Concomitant modulation of PTEN and Livin in gastric cancer treatment

Zhao,Chun‑Lin; Han,Sheng‑Na; Wang,Zhi‑Ju; Wang,Shu‑Hui; Zhao,Guo‑Qiang; Zhang,Xie‑Fu; Wang,Jia‑Xiang

doi:10.3892/ijmm.2018.3475

Concomitant modulation of PTEN and Livin in gastric cancer treatment

Authors:
- Chun‑Lin Zhao
- Sheng‑Na Han
- Zhi‑Ju Wang
- Shu‑Hui Wang
- Guo‑Qiang Zhao
- Xie‑Fu Zhang
- Jia‑Xiang Wang
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Affiliations: Department of General Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China, Department of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China, Department of Physiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, Henan 450052, P.R. China, Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
Published online on: February 8, 2018 https://doi.org/10.3892/ijmm.2018.3475
Pages: 2901-2908

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Abstract

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) and Livin are important in the development of gastric cancer (GC). PTEN and Livin are involved in the regulation of tumor cell proliferation, migration and apoptosis. The modulation of PTEN or Livin has been investigated extensively in various cancer models. However, no studies have been performed to evaluate the combined effect of concurrently modulating these two genes on the development of GC. In the present study, the BGC823 human gastric carcinoma cell line was transfected with a dual gene modified vector (pCL-neo-PTEN-siLivin) in parallel with single gene modified vectors (pCL‑neo‑PTEN or pRNAT‑U6.1‑siLivin), and an empty control vector. Dual gene modulation (pCL‑neo‑PTEN‑siLivin) had a more marked effect on the inhibition of cell proliferation, induction of apoptosis, and reduction of cell penetration in Matrigel, compared with either single gene alone or empty vector transfection. In a xenograft nude mouse model, the inoculation of pCL‑neo‑PTEN‑siLivin‑transfected BGC823 cells led to a markedly reduced tumor burden, compared with that in all other inoculation groups. In conclusion, the overexpression of PTEN concomitant with Livin gene silencing was confirmed as a feasible and effective in vitro and in vivo gene modulation method, which may represent a potential therapeutic strategy for the treatment of GC.

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1	Guggenheim DE and Shah MA: Gastric cancer epidemiology and risk factors. J Surg Oncol. 107:230–236. 2013. View Article : Google Scholar
2	Yeoh KG: How do we improve outcomes for gastric cancer? J Gastroenterol Hepatol. 22:970–972. 2007. View Article : Google Scholar : PubMed/NCBI
3	Tan IB, Ng I, Tai WM and Tan P: Understanding the genetic basis of gastric cancer: Recent advances. Expert Rev Gastroenterol Hepatol. 6:335–341. 2012. View Article : Google Scholar : PubMed/NCBI
4	Nagini S: Carcinoma of the stomach: A review of epidemiology, pathogenesis, molecular genetics and chemoprevention. World J Gastrointest Oncol. 4:156–169. 2012. View Article : Google Scholar : PubMed/NCBI
5	Stambolic V, Suzuki A, de la Pompa JL, Brothers GM, Mirtsos C, Sasaki T, Ruland J, Penninger JM, Siderovski DP and Mak TW: Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell. 95:29–39. 1998. View Article : Google Scholar : PubMed/NCBI
6	She QB, Solit DB, Ye Q, O'Reilly KE, Lobo J and Rosen N: The BAD protein integrates survival signaling by EGFR/MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell. 8:287–297. 2005. View Article : Google Scholar : PubMed/NCBI
7	Zhang LL, Liu J, Lei S, Zhang J, Zhou W and Yu HG: PTEN inhibits the invasion and metastasis of gastric cancer via downregulation of FAK expression. Cell Signal. 26:1011–1020. 2014. View Article : Google Scholar : PubMed/NCBI
8	Katoh M: WNT/PCP signaling pathway and human cancer (review). Oncol Rep. 14:1583–1588. 2005.PubMed/NCBI
9	Chen Z, Trotman LC, Shaffer D, Lin HK, Dotan ZA, Niki M, Koutcher JA, Scher HI, Ludwig T, Gerald W, et al: Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature. 436:725–730. 2005. View Article : Google Scholar : PubMed/NCBI
10	Xu WT, Yang Z and Lu NH: Roles of PTEN (Phosphatase and Tensin Homolog) in gastric cancer development and progression. Asian Pac J Cancer Prev. 15:17–24. 2014. View Article : Google Scholar : PubMed/NCBI
11	Koike H, Nozawa M, De Velasco MA, Kura Y, Ando N, Fukushima E, Yamamoto Y, Hatanaka Y, Yoshikawa K, Nishio K and Uemura H: Conditional PTEN-deficient mice as a prostate cancer chemoprevention model. Asian Pac J Cancer Prev. 16:1827–1831. 2015. View Article : Google Scholar : PubMed/NCBI
12	Kechagioglou P, Papi RM, Provatopoulou X, Kalogera E, Papadimitriou E, Grigoropoulos P, Nonni A, Zografos G, Kyriakidis DA and Gounaris A: Tumor suppressor PTEN in breast cancer: Heterozygosity, mutations and protein expression. Anticancer Res. 34:1387–1400. 2014.PubMed/NCBI
13	Nakanishi A, Kitagishi Y, Ogura Y and Matsuda S: The tumor suppressor PTEN interacts with p53 in hereditary cancer (Review). Int J Oncol. 44:1813–1819. 2014. View Article : Google Scholar : PubMed/NCBI
14	Kim DK, Alvarado CS, Abramowsky CR, Gu L, Zhou M, Soe MM, Sullivan K, George B, Schemankewitz E and Findley HW: Expression of inhibitor-of-apoptosis protein (IAP) livin by neuroblastoma cells: Correlation with prognostic factors and outcome. Pediatr Dev Pathol. 8:621–629. 2005. View Article : Google Scholar : PubMed/NCBI
15	Kleinberg L, Lie AK, Florenes VA, Nesland JM and Davidson B: Expression of inhibitor-of-apoptosis protein family members in malignant mesothelioma. Hum Pathol. 38:986–994. 2007. View Article : Google Scholar : PubMed/NCBI
16	Li CJ, Cong Y, Liu XZ, Zhou X, Shi X, Wu SJ, Zhou GX and Lu M: Research progress on the livin gene and osteosarcomas. Asian Pac J Cancer Prev. 15:8577–8579. 2014. View Article : Google Scholar : PubMed/NCBI
17	Ou JM, Ye B, Qiu MK, Dai YX, Dong Q, Shen J, Dong P, Wang XF, Liu YB, Quan ZW and Fei ZW: Knockdown of Livin inhibits growth and invasion of gastric cancer cells through blokkade of the MAPK pathway in vitro and in vivo. Int J Oncol. 44:276–284. 2014. View Article : Google Scholar
18	Chung CY, Park YL, Kim N, Park HC, Park HB, Myung DS, Kim JS, Cho SB, Lee WS and Joo YE: Expression and prognostic significance of Livin in gastric cancer. Oncol Rep. 30:2520–2528. 2013. View Article : Google Scholar : PubMed/NCBI
19	Crnković-Mertens I, Wagener N, Semzow J, Gröne EF, Haferkamp A, Hohenfellner M, Butz K and Hoppe-Seyler F: Targeted inhibition of Livin resensitizes renal cancer cells towards apoptosis. Cell Mol Life Sci. 64:1137–1144. 2007. View Article : Google Scholar
20	Zhao CL, Wang JX, Zhang XF, Zhao GQ and Wang ZJ: Construction and identification of gene vector expressing PTEN while simultaneously silencing Livin. Zhonghua Yi Xue Za Zhi. 90:2428–2432. 2010.In Chinese. PubMed/NCBI
21	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
22	Hwang TL, Changchien TT, Wang CC and Wu CM: Claudin-4 expression in gastric cancer cells enhances the invasion and is associated with the increased level of matrix metalloproteinase-2 and -9 expression. Oncol Lett. 8:1367–1371. 2014. View Article : Google Scholar : PubMed/NCBI
23	Krajewska M, Wang HG, Krajewski S, Zapata JM, Shabaik A, Gascoyne R and Reed JC: Immunohistochemical analysis of in vivo patterns of expression of CPP32 (Caspase-3), a cell death protease. Cancer Res. 57:1605–1613. 1997.PubMed/NCBI
24	Schwartzbauer G and Robbins J: The tumor suppressor gene PTEN can regulate cardiac hypertrophy and survival. J Biol Chem. 276:35786–35793. 2001. View Article : Google Scholar : PubMed/NCBI
25	Sun CH, Chang YH and Pan CC: Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder. Histopathology. 58:1054–1063. 2011. View Article : Google Scholar : PubMed/NCBI
26	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
27	Hinds MG, Norton RS, Vaux DL and Day CL: Solution structure of a baculoviral inhibitor of apoptosis (IAP) repeat. Nat Struct Biol. 6:648–651. 1999. View Article : Google Scholar : PubMed/NCBI
28	Chu ZL, McKinsey TA, Liu L, Gentry JJ, Malim MH and Ballard DW: Suppression of tumor necrosis factor-induced cell death by inhibitor of apoptosis c-IAP2 is under NF-kappaB control. Proc Natl Acad Sci USA. 94:10057–10062. 1997. View Article : Google Scholar : PubMed/NCBI
29	Chang H and Schimmer AD: Livin/melanoma inhibitor of apoptosis protein as a potential therapeutic target for the treatment of malignancy. Mol Cancer Ther. 6:24–30. 2007. View Article : Google Scholar : PubMed/NCBI
30	Ma L, Huang Y, Song Z, Feng S, Tian X, Du W, Qiu X, Heese K and Wu M: Livin promotes Smac/DIABLO degradation by ubiquitin-proteasome pathway. Cell Death Differ. 13:2079–2088. 2006. View Article : Google Scholar : PubMed/NCBI
31	Hwang PH, Yi HK, Kim DS, Nam SY, Kim JS and Lee DY: Suppression of tumorigenicity and metastasis in B16F10 cells by PTEN/MMAC1/TEP1 gene. Cancer Lett. 172:83–91. 2001. View Article : Google Scholar : PubMed/NCBI
32	Leslie NR: PTEN: An intercellular peacekeeper? Sci Signal. 5:pe502012. View Article : Google Scholar : PubMed/NCBI
33	Maehama T, Taylor GS and Dixon JE: PTEN and myotubularin: novel phosphoinositide phosphatases. Annu Rev Biochem. 70:247–279. 2001. View Article : Google Scholar : PubMed/NCBI
34	Chen F, Yang D, Che X, Wang J, Li X, Zhang Z, Chen X and Song X: Livin mediates tumor cell invasion in the DU-145 cell line via NF-κB. Oncol Rep. 27:2010–2016. 2012.PubMed/NCBI
35	Chen F, Yang D, Wang S, Che X, Wang J, Li X, Zhang Z, Chen X and Song X: Livin regulates prostate cancer cell invasion by impacting the NF-κB signaling pathway and the expression of FN and CXCR4. IUBMB Life. 64:274–283. 2012. View Article : Google Scholar : PubMed/NCBI
36	Yoon TM, Kim SA, Lee DH, Lee JK, Park YL, Lee KH, Chung IJ, Joo YE and Lim SC: Expression of Livin and the inhibition of tumor progression by Livin silencing in laryngohypopharyngeal cancer. In Vivo. 28:751–759. 2014.PubMed/NCBI