Hospital of Taishan Medical University, Taian, Shandong 27100, P.R. China
Published online on: December 19, 2017 https://doi.org/10.3892/or.2017.6162
Pages: 1155-1162

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Abstract

Interleukin-32α (IL-32α) was reported to exhibit pluripotent pro-inflammatory properties. Recent studies indicate that it promotes the migration and invasion of cancers. We detected the expression of IL-32 in hepatocellular carcinoma (HCC) tissues and investigated its role in tumor angiogenesis and invasion. IL-32α expression in HCC was evaluated by real-time PCR, western blot analysis and immunohistochemical (IHC) staining. Secreted serum IL-32α and VEGF concentrations were detected using a custom-made sandwich ELISA. Furthermore, IL-32α was knocked down in HCC cell lines using siRNA and the cell migration and invasion abilities were assessed. IHC staining showed that IL32α-positive particles were mainly located in the cytoplasm of cancer cells, and it was significantly upregulated in the tumor tissues compared with that in peritumoral tissues. Notably, IL-32α was strongly expressed in perivascular areas. The mean serum concentration of IL-32α in HCC patients was significantly higher than that in the control group (571.45±102.28 vs. 144.60±51.172 pg/ml; P<0.01). Real-time RT-PCR showed that IL-32α mRNA was significantly overexpressed in HCC tumor tissues (IL-32/β-actin, 15.59±7.8 vs. 3.37±0.47; P<0.01). The in vitro results indicated that IL-32α knockdown inhibited the activation of VEGF-STAT3 signaling in HCC tumor cell lines. IL-32α expression was correlated with clinical relevance in HCC tumor tissues. It is strongly suggested that IL-32α may be a potential predictor of anti-angiogenesis therapy and prognosis of HCC.

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1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
2	Yu SJ: A concise review of updated guidelines regarding the management of hepatocellular carcinoma around the world: 2010–2016. Clin Mol Hepatol. 22:7–17. 2016. View Article : Google Scholar : PubMed/NCBI
3	Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, Jemal A, Yu XQ and He J: Cancer statistics in China, 2015. CA Cancer J Clin. 66:115–132. 2016. View Article : Google Scholar : PubMed/NCBI
4	Poon D, Anderson BO, Chen LT, Tanaka K, Lau WY, Van Cutsem E, Singh H, Chow WC, Ooi LL, Chow P, et al: Asian Oncology Summit: Management of hepatocellular carcinoma in Asia: Consensus statement from the Asian Oncology Summit 2009. Lancet Oncol. 10:1111–1118. 2009. View Article : Google Scholar : PubMed/NCBI
5	Bellissimo F, Pinzone MR, Cacopardo B and Nunnari G: Diagnostic and therapeutic management of hepatocellular carcinoma. World J Gastroenterol. 21:12003–12021. 2015. View Article : Google Scholar : PubMed/NCBI
6	Flores A and Marrero JA: Emerging trends in hepatocellular carcinoma: Focus on diagnosis and therapeutics. Clin Med Insights Oncol. 8:71–76. 2014. View Article : Google Scholar : PubMed/NCBI
7	Petrick JL, Kelly SP, Altekruse SF, McGlynn KA and Rosenberg PS: Future of hepatocellular carcinoma incidence in the united states forecast through 2030. J Clin Oncol. 34:1787–1794. 2016. View Article : Google Scholar : PubMed/NCBI
8	Han KQ, He XQ, Ma MY, Guo XD, Zhang XM, Chen J, Han H, Zhang WW, Zhu QG, Nian H, et al: Inflammatory microenvironment and expression of chemokines in hepatocellular carcinoma. World J Gastroenterol. 21:4864–4874. 2015. View Article : Google Scholar : PubMed/NCBI
9	Moschen AR, Fritz T, Clouston AD, Rebhan I, Bauhofer O, Barrie HD, Powell EE, Kim SH, Dinarello CA, Bartenschlager R, et al: Interleukin-32: A new proinflammatory cytokine involved in hepatitis C virus-related liver inflammation and fibrosis. Hepatology. 53:1819–1829. 2011. View Article : Google Scholar : PubMed/NCBI
10	Felaco P, Castellani ML, De Lutiis MA, Felaco M, Pandolfi F, Salini V, De Amicis D, Vecchiet J, Tete S, Ciampoli C, et al: IL-32: A newly-discovered proinflammatory cytokine. J Biol Regul Homeost Agents. 23:141–147. 2009.PubMed/NCBI
11	Jeong HJ, Shin SY, Oh HA, Kim MH, Cho JS and Kim HM: IL-32 up-regulation is associated with inflammatory cytokine production in allergic rhinitis. J Pathol. 224:553–563. 2011. View Article : Google Scholar : PubMed/NCBI
12	Kim S: Interleukin-32 in inflammatory autoimmune diseases. Immune Netw. 14:123–127. 2014. View Article : Google Scholar : PubMed/NCBI
13	Khawar MB, Abbasi MH and Sheikh N: IL-32: A novel pluripotent inflammatory interleukin, towards gastric inflammation, gastric cancer, and chronic rhino sinusitis. Mediators Inflamm. 2016:84137682016. View Article : Google Scholar : PubMed/NCBI
14	Park JS, Choi SY, Lee JH, Lee M, Nam ES, Jeong AL, Lee S, Han S, Lee MS, Lim JS, et al: Interleukin-32β stimulates migration of MDA-MB-231 and MCF-7 cells via the VEGF-STAT3 signaling pathway. Cell Oncol. 36:493–503. 2013. View Article : Google Scholar
15	Zeng Q, Li S, Zhou Y, Ou W, Cai X, Zhang L, Huang W, Huang L and Wang Q: Interleukin-32 contributes to invasion and metastasis of primary lung adenocarcinoma via NF-kappaB induced matrix metalloproteinases 2 and 9 expression. Cytokine. 65:24–32. 2014. View Article : Google Scholar : PubMed/NCBI
16	Wang S, Chen F and Tang L: IL-32 promotes breast cancer cell growth and invasiveness. Oncol Lett. 9:305–307. 2015. View Article : Google Scholar : PubMed/NCBI
17	Ghaffari A, Hoskin V, Szeto A, Hum M, Liaghati N, Nakatsu K, LeBrun D, Madarnas Y, Sengupta S and Elliott BE: A novel role for ezrin in breast cancer angio/lymphangiogenesis. Breast Cancer Res. 16:4382014. View Article : Google Scholar : PubMed/NCBI
18	Liu X, Guo X, Li H, Chen J and Qi X: Src/STAT3 signaling pathways are involved in KAI1-induced downregulation of VEGF-C expression in pancreatic cancer. Mol Med Rep. 13:4774–4778. 2016. View Article : Google Scholar : PubMed/NCBI
19	Galun E: Liver inflammation and cancer: The role of tissue microenvironment in generating the tumor-promoting niche (TPN) in the development of hepatocellular carcinoma. Hepatology. 63:354–356. 2016. View Article : Google Scholar : PubMed/NCBI
20	Chen Q, Carroll HP and Gadina M: The newest interleukins: Recent additions to the ever-growing cytokine family. Vitam Horm. 74:207–228. 2006. View Article : Google Scholar : PubMed/NCBI
21	Kim SH, Han SY, Azam T, Yoon DY and Dinarello CA: Interleukin-32: A cytokine and inducer of TNFalpha. Immunity. 22:131–142. 2005. View Article : Google Scholar : PubMed/NCBI
22	Nishida A, Andoh A, Inatomi O and Fujiyama Y: Interleukin-32 expression in the pancreas. J Biol Chem. 284:17868–17876. 2009. View Article : Google Scholar : PubMed/NCBI
23	Heinhuis B, Koenders MI, Van den Berg WB, Netea MG, Dinarello CA and Joosten LA: Interleukin 32 (IL-32) contains a typical α-helix bundle structure that resembles focal adhesion targeting region of focal adhesion kinase-1. J Biol Chem. 287:5733–5743. 2012. View Article : Google Scholar : PubMed/NCBI
24	Heinhuis B, Netea MG, Van den Berg WB, Dinarello CA and Joosten LA: Interleukin-32: A predominantly intracellular proinflammatory mediator that controls cell activation and cell death. Cytokine. 60:321–327. 2012. View Article : Google Scholar : PubMed/NCBI
25	Ishigami S, Arigami T, Uchikado Y, Setoyama T, Kita Y, Sasaki K, Okumura H, Kurahara H, Kijima Y, Harada A, et al: IL-32 expression is an independent prognostic marker for gastric cancer. Med Oncol. 30:4722013. View Article : Google Scholar : PubMed/NCBI
26	Tsai CY, Wang CS, Tsai MM, Chi HC, Cheng WL, Tseng YH, Chen CY, Lin CD, Wu JI, Wang LH, et al: Interleukin-32 increases human gastric cancer cell invasion associated with tumor progression and metastasis. Clin Cancer Res. 20:2276–2288. 2014. View Article : Google Scholar : PubMed/NCBI
27	Yousif NG, Al-Amran FG, Hadi N, Lee J and Adrienne J: Expression of IL-32 modulates NF-κB and p38 MAP kinase pathways in human esophageal cancer. Cytokine. 61:223–227. 2013. View Article : Google Scholar : PubMed/NCBI
28	Kang YH, Park MY, Yoon DY, Han SR, Lee CI, Ji NY, Myung PK, Lee HG, Kim JW, Yeom YI, et al: Dysregulation of overexpressed IL-32α in hepatocellular carcinoma suppresses cell growth and induces apoptosis through inactivation of NF-κB and Bcl-2. Cancer Lett. 318:226–233. 2012. View Article : Google Scholar : PubMed/NCBI
29	Liu K, Min XL, Peng J, Yang K, Yang L and Zhang XM: The changes of HIF-1α and VEGF expression after TACE in patients with hepatocellular carcinoma. J Clin Med Res. 8:297–302. 2016. View Article : Google Scholar : PubMed/NCBI
30	Tsuchiya K, Asahina Y, Matsuda S, Muraoka M, Nakata T, Suzuki Y, Tamaki N, Yasui Y, Suzuki S, Hosokawa T, et al: Changes in plasma vascular endothelial growth factor at 8 weeks after sorafenib administration as predictors of survival for advanced hepatocellular carcinoma. Cancer. 120:229–237. 2014. View Article : Google Scholar : PubMed/NCBI
31	Nold-Petry CA, Nold MF, Zepp JA, Kim SH, Voelkel NF and Dinarello CA: IL-32-dependent effects of IL-1beta on endothelial cell functions. Proc Natl Acad Sci USA. 106:pp. 3883–3888. 2009; View Article : Google Scholar : PubMed/NCBI
32	Nold-Petry CA, Rudloff I, Baumer Y, Ruvo M, Marasco D, Botti P, Farkas L, Cho SX, Zepp JA, Azam T, et al: IL-32 promotes angiogenesis. J Immunol. 192:589–602. 2014. View Article : Google Scholar : PubMed/NCBI
33	Hoshida Y, Fuchs BC and Tanabe KK: Prevention of hepatocellular carcinoma: Potential targets, experimental models, and clinical challenges. Curr Cancer Drug Targets. 12:1129–1159. 2012. View Article : Google Scholar : PubMed/NCBI
34	Welker MW and Trojan J: Antiangiogenic treatment in hepatocellular carcinoma: The balance of efficacy and safety. Cancer Manag Res. 5:337–347. 2013.PubMed/NCBI