Upregulation of GRIM-19 suppresses the growth of oral squamous cell carcinoma in vitro and in vivo

Li,Minghe; Li,Zhihong; Liang,Chongyang; Han,Chengmin; Huang,Wei; Sun,Fei

doi:10.3892/or.2014.3423

Upregulation of GRIM-19 suppresses the growth of oral squamous cell carcinoma in vitro and in vivo

Authors:
- Minghe Li
- Zhihong Li
- Chongyang Liang
- Chengmin Han
- Wei Huang
- Fei Sun
View Affiliations

Affiliations: Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130022, P.R. China, Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China, Department of Oral and Maxillofacial Surgery, School and Hospital of Stomatology, Jilin University, Changchun, Jilin 130021, P.R. China
Published online on: August 20, 2014 https://doi.org/10.3892/or.2014.3423
Pages: 2183-2190

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Constitutive activation of the signal transducer and activator of transcription 3 (STAT3) and its upregulation contribute to the progression and metastasis of several different tumor types. The gene associated with retinoid‑interferon‑induced mortality-19 (GRIM-19) is known to functionally interact with STAT3 and inhibit its transcriptional activity. It has been reported that upregulation of genes associated with GRIM-19 can significantly reduce the tumor growth of several types of tumors. However, little is known in regards to its role in oral squamous cell carcinoma (OSCC). In the present study, a recombinant eukaryotic expression plasmid carrying GRIM-19 was constructed to evaluate its effects on OSCC cancer growth. Upregulation of GRIM-19 in OSCC cells significantly inhibited cell proliferation, migration and invasion in vitro and suppressed tumor growth in vivo. Moreover, we found that upregulation of GRIM-19 reduced cyclin D1, Bcl-2, vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2) expression whose protein is involved in STAT3 activation. Taken together, these findings suggest that GRIM-19 plays an inhibitory role in the progression of OSCC, and contribute to the future development of STAT3-based gene therapeutic approaches for OSCC.

View Figures

View References

1	Lu L, Xue X, Lan J, et al: MicroRNA-29a upregulates MMP2 in oral squamous cell carcinoma to promote cancer invasion and anti-apoptosis. Biomed Pharmacother. 68:13–19. 2014. View Article : Google Scholar : PubMed/NCBI
2	Sharma P, Saxena S and Aggarwal P: Trends in the epidemiology of oral squamous cell carcinoma in Western UP: an institutional study. Indian J Dent Res. 21:316–319. 2010. View Article : Google Scholar : PubMed/NCBI
3	Rautava J, Luukkaa M, Heikinheimo K, Alin J, Grenman R and Happonen RP: Squamous cell carcinomas arising from different types of oral epithelia differ in their tumor and patient characteristics and survival. Oral Oncol. 43:911–919. 2007. View Article : Google Scholar
4	Peng CH, Liao CT, Peng SC, et al: A novel molecular signature identified by systems genetics approach predicts prognosis in oral squamous cell carcinoma. PLoS One. 6:e234522011. View Article : Google Scholar : PubMed/NCBI
5	Chen R, Yang K, Zhao NB, et al: Abnormal expression of PER1 circadian-clock gene in oral squamous cell carcinoma. Onco Targets Ther. 5:403–407. 2012.
6	Angell JE, Lindner DJ, Shapiro PS, Hofmann ER and Kalvakolanu DV: Identification of GRIM-19, a novel cell death-regulatory gene induced by the interferon-β and retinoic acid combination, using a genetic approach. J Biol Chem. 275:33416–33426. 2000.PubMed/NCBI
7	Wen LJ, Gao LF, Jin CS, et al: Small interfering RNA survivin and GRIM-19 co-expression salmonella plasmid inhibited the growth of laryngeal cancer cells in vitro and in vivo. Int J Clin Exp Pathol. 6:2071–2081. 2013.PubMed/NCBI
8	Nallar SC, Kalakonda S, Lindner DJ, et al: Tumor-derived mutations in the gene associated with retinoid interferon-induced mortality (GRIM-19) disrupt its anti-signal transducer and activator of transcription 3 (STAT3) activity and promote oncogenesis. J Biol Chem. 288:7930–7941. 2013. View Article : Google Scholar
9	Alchanati I, Nallar SC, Sun P, et al: A proteomic analysis reveals the loss of expression of the cell death regulatory gene GRIM-19 in human renal cell carcinomas. Oncogene. 25:7138–7147. 2006. View Article : Google Scholar : PubMed/NCBI
10	Fusco A, Viglietto G and Santoro M: Point mutation in GRIM-19: a new genetic lesion in Hurthle cell thyroid carcinomas. Br J Cancer. 92:1817–1818. 2005.
11	Maximo V, Botelho T, Capela J, et al: Somatic and germline mutation in GRIM-19, a dual function gene involved in mitochondrial metabolism and cell death, is linked to mitochondrion-rich (Hurthle cell) tumours of the thyroid. Br J Cancer. 92:1892–1898. 2005.PubMed/NCBI
12	Zhou Y, Li M, Wei Y, et al: Down-regulation of GRIM-19 expression is associated with hyperactivation of STAT3-induced gene expression and tumor growth in human cervical cancers. J Interferon Cytokine Res. 29:695–703. 2009.
13	Zhang L, Gao L, Li Y, et al: Effects of plasmid-based Stat3- specific short hairpin RNA and GRIM-19 on PC-3M tumor cell growth. Clin Cancer Res. 14:559–568. 2008. View Article : Google Scholar : PubMed/NCBI
14	Hao H, Liu J, Liu G, et al: Depletion of GRIM-19 accelerates hepatocellular carcinoma invasion via inducing EMT and loss of contact inhibition. J Cell Physiol. 227:1212–1219. 2012. View Article : Google Scholar : PubMed/NCBI
15	Okamoto T, Inozume T, Mitsui H, et al: Overexpression of GRIM-19 in cancer cells suppresses STAT3-mediated signal transduction and cancer growth. Mol Cancer Ther. 9:2333–2343. 2010. View Article : Google Scholar : PubMed/NCBI
16	Wang T, Yan XB, Zhao JJ, et al: Gene associated with retinoid-interferon-induced mortality-19 suppresses growth of lung adenocarcinoma tumor in vitro and in vivo. Lung Cancer. 72:287–293. 2011. View Article : Google Scholar : PubMed/NCBI
17	Kalvakolanu DV: The GRIMs: a new interface between cell death regulation and interferon/retinoid induced growth suppression. Cytokine Growth Factor Rev. 15:169–194. 2004. View Article : Google Scholar : PubMed/NCBI
18	Lufei C, Ma J, Huang G, et al: GRIM-19, a death-regulatory gene product, suppresses Stat3 activity via functional interaction. EMBO J. 22:1325–1335. 2003. View Article : Google Scholar : PubMed/NCBI
19	Turkson J: STAT proteins as novel targets for cancer drug discovery. Expert Opin Ther Targets. 8:409–422. 2004. View Article : Google Scholar : PubMed/NCBI
20	Niu G, Wright KL, Huang M, et al: Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene. 21:2000–2008. 2002. View Article : Google Scholar : PubMed/NCBI
21	Xie TX, Wei D, Liu M, et al: Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene. 23:3550–3560. 2004. View Article : Google Scholar : PubMed/NCBI
22	Sobin LH and Wittekind CH: UICC TNM Classification of Malignant Tumors. 7th edition. Springer-Verlag; Berlin: 2010
23	Hamilton SR and Aaltonen LA: Pathology and Genetics Tumours of the Digestive System. 3rd edition. IARC Press; Lyon: 2000
24	Zhang H, Li Z and Wang K: Combining sorafenib with celecoxib synergistically inhibits tumor growth of non-small cell lung cancer cells in vitro and in vivo. Oncol Rep. 31:1954–1960. 2014.
25	Gao L, Zhang L, Hu J, et al: Down-regulation of signal transducer and activator of transcription 3 expression using vector-based small interfering RNAs suppresses growth of human prostate tumor in vivo. Clin Cancer Res. 11:6333–6341. 2005. View Article : Google Scholar : PubMed/NCBI
26	Hanahan D and Weinberg RA: Hallmarks of cancer: the next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
27	Evan GI and Vousden KH: Proliferation, cell cycle and apoptosis in cancer. Nature. 411:342–348. 2001. View Article : Google Scholar : PubMed/NCBI
28	Thompson CB: Apoptosis in the pathogenesis and treatment of disease. Science. 267:1456–1462. 1995. View Article : Google Scholar : PubMed/NCBI
29	Hanahan D and Weinberg RA: The hallmarks of cancer. Cell. 100:57–70. 2000. View Article : Google Scholar
30	Ribatti D and Vacca A: The role of microenvironment in tumor angiogenesis. Genes Nutr. 3:29–34. 2008. View Article : Google Scholar
31	MacDougall JR and Matrisian LM: Contributions of tumor and stromal matrix metalloproteinases to tumor progression, invasion and metastasis. Cancer Metastasis Rev. 14:351–362. 1995. View Article : Google Scholar : PubMed/NCBI
32	Fullar A, Kovalszky I, Bitsche M, et al: Tumor cell and carcinoma-associated fibroblast interaction regulates matrix metalloproteinases and their inhibitors in oral squamous cell carcinoma. Exp Cell Res. 318:1517–1527. 2012. View Article : Google Scholar : PubMed/NCBI
33	Bjorklund M and Koivunen E: Gelatinase-mediated migration and invasion of cancer cells. Biochim Biophys Acta. 1755:37–69. 2005.PubMed/NCBI
34	Darnell JE Jr: STATs and gene regulation. Science. 277:1630–1635. 1997. View Article : Google Scholar : PubMed/NCBI
35	Lu Y, Fukuyama S, Yoshida R, et al: Loss of SOCS3 gene expression converts STAT3 function from anti-apoptotic to pro-apoptotic. J Biol Chem. 281:36683–36690. 2006. View Article : Google Scholar : PubMed/NCBI
36	Bromberg JF, Wrzeszczynska MH, Devgan G, et al: Stat3 as an oncogene. Cell. 98:295–303. 1999. View Article : Google Scholar
37	Macha MA, Matta A, Kaur J, et al: Prognostic significance of nuclear pSTAT3 in oral cancer. Head Neck. 33:482–489. 2011. View Article : Google Scholar : PubMed/NCBI