Association between integrin‑linked kinase and hyperthermia in oral squamous cell carcinoma

Zhao,Jun; Liu,Na; Hao,Xinhe; Que,Lin; Liu,Jiyuan; Tang,Xiufa

doi:10.3892/ol.2017.7222

Association between integrin‑linked kinase and hyperthermia in oral squamous cell carcinoma

Authors:
- Jun Zhao
- Na Liu
- Xinhe Hao
- Lin Que
- Jiyuan Liu
- Xiufa Tang
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Affiliations: Department of Oral and Maxillofacial Surgery, Hefei Stomatological Hospital, Hefei, Anhui 230001, P.R. China, State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University, Chengdu, Sichuan 610041, P.R. China
Published online on: October 19, 2017 https://doi.org/10.3892/ol.2017.7222
Pages: 7705-7714
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present study aimed to observe the effect of the biological functions of integrin‑linked kinase (ILK) silencing combined with hyperthermia on Tca8113 cells. Lentivirus‑mediated short hairpin RNA (shRNA)‑targeting ILK was transfected into oral squamous cell carcinoma (OSCC) Tca8113 cells and, combined with hyperthermia, several experimental methods were used to detect their biological behavior in vitro. On the basis of in vitro experiments, Tca8113 cells were transplanted into nude mice models, and ILK‑shRNA‑lentivirus was injected into the nude mice transplanted tumor and combined with hyperthermia. Tumor morphology and the associated protein expression changes were determined. Subsequent to ILK silencing combined with hyperthermia, the growth, migration and proliferation of Tca8113 cells were significantly inhibited. Flow cytometry revealed that the cells were blocked in the S phase, and western blot analysis demonstrated that ILK, phosphorylated (p)‑RAC‑alpha serine/threonine‑protein kinase (Akt), p‑glycogen synthase kinase‑3β and p‑heat shock factor 1 protein expression levels were significantly decreased, while apoptosis‑associated protein B‑cell lymphoma‑2‑associated X protein expression and the efficacy of hypothermia were significantly increased. By ILK silencing combined with hyperthermia, a significant therapeutic effect on transplanted tumors was observed in nude mice. Immunohistochemistry revealed the same results as the in vitro experiments. ILK silencing combined with hyperthermia can inhibit the growth, proliferation and migration of Tca8113 cells, promote Tca8113 cell apoptosis, inhibit the phosphatidylinositol‑3‑kinase/Akt signaling pathway and increase hyperthermia sensitivity; the combination therapy exhibits a synergistic sensitizing effect. Therefore, ILK silencing combined with hypothermia may serve as a novel combination therapy strategy against OSCC.

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1	Perri F, Muto P, Aversa C, Daponte A, Della Vittoria G, Pepe S and Caponigro F: Integrated therapeutic approaches in head and neck cancer: The importance of multidisciplinary team management. Anticancer Agents Med Chem. 13:834–843. 2013. View Article : Google Scholar : PubMed/NCBI
2	Antoniv TT and Ivashkiv LB: Interleukin-10-induced gene expression and suppressive function are selectively modulated by the PI3K-Akt-GSK3 pathway. Immunology. 132:567–577. 2011. View Article : Google Scholar : PubMed/NCBI
3	Aksamitiene E, Kiyatkin A and Kholodenko BN: Cross-talk between mitogenic Ras/MAPK and survival PI3K/Akt pathways: A fine balance. Biochem Soc Trans. 40:139–146. 2012. View Article : Google Scholar : PubMed/NCBI
4	Troussard AA, Mawji NM, Ong C, Mui A, St-Arnaud R and Dedhar S: Conditional knock-out of integrin-linked kinase demonstrates an essential role in protein kinase B/Akt activation. J Biol Chem. 278:22374–22378. 2003. View Article : Google Scholar : PubMed/NCBI
5	Marotta A, Parhar K, Owen D, Dedhar S and Salh B: Characterisation of integrin-linked kinase signalling in sporadic human colon cancer. Br J Cancer. 88:1755–1762. 2003. View Article : Google Scholar : PubMed/NCBI
6	Tasian SK, Teachey DT and Rheingold SR: Targeting the PI3K/mTOR pathway in pediatric hematologic malignancies. Front Oncol. 4:1082014. View Article : Google Scholar : PubMed/NCBI
7	Zheng K, Wang G, Li C, Shan X and Liu H: Knockdown of ILK inhibits glioma development via upregulation of E-cadherin and downregulation of cyclin D1. Oncol Rep. 34:272–278. 2015. View Article : Google Scholar : PubMed/NCBI
8	Zhao X, Xu Z, Wang Z, Wu Z, Gong Y, Zhou L and Xiang Y: RNA silencing of integrin-linked kinase increases the sensitivity of the A549 lung cancer cell line to cisplatin and promotes its apoptosis. Mol Med Rep. 12:960–966. 2015. View Article : Google Scholar : PubMed/NCBI
9	Dicheva BM and Koning GA: Targeted thermosensitive liposomes: An attractive novel approach for increased drug delivery to solid tumors. Expert Opin Drug Deliv. 11:83–100. 2014. View Article : Google Scholar : PubMed/NCBI
10	Yamamoto D, Inui T, Tsubota Y, Sueoka N, Yamamoto C, Kuwana K and Yamamoto M: The utility of hyperthermia for local recurrence of breast cancer. World J Surg Oncol. 10:2012012. View Article : Google Scholar : PubMed/NCBI
11	Liang XH, He YW, Tang YL, Wu JL, Gao XP, Xiao GZ and Mao ZY: Thermochemotherapy of lower lip squamous cell carcinoma without metastases: An experience of 31 cases. J Craniomaxillofac Surg. 38:260–265. 2010. View Article : Google Scholar : PubMed/NCBI
12	Tao Y, Guo Y, Liu W, Zhang J, Li X, Shen L, Ru Y, Xue Y, Zheng J, Liu X, et al: AKT inhibitor suppresses hyperthermia-induced Ndrg2 phosphorylation in gastric cancer cells. Braz J Med Biol Res. 46:394–404. 2013. View Article : Google Scholar : PubMed/NCBI
13	Schaeffer DF, Assi K, Chan K, Buczkowski AK, Chung SW, Scudamore CH, Weiss A, Salh B and Owen DA: Tumor expression of integrin-linked kinase (ILK) correlates with the expression of the E-cadherin repressor snail: An immunohistochemical study in ductal pancreatic adenocarcinoma. Virchows Arch. 456:261–268. 2010. View Article : Google Scholar : PubMed/NCBI
14	Gao Z, Liu F, Yin P, Wan C, He S, Liu X, Zhao H, Liu T, Xu J and Guo S: Inhibition of heat-induced apoptosis in rat small intestine and IEC-6 cells through the AKT signaling pathway. BMC Vet Res. 9:2412013. View Article : Google Scholar : PubMed/NCBI
15	Zhao D, Tang XF, Yang K, Liu JY and Ma XR: Over-expression of integrin-linked kinase correlates with aberrant expression of Snail, E-cadherin and N-cadherin in oral squamous cell carcinoma: implications in tumor progression and metastasis. Clin Exp Metastasis. 29:957–969. 2012. View Article : Google Scholar : PubMed/NCBI
16	Nakagawa T, Ohnishi K, Kosaki Y, Saito Y, Horlad H, Fujiwara Y, Takeya M and Komohara Y: Optimum immunohistochemical procedures for analysis of macrophages in human and mouse formalin fixed paraffin-embedded tissue samples. J Clin Exp Hematop. 57:31–36. 2017. View Article : Google Scholar : PubMed/NCBI
17	He B, Meng YH and Mivechi NF: Glycogen synthase kinase 3beta and extracellular signal-regulated kinase inactivate heat shock transcription factor1 by facilitating the disappearance of transcriptionally active granules after heat shock. Mol Cell Biol. 18:6624–6633. 1998. View Article : Google Scholar : PubMed/NCBI
18	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. View Article : Google Scholar : PubMed/NCBI
19	Chen X and Zhang J, Han C, Dai H, Kong X, Xu L, Xia Q, Zhang M and Zhang J: A sexual dimorphism influences bicyclol-induced hepatic heat shock factor 1 activation and hepatoprotection. Mol Pharmacol. 88:38–47. 2015. View Article : Google Scholar : PubMed/NCBI
20	Rahman MA, Amin AR, Wang D, Koenig L, Nannapaneni S, Chen Z, Wang Z, Sica G, Deng X, Chen ZG and Shin DM: RRM2 regulates Bcl-2 in head and neck and lung cancers: A potential target for cancer therapy. Clin Cancer Res. 19:3416–3428. 2013. View Article : Google Scholar : PubMed/NCBI
21	de la Torre NG, Buley I, Wass JA and Turner HE: Angiogensis and lymphangiogenesis in thyroid proliferative lesions: Relationship to type and tumour behaviour. Endocr Relat Cancer. 13:931–944. 2006. View Article : Google Scholar : PubMed/NCBI
22	Marchesin V, Castro-Castro A, Lodillinsky C, Castagnino A, Cyrta J, Bonsang-Kitzis H, Fuhrmann L, Irondelle M, Infante E, Montagnac G, et al: ARF6-JIP3/4 regulate endosomal tubules for MT1-MMP exocytosis in cancer invasion. J Cell Biol. 211:339–358. 2015. View Article : Google Scholar : PubMed/NCBI
23	Qian DC, Byun J, Han Y, Greene CS, Field JK, Hung RJ, Brhane Y, Mclaughlin JR, Fehringer G, Landi MT, et al: Identification of shared and unique susceptibility pathways among cancers of the lung, breast, and prostate from genome-wide association studies and tissue-specific protein interactions. Hum Mol Genet. 24:7406–7420. 2015. View Article : Google Scholar : PubMed/NCBI
24	Zeise E and Rensing L: Hyperthermia pre-treatment protects rats IPC-81 leukaemia cells against heat- and hydrogen peroxide-induced apoptosis. Int J Hyperthermia. 18:344–360. 2002. View Article : Google Scholar : PubMed/NCBI
25	Bijur GN and Jope RS: Opposing actions of phosphatidylinositol 3-kinase and glycogen synthase kinase-3beta in the regulation of HSF-1 activity. J Neurochem. 75:2401–2408. 2000. View Article : Google Scholar : PubMed/NCBI
26	Zhu XY, Liu N, Liu W, Song SW and Guo KJ: Silencing of the integrin-linked kinase gene suppresses the proliferation, migration and invasion of pancreatic cancer cells (Panc-1). Genet Mol Biol. 35:538–544. 2012. View Article : Google Scholar : PubMed/NCBI
27	Li Q, Li C, Zhang YY, Chen W, Lv JL, Sun J and You QS: Silencing of integrin-linked kinase suppresses in vivo tumorigenesis of human ovarian carcinoma cells. Mol Med Rep. 7:1050–1054. 2013. View Article : Google Scholar : PubMed/NCBI
28	Persad S, Attwell S, Gray V, Delcommenne M, Troussard A, Sanghera J and Dedhar S: Inhibition of integrin-linked kinase (ILK) suppresses activation of protein kinase B/Akt and induces cell cycle arrest and apoptosis of PTEN-mutant prostate cancer cells. Proc Natl Acad Sci USA. 97:pp. 3207–3212. 2000, View Article : Google Scholar : PubMed/NCBI
29	Makino K, Day CP, Wang SC, Li YM and Hung MC: Upregulation of IKKalpha/IKKbeta by integrin-linked kinase is required for HER2/neu-induced NF-kappaB antiapoptotic pathway. Oncogene. 23:3883–3887. 2004. View Article : Google Scholar : PubMed/NCBI
30	Jevtov I, Zacharogianni M, van Oorschot MM, van Zadelhoff G, Aguilera-Gomez A, Vuillez I, Braakman I, Hafen E, Stocker H and Rabouille C: TORC2 mediates the heat stress response in Drosophila by promoting the formation of stress granules. J Cell Sci. 128:2497–2508. 2015. View Article : Google Scholar : PubMed/NCBI
31	Ohnishi K, Yasumoto J, Takahashi A and Ohnishi T: LY294002, an inhibitor of PI-3K, enhances heat sensitivity independently of p53 status in human lung cancer cells. Int J Oncol. 29:249–253. 2006.PubMed/NCBI
32	Ma N, Szmitko P, Brade A, Chu I, Lo A, Woodgett J, Klamut H and Liu FF: Kinase-dead PKB gene therapy combined with hyperthermia for human breast cancer. Cancer Gene Ther. 11:52–60. 2004. View Article : Google Scholar : PubMed/NCBI